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Endoplasmic reticulum stress: molecular mechanism and therapeutic targets – Signal Transduction and Targeted Therapy


  • Balch, W. E., Morimoto, R. I., Dillin, A. & Kelly, J. W. Adapting proteostasis for disease intervention. Science 319, 916–919 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hurtley, S. M. et al. Interactions of misfolded influenza virus hemagglutinin with binding protein (BiP). J. Cell Biol. 108, 2117–2126 (1989).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kaushik, S. & Cuervo, A. M. Proteostasis and aging. Nat. Med. 21, 1406–1415 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Smith, M. H., Ploegh, H. L. & Weissman, J. S. Road to ruin: targeting proteins for degradation in the endoplasmic reticulum. Science 334, 1086–1090 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Travers, K. J. et al. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101, 249–258 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Harding, H. P. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell 6, 1099–1108 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lin, J. H. et al. IRE1 signaling affects cell fate during the unfolded protein response. Science 318, 944–949 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bertolotti, A. et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat. Cell Biol. 2, 326–332 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, M. & Kaufman, R. J. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529, 326–335 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dombroski, B. A. et al. Gene expression and genetic variation in response to endoplasmic reticulum stress in human cells. Am. J. Hum. Genet. 86, 719–729 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ma, K., Vattem, K. M. & Wek, R. C. Dimerization and release of molecular chaperone inhibition facilitate activation of eukaryotic initiation factor-2 kinase in response to endoplasmic reticulum stress. J. Biol. Chem. 277, 18728–18735 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Han, J. et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 15, 481–490 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, K. P. et al. Structure of the dual enzyme Ire1 reveals the basis for catalysis and regulation in nonconventional RNA splicing. Cell 132, 89–100 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Credle, J. J. et al. On the mechanism of sensing unfolded protein in the endoplasmic reticulum. Proc. Natl Acad. Sci. USA 102, 18773–18784 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sidrauski, C. & Walter, P. The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell 90, 1031–1039 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhu, C., Johansen, F. E. & Prywes, R. Interaction of ATF6 and serum response factor. Mol. Cell Biol. 17, 4957–4966 (1997).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Haze, K. et al. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell 10, 3787–3799 (1999).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Walter, P. & Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Olzmann, J. A., Kopito, R. R. & Christianson, J. C. The mammalian endoplasmic reticulum-associated degradation system. Cold Spring Harb. Perspect. Biol. 5, a013185 (2013).

  • Lemberg, M. K. & Strisovsky, K. Maintenance of organellar protein homeostasis by ER-associated degradation and related mechanisms. Mol. Cell 81, 2507–2519 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Belmont, P. J. et al. Roles for endoplasmic reticulum-associated degradation and the novel endoplasmic reticulum stress response gene Derlin-3 in the ischemic heart. Circ. Res. 106, 307–316 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lee, A. H., Iwakoshi, N. N. & Glimcher, L. H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell Biol. 23, 7448–7459 (2003).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Genestra, M. Oxyl radicals, redox-sensitive signalling cascades and antioxidants. Cell. Signal. 19, 1807–1819 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Esmaeili, Y. et al. Targeting autophagy, oxidative stress, and ER stress for neurodegenerative disease treatment. J. Control. Release 345, 147–175 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Marciniak, S. J. et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 18, 3066–3077 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mizushima, N. & Komatsu, M. Autophagy: renovation of cells and tissues. Cell 147, 728–741 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rashid, H. O., Yadav, R. K., Kim, H. R. & Chae, H. J. ER stress: autophagy induction, inhibition and selection. Autophagy 11, 1956–1977 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Smith, M. D. et al. CCPG1 is a non-canonical autophagy cargo receptor essential for ER-phagy and pancreatic ER proteostasis. Dev. Cell 44, 217.e1–232.e1 (2018).

    Article 

    Google Scholar
     

  • Zielke, S. et al. ATF4 links ER stress with reticulophagy in glioblastoma cells. Autophagy 17, 2432–2448 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liang, J. R. et al. A genome-wide ER-phagy screen highlights key roles of mitochondrial metabolism and ER-resident UFMylation. Cell 180, 1160.e20–1177.e20 (2020).

    Article 

    Google Scholar
     

  • Zhang, X. et al. Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury: Involvement of PARK2-dependent mitophagy. Autophagy 10, 1801–1813 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • B’Chir, W. et al. The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 41, 7683–7699 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sekine, Y., Takeda, K. & Ichijo, H. The ASK1-MAP kinase signaling in ER stress and neurodegenerative diseases. Curr. Mol. Med. 6, 87–97 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Deegan, S. et al. Deficiency in the mitochondrial apoptotic pathway reveals the toxic potential of autophagy under ER stress conditions. Autophagy 10, 1921–1936 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Giacomello, M. & Pellegrini, L. The coming of age of the mitochondria-ER contact: a matter of thickness. Cell Death Differ. 23, 1417–1427 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pereira, A. C. et al. ER-mitochondria communication is involved in NLRP3 inflammasome activation under stress conditions in the innate immune system. Cell Mol. Life Sci. 79, 213 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Muñoz, J. P. et al. Mfn2 modulates the UPR and mitochondrial function via repression of PERK. EMBO J. 32, 2348–2361 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, H. et al. The XBP1‒MARCH5‒MFN2 axis confers endoplasmic reticulum stress resistance by coordinating mitochondrial fission and mitophagy in melanoma. J. Invest. Dermatol. 141, 2932–2943.e2912 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • McCullough, K. D. et al. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol. Cell. Biol. 21, 1249–1259 (2001).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Puthalakath, H. et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129, 1337–1349 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Han, J. & Kaufman, R. J. The role of ER stress in lipid metabolism and lipotoxicity. J. Lipid Res. 57, 1329–1338 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ye, J. et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol. Cell 6, 1355–1364 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zeng, L. et al. ATF6 modulates SREBP2-mediated lipogenesis. EMBO J. 23, 950–958 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, X. et al. Hepatic ATF6 increases fatty acid oxidation to attenuate hepatic steatosis in mice through peroxisome proliferator-activated receptor α. Diabetes 65, 1904–1915 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sriburi, R. et al. Coordinate regulation of phospholipid biosynthesis and secretory pathway gene expression in XBP-1(S)-induced endoplasmic reticulum biogenesis. J. Biol. Chem. 282, 7024–7034 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lee, A. H., Scapa, E. F., Cohen, D. E. & Glimcher, L. H. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 320, 1492–1496 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shao, M. et al. Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s-PPARα axis signalling. Nat. Commun. 5, 3528 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Oyadomari, S. et al. Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab. 7, 520–532 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • GBD 2019 Blindness and Vision Impairment Collaborators & Vision Loss Expert Group of the Global Burden of Disease Study. Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the Right to Sight: an analysis for the Global Burden of Disease Study. Lancet Glob. Health 9, e144–e160 (2021).

  • Dandona, L. & Dandona, R. What is the global burden of visual impairment? BMC Med. 4, 6 (2006).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Casson, R. J. et al. Definition of glaucoma: clinical and experimental concepts. Clin. Exp. Ophthalmol. 40, 341–349 (2012).

    Article 
    PubMed 

    Google Scholar
     

  • Tham, Y. C. et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology 121, 2081–2090 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Weinreb, R. N., Aung, T. & Medeiros, F. A. The pathophysiology and treatment of glaucoma: a review. JAMA 311, 1901–1911 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yan, X. et al. Myocilin gene mutation induced autophagy activation causes dysfunction of trabecular meshwork cells. Front. Cell Dev. Biol. 10, 900777 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cheng, Y. et al. Human Pro370Leu mutant myocilin induces the phenotype of open-angle glaucoma in transgenic mice. Cell. Mol. Neurobiol. 43, 2021–2033 (2023).

  • Allingham, R. R. et al. Gln368STOP myocilin mutation in families with late-onset primary open-angle glaucoma. Invest. Ophthalmol. Vis. Sci. 39, 2288–2295 (1998).

    CAS 
    PubMed 

    Google Scholar
     

  • Yang, Y. et al. Cross-talk between MYOC p. Y437H mutation and TGF-β2 in the pathology of glaucoma. Int. J. Med. Sci. 17, 1062–1070 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Saccuzzo, E. G. et al. Calcium dysregulation potentiates wild-type myocilin misfolding: implications for glaucoma pathogenesis. J. Biol. Inorg. Chem. 27, 553–564 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Joe, M. K. et al. Accumulation of mutant myocilins in ER leads to ER stress and potential cytotoxicity in human trabecular meshwork cells. Biochem. Biophys. Res. Commun. 312, 592–600 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Peters, J. C., Bhattacharya, S., Clark, A. F. & Zode, G. S. Increased endoplasmic reticulum stress in human glaucomatous trabecular meshwork cells and tissues. Invest. Ophthalmol. Vis. Sci. 56, 3860–3868 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ying, Y. et al. Activation of ATF4 triggers trabecular meshwork cell dysfunction and apoptosis in POAG. Aging 13, 8628–8642 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Suntharalingam, A. et al. Glucose-regulated protein 94 triage of mutant myocilin through endoplasmic reticulum-associated degradation subverts a more efficient autophagic clearance mechanism. J. Biol. Chem. 287, 40661–40669 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kasetti, R. B. et al. ATF4 leads to glaucoma by promoting protein synthesis and ER client protein load. Nat. Commun. 11, 5594 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yasuda, M. et al. RNA sequence reveals mouse retinal transcriptome changes early after axonal injury. PLoS ONE 9, e93258 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, Y. et al. Endoplasmic reticulum stress response of trabecular meshwork stem cells and trabecular meshwork cells and protective effects of activated PERK pathway. Invest. Ophthalmol. Vis. Sci. 60, 265–273 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stothert, A. R., Fontaine, S. N., Sabbagh, J. J. & Dickey, C. A. Targeting the ER-autophagy system in the trabecular meshwork to treat glaucoma. Exp. Eye Res. 144, 38–45 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kasetti, R. B. et al. Autophagy stimulation reduces ocular hypertension in a murine glaucoma model via autophagic degradation of mutant myocilin. JCI Insight. 6, e143359 (2021).

  • Kasetti, R. B. et al. Increased synthesis and deposition of extracellular matrix proteins leads to endoplasmic reticulum stress in the trabecular meshwork. Sci. Rep. 7, 14951 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kasetti, R. B., Patel, P. D., Maddineni, P. & Zode, G. S. Ex-vivo cultured human corneoscleral segment model to study the effects of glaucoma factors on trabecular meshwork. PLoS ONE 15, e0232111 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Takai, Y., Tanito, M. & Ohira, A. Multiplex cytokine analysis of aqueous humor in eyes with primary open-angle glaucoma, exfoliation glaucoma, and cataract. Invest. Ophthalmol. Vis. Sci. 53, 241–247 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gottanka, J. et al. Effects of TGF-beta2 in perfused human eyes. Invest. Ophthalmol. Vis. Sci. 45, 153–158 (2004).

    Article 
    PubMed 

    Google Scholar
     

  • Kasetti, R. B. et al. Astragaloside IV attenuates ocular hypertension in a mouse model of TGFβ2 induced primary open angle glaucoma. Int. J. Mol. Sci. 22, 12508 (2021).

  • Shepard, A. R. et al. Adenoviral gene transfer of active human transforming growth factor-{beta}2 elevates intraocular pressure and reduces outflow facility in rodent eyes. Invest. Ophthalmol. Vis. Sci. 51, 2067–2076 (2010).

    Article 
    PubMed 

    Google Scholar
     

  • Li, M., Xu, J., Chen, X. & Sun, X. RNA interference as a gene silencing therapy for mutant MYOC protein in primary open angle glaucoma. Diagn. Pathol. 4, 46 (2009).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zode, G. S. et al. Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma. J. Clin. Investig. 121, 3542–3553 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jain, A. et al. CRISPR-Cas9-based treatment of myocilin-associated glaucoma. Proc. Natl Acad. Sci. USA 114, 11199–11204 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kasetti, R. B., Phan, T. N., Millar, J. C. & Zode, G. S. Expression of mutant myocilin induces abnormal intracellular accumulation of selected extracellular matrix proteins in the trabecular meshwork. Invest. Ophthalmol. Vis. Sci. 57, 6058–6069 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Goldberg, A. D., Allis, C. D. & Bernstein, E. Epigenetics: a landscape takes shape. Cell 128, 635–638 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Esteve-Puig, R., Bueno-Costa, A. & Esteller, M. Writers, readers and erasers of RNA modifications in cancer. Cancer Lett. 474, 127–137 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, S. et al. SNHG3 cooperates with ELAVL2 to modulate cell apoptosis and extracellular matrix accumulation by stabilizing SNAI2 in human trabecular meshwork cells under oxidative stress. Environ. Toxicol. 36, 1070–1079 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • De Groef, L. et al. Aberrant collagen composition of the trabecular meshwork results in reduced aqueous humor drainage and elevated IOP in MMP-9 null mice. Invest. Ophthalmol. Vis. Sci. 57, 5984–5995 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cuevas, E. P. et al. LOXL2 drives epithelial-mesenchymal transition via activation of IRE1-XBP1 signalling pathway. Sci. Rep. 7, 44988 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Toth, R. P. & Atkin, J. D. Dysfunction of optineurin in amyotrophic lateral sclerosis and glaucoma. Front. Immunol. 9, 1017 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sears, N. C., Boese, E. A., Miller, M. A. & Fingert, J. H. Mendelian genes in primary open angle glaucoma. Exp. Eye Res. 186, 107702 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Minegishi, Y. et al. Enhanced optineurin E50K-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma. Hum. Mol. Genet. 22, 3559–3567 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rezaie, T. et al. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295, 1077–1079 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Quist, T. S., Johnson, C. A., Robin, A. L. & Fingert, J. H. Long-term follow-up of normal tension glaucoma patients with TBK1 gene mutations in one large pedigree. Am. J. Ophthalmol. 214, 52–62 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rozpędek-Kamińska, W. et al. The genetic and endoplasmic reticulum-mediated molecular mechanisms of primary open-angle glaucoma. Int. J. Mol. Sci. 21, 4171 (2020).

  • Quigley, H. A. et al. Morphologic changes in the lamina cribrosa correlated with neural loss in open-angle glaucoma. Am. J. Ophthalmol. 95, 673–691 (1983).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu, X. et al. Neuroprotective effects of bone marrow Sca-1(+) cells against age-related retinal degeneration in OPTN E50K mice. Cell Death Dis. 12, 613 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guttenplan, K. A. et al. Neurotoxic reactive astrocytes drive neuronal death after retinal injury. Cell Rep. 31, 107776 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Joshi, A. U. et al. Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. Nat. Neurosci. 22, 1635–1648 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gomes, C. et al. Astrocytes modulate neurodegenerative phenotypes associated with glaucoma in OPTN(E50K) human stem cell-derived retinal ganglion cells. Stem Cell Rep. 17, 1636–1649 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Hou, M. et al. Age-related visual impairments and retinal ganglion cells axonal degeneration in a mouse model harboring OPTN (E50K) mutation. Cell Death Dis. 13, 362 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, X. et al. Dysfunctional endoplasmic reticulum-mitochondrion coupling is associated with endoplasmic reticulum stress-induced apoptosis and neurological deficits in a rodent model of severe head injury. J. Neurotrauma 39, 560–576 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhang, S. et al. The E50K optineurin mutation impacts autophagy-mediated degradation of TDP-43 and leads to RGC apoptosis in vivo and in vitro. Cell Death Discov. 7, 49 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhao, C., Liao, Y., Rahaman, A. & Kumar, V. Towards understanding the relationship between ER stress and unfolded protein response in amyotrophic lateral sclerosis. Front. Aging Neurosci. 14, 892518 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Medchalmi, S., Tare, P., Sayyad, Z. & Swarup, G. A glaucoma- and ALS-associated mutant of OPTN induces neuronal cell death dependent on Tbk1 activity, autophagy and ER stress. FEBS J. 288, 4576–4595 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sayyad, Z. et al. A glaucoma-associated OPTN polymorphism, M98K sensitizes retinal cells to endoplasmic reticulum stress and tumour necrosis factor α. FEBS J. 290, 3110–3127 (2023).

  • Huang, K. C. et al. Autophagy disruption reduces mTORC1 activation leading to retinal ganglion cell neurodegeneration associated with glaucoma. Preprint at bioRxiv https://doi.org/10.1101/2023.01.04.522687 (2023).

  • Ojino, K. et al. Involvement of endoplasmic reticulum stress in optic nerve degeneration after chronic high intraocular pressure in DBA/2J mice. J. Neurosci. Res. 93, 1675–1683 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Uchibayashi, R. et al. Involvement of Bid and caspase-2 in endoplasmic reticulum stress- and oxidative stress-induced retinal ganglion cell death. J. Neurosci. Res. 89, 1783–1794 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Naidoo, N. et al. Endoplasmic reticulum stress in wake-active neurons progresses with aging. Aging Cell 10, 640–649 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • McLaughlin, T. et al. Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration. Mol. Neurodegener. 13, 16 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leger, F. et al. Protein aggregation in the aging retina. J. Neuropathol. Exp. Neurol. 70, 63–68 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen, W. et al. Maprotiline restores ER homeostasis and rescues neurodegeneration via histamine receptor H1 inhibition in retinal ganglion cells. Nat. Commun. 13, 6796 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hu, Y. et al. Differential effects of unfolded protein response pathways on axon injury-induced death of retinal ganglion cells. Neuron 73, 445–452 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mavlyutov, T. A. & Guo, L. W. Peeking into Sigma-1 receptor functions through the retina. Adv. Exp. Med. Biol. 964, 285–297 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mysona, B., Kansara, N., Zhao, J. & Bollinger, K. The role of Sigma 1 receptor as a neuroprotective target in glaucoma. Adv. Exp. Med. Biol. 964, 299–307 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mori, T., Hayashi, T., Hayashi, E. & Su, T. P. Sigma-1 receptor chaperone at the ER-mitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival. PLoS ONE 8, e76941 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ha, Y. et al. Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons. Invest. Ophthalmol. Vis. Sci. 52, 527–540 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McLaughlin, T. et al. p58(IPK) is an endogenous neuroprotectant for retinal ganglion cells. Front. Aging Neurosci. 10, 267 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Boriushkin, E. et al. Identification of p58IPK as a novel neuroprotective factor for retinal neurons. Invest. Ophthalmol. Vis. Sci. 56, 1374–1386 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Apostolou, A. et al. Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. Exp. Cell Res. 314, 2454–2467 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gao, F. J. et al. Identification of mesencephalic astrocyte-derived neurotrophic factor as a novel neuroprotective factor for retinal ganglion cells. Front. Mol. Neurosci. 10, 76 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hayashi, A. et al. The role of brain-derived neurotrophic factor (BDNF)-induced XBP1 splicing during brain development. J. Biol. Chem. 282, 34525–34534 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Saito, A. et al. Neuronal activity-dependent local activation of dendritic unfolded protein response promotes expression of brain-derived neurotrophic factor in cell soma. J. Neurochem. 144, 35–49 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen, G. et al. Brain-derived neurotrophic factor suppresses tunicamycin-induced upregulation of CHOP in neurons. J. Neurosci. Res. 85, 1674–1684 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, Q. et al. Phosphorylation of SHP-2 regulates interactions between the endoplasmic reticulum and focal adhesions to restrict interleukin-1-induced Ca2+ signaling. J. Biol. Chem. 281, 31093–31105 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chitranshi, N. et al. Loss of Shp2 rescues BDNF/TrkB signaling and contributes to improved retinal ganglion cell neuroprotection. Mol. Ther. 27, 424–441 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lin, B., Zhang, X. & Xu, X. Nerve growth factor protects retinal ganglion cells related to inhibiting endoplasmic reticulum stress by inhibiting IRE1-JNK-CHOP signaling pathway. Ocul. Immunol. Inflamm. 30, 1341–1346 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sato, K. et al. CHOP deletion and anti-neuroinflammation treatment with hesperidin synergistically attenuate NMDA retinal injury in mice. Exp. Eye Res. 213, 108826 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bronner, D. N. et al. Endoplasmic reticulum stress activates the inflammasome via NLRP3- and caspase-2-driven mitochondrial damage. Immunity 43, 451–462 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, H. et al. NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma. Mol. Neurodegener. 15, 26 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chi, W. et al. HMGB1 promotes the activation of NLRP3 and caspase-8 inflammasomes via NF-κB pathway in acute glaucoma. J. Neuroinflammation 12, 137 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, L. et al. Airborne particulate matter (PM(2.5)) triggers ocular hypertension and glaucoma through pyroptosis. Part Fibre Toxicol. 18, 10 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ye, D. et al. Anti-PANoptosis is involved in neuroprotective effects of melatonin in acute ocular hypertension model. J. Pineal Res. 73, e12828 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yao, F. et al. Pathologically high intraocular pressure disturbs normal iron homeostasis and leads to retinal ganglion cell ferroptosis in glaucoma. Cell Death Differ. 30, 69–81 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ha, Y. et al. Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma. Cell Death Dis. 6, e1900 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rappert, A. et al. CXCR3-dependent microglial recruitment is essential for dendrite loss after brain lesion. J. Neurosci. 24, 8500–8509 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, M. et al. GSK872 and necrostatin-1 protect retinal ganglion cells against necroptosis through inhibition of RIP1/RIP3/MLKL pathway in glutamate-induced retinal excitotoxic model of glaucoma. J. Neuroinflammation 19, 262 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yuan, H. et al. Involvement of HDAC6 in ischaemia and reperfusion-induced rat retinal injury. BMC Ophthalmol. 18, 300 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Baumeister, P. et al. Endoplasmic reticulum stress induction of the Grp78/BiP promoter: activating mechanisms mediated by YY1 and its interactive chromatin modifiers. Mol. Cell. Biol. 25, 4529–4540 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, Z. et al. Valproate protects the retina from endoplasmic reticulum stress-induced apoptosis after ischemia-reperfusion injury. Neurosci. Lett. 504, 88–92 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nashine, S. et al. Role of C/EBP homologous protein in retinal ganglion cell death after ischemia/reperfusion injury. Invest. Ophthalmol. Vis. Sci. 56, 221–231 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Rhee, S. G. Overview on peroxiredoxin. Mol. Cells 39, 1–5 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Parmigiani, R. B. et al. HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation. Proc. Natl Acad. Sci. USA 105, 9633–9638 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kang, J. H. et al. Peroxiredoxin 4 attenuates glutamate-induced neuronal cell death through inhibition of endoplasmic reticulum stress. Free Radic. Res. 54, 207–220 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zode, G. S. et al. Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma. J. Clin. Investig. 124, 1956–1965 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kasetti, R. B. et al. Transforming growth factor β2 (TGFβ2) signaling plays a key role in glucocorticoid-induced ocular hypertension. J. Biol. Chem. 293, 9854–9868 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ritch, R. Exfoliation syndrome. Curr. Opin. Ophthalmol. 12, 124–130 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tawfik, A. & Smith, S. B. Increased ER stress as a mechanism of retinal neurovasculopathy in mice with severe hyperhomocysteinemia. Austin J. Clin. Ophthalmol. 1, 1023 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hayat, B., Padhy, B., Mohanty, P. P. & Alone, D. P. Altered unfolded protein response and proteasome impairment in pseudoexfoliation pathogenesis. Exp. Eye Res. 181, 197–207 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Boland, M. V. et al. Comparative effectiveness of treatments for open-angle glaucoma: a systematic review for the U.S. Preventive Services Task Force. Ann. Intern. Med. 158, 271–279 (2013).

    Article 
    PubMed 

    Google Scholar
     

  • Gaton, D. D. et al. Increased matrix metalloproteinases 1, 2, and 3 in the monkey uveoscleral outflow pathway after topical prostaglandin F(2 alpha)-isopropyl ester treatment. Arch. Ophthalmol. 119, 1165–1170 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Stothert, A. R. et al. Exploiting the interaction between Grp94 and aggregated myocilin to treat glaucoma. Hum. Mol. Genet. 23, 6470–6480 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stothert, A. R. et al. Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma. Sci. Rep. 7, 17951 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rozpędek-Kamińska, W. et al. The potential role of small-molecule PERK inhibitor LDN-0060609 in primary open-angle glaucoma treatment. Int. J. Mol. Sci. 22, 4494 (2021).

  • Jia, L. Y. et al. Correction of the disease phenotype of myocilin-causing glaucoma by a natural osmolyte. Invest. Ophthalmol. Vis. Sci. 50, 3743–3749 (2009).

    Article 
    PubMed 

    Google Scholar
     

  • Maddineni, P. et al. Sodium 4-phenylbutyrate reduces ocular hypertension by degrading extracellular matrix deposition via activation of MMP9. Int. J. Mol. Sci. 22, 10095 (2021).

  • Dong, Z. et al. Astragaloside-IV alleviates heat-induced inflammation by inhibiting endoplasmic reticulum stress and autophagy. Cell. Physiol. Biochem. 42, 824–837 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Deveau, H., Garneau, J. E. & Moineau, S. CRISPR/Cas system and its role in phage-bacteria interactions. Annu. Rev. Microbiol. 64, 475–493 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ran, F. A. et al. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 8, 2281–2308 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dong, Y., Siegwart, D. J. & Anderson, D. G. Strategies, design, and chemistry in siRNA delivery systems. Adv. Drug Deliv. Rev. 144, 133–147 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gaynor, J. W., Campbell, B. J. & Cosstick, R. RNA interference: a chemist’s perspective. Chem. Soc. Rev. 39, 4169–4184 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Du, Y. et al. Multipotent stem cells from trabecular meshwork become phagocytic TM cells. Invest. Ophthalmol. Vis. Sci. 53, 1566–1575 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McGowan, S. L., Edelhauser, H. F., Pfister, R. R. & Whikehart, D. R. Stem cell markers in the human posterior limbus and corneal endothelium of unwounded and wounded corneas. Mol. Vis. 13, 1984–2000 (2007).

    CAS 
    PubMed 

    Google Scholar
     

  • Yun, H. et al. Human stem cells home to and repair laser-damaged trabecular meshwork in a mouse model. Commun. Biol. 1, 216 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xiong, S. et al. α5β1 Integrin promotes anchoring and integration of transplanted stem cells to the trabecular meshwork in the eye for regeneration. Stem Cells Dev. 29, 290–300 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhu, W. et al. Restoration of aqueous humor outflow following transplantation of iPSC-derived trabecular meshwork cells in a transgenic mouse model of glaucoma. Invest. Ophthalmol. Vis. Sci. 58, 2054–2062 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ding, Q. J. et al. Induction of trabecular meshwork cells from induced pluripotent stem cells. Invest. Ophthalmol. Vis. Sci. 55, 7065–7072 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Roubeix, C. et al. Intraocular pressure reduction and neuroprotection conferred by bone marrow-derived mesenchymal stem cells in an animal model of glaucoma. Stem Cell Res. Ther. 6, 177 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Snider, E. J. et al. Improving stem cell delivery to the trabecular meshwork using magnetic nanoparticles. Sci. Rep. 8, 12251 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhou, Y. et al. Adipose-derived stem cells integrate into trabecular meshwork with glaucoma treatment potential. FASEB J. 34, 7160–7177 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Khater, S. I. et al. β-Cell autophagy pathway and endoplasmic reticulum stress regulating-role of liposomal curcumin in experimental diabetes mellitus: a molecular and morphometric study. Antioxidants 11, 2400 (2022).

  • Lerner, N., Schreiber-Avissar, S. & Beit-Yannai, E. Extracellular vesicle-mediated crosstalk between NPCE cells and TM cells result in modulation of Wnt signalling pathway and ECM remodelling. J. Cell. Mol. Med. 24, 4646–4658 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lerner, N., Chen, I., Schreiber-Avissar, S. & Beit-Yannai, E. Extracellular vesicles mediate anti-oxidative response-in vitro study in the ocular drainage system. Int. J. Mol. Sci. 21, 6105 (2020).

  • Hata, M. & Ikeda, H. O. Modulation of valosin-containing protein by Kyoto University Substances (KUS) as a novel therapeutic strategy for ischemic neuronal diseases. Neural Regen. Res. 12, 1252–1255 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hata, M. et al. KUS121, a VCP modulator, attenuates ischemic retinal cell death via suppressing endoplasmic reticulum stress. Sci. Rep. 7, 44873 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hasegawa, T. et al. Effect of VCP modulators on gene expression profiles of retinal ganglion cells in an acute injury mouse model. Sci. Rep. 10, 4251 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, L. et al. Rescue of glaucomatous neurodegeneration by differentially modulating neuronal endoplasmic reticulum stress molecules. J. Neurosci. 36, 5891–5903 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ha, Y. et al. AAV2-mediated GRP78 transfer alleviates retinal neuronal injury by downregulating ER stress and tau oligomer formation. Invest. Ophthalmol. Vis. Sci. 59, 4670–4682 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tian, F. et al. Core transcription programs controlling injury-induced neurodegeneration of retinal ganglion cells. Neuron 110, 2607–2624.e2608 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shimazawa, M., Ito, Y., Inokuchi, Y. & Hara, H. Involvement of double-stranded RNA-dependent protein kinase in ER stress-induced retinal neuron damage. Invest. Ophthalmol. Vis. Sci. 48, 3729–3736 (2007).

    Article 
    PubMed 

    Google Scholar
     

  • Gao, Z. et al. Valdecoxib protects against cell apoptosis induced by endoplasmic reticulum stress via the inhibition of PERK-ATF4-CHOP pathway in experimental glaucoma. Int. J. Mol. Sci. 23, 12983 (2022).

  • Dheer, Y. et al. Retinoid x receptor modulation protects against ER stress response and rescues glaucoma phenotypes in adult mice. Exp. Neurol. 314, 111–125 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rong, R. et al. Targeting cell membranes, depleting ROS by dithiane and thioketal-containing polymers with pendant cholesterols delivering necrostatin-1 for glaucoma treatment. ACS Nano 16, 21225–21239 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang, E. J. & Reichardt, L. F. Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736 (2001).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Beykin, G. et al. Phase 1b randomized controlled study of short course topical recombinant human nerve growth factor (rhNGF) for neuroenhancement in glaucoma: safety, tolerability, and efficacy measure outcomes. Am. J. Ophthalmol. 234, 223–234 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Guimarães, E. S. et al. Brucella abortus cyclic dinucleotides trigger STING-dependent unfolded protein response that favors bacterial replication. J. Immunol. 202, 2671–2681 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Congdon, N. G., Friedman, D. S. & Lietman, T. Important causes of visual impairment in the world today. JAMA 290, 2057–2060 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhong, Y., Wang, J. J. & Zhang, S. X. Intermittent but not constant high glucose induces ER stress and inflammation in human retinal pericytes. Adv. Exp. Med. Biol. 723, 285–292 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fresia, D., Cannizzaro, E., Borgo, A. & Roduit, R. GSH-independent induction of ER stress during hypoglycaemia in the retinal cells of mice. J. Clin. Med. 10, 2529 (2021).

  • Aloysius Dhivya, M., Sulochana, K. N. & Bharathi Devi, S. R. High glucose induced inflammation is inhibited by copper chelation via rescuing mitochondrial fusion protein 2 in retinal pigment epithelial cells. Cell. Signal. 92, 110244 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shruthi, K., Reddy, S. S. & Reddy, G. B. Ubiquitin-proteasome system and ER stress in the retina of diabetic rats. Arch. Biochem. Biophys. 627, 10–20 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jiang, L., Wang, C. & Shen, X. LncRNA GAS5 suppresses ER stress‑induced apoptosis and inflammation by regulating SERCA2b in HG‑treated retinal epithelial cell. Mol. Med. Rep. 22, 1072–1080 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Peng, Q. H., Tong, P., Gu, L. M. & Li, W. J. Astragalus polysaccharide attenuates metabolic memory-triggered ER stress and apoptosis via regulation of miR-204/SIRT1 axis in retinal pigment epithelial cells. Biosci. Rep. 40, BSR20192121 (2020).

  • Wang, Y., Gao, S., Zhu, Y. & Shen, X. Elevated activating transcription factor 4 and glucose-regulated 78 Kda protein levels correlate with inflammatory cytokines in the aqueous humor and vitreous of proliferative diabetic retinopathy. Curr. Eye Res. 42, 1202–1208 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yang, J. et al. Loss of X-box binding protein 1 in Müller cells augments retinal inflammation in a mouse model of diabetes. Diabetologia 62, 531–543 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dai, W., Toro, A., Dierschke, S. K. & Dennis, M. D. High-fat diet/palmitate–induced ER stress promotes protein O-GlcNAcylation in retina and retinal Muller cells. Diabetes 67, 607-P (2018).

  • Fu, D. et al. Mechanisms of modified LDL-induced pericyte loss and retinal injury in diabetic retinopathy. Diabetologia 55, 3128–3140 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kang, M. K. et al. Chrysin ameliorates malfunction of retinoid visual cycle through blocking activation of AGE-RAGE-ER stress in glucose-stimulated retinal pigment epithelial cells and diabetic eyes. Nutrients. 10, 1046 (2018).

  • Kaur, C., Foulds, W. S. & Ling, E. A. Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog. Retin. Eye Res. 27, 622–647 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tawfik, A., Samra, Y. A., Elsherbiny, N. M. & Al-Shabrawey, M. Implication of hyperhomocysteinemia in blood retinal barrier (BRB) dysfunction. Biomolecules. 10, 1119 (2020).

  • dos Santos, K. G. et al. The -106CC genotype of the aldose reductase gene is associated with an increased risk of proliferative diabetic retinopathy in Caucasian-Brazilians with type 2 diabetes. Mol. Genet. Metab. 88, 280–284 (2006).

    Article 
    PubMed 

    Google Scholar
     

  • Zhou, M., Zhang, P., Xu, X. & Sun, X. The relationship between aldose reductase C106T polymorphism and diabetic retinopathy: an updated meta-analysis. Invest. Ophthalmol. Vis. Sci. 56, 2279–2289 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Steentoft, C. et al. Mining the O-glycoproteome using zinc-finger nuclease-glycoengineered SimpleCell lines. Nat. Methods 8, 977–982 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kornfeld, R. & Kornfeld, S. Assembly of asparagine-linked oligosaccharides. Annu. Rev. Biochem. 54, 631–664 (1985).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Saha, A., Bello, D. & Fernández-Tejada, A. Advances in chemical probing of protein O-GlcNAc glycosylation: structural role and molecular mechanisms. Chem. Soc. Rev. 50, 10451–10485 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lenin, R., Nagy, P. G., Jha, K. A. & Gangaraju, R. GRP78 translocation to the cell surface and O-GlcNAcylation of VE-Cadherin contribute to ER stress-mediated endothelial permeability. Sci. Rep. 9, 10783 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dierschke, S. K. et al. Diabetes enhances translation of Cd40 mRNA in murine retinal Müller glia via a 4E-BP1/2-dependent mechanism. J. Biol. Chem. 295, 10831–10841 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xu, Y. et al. LncRNA GAS5 inhibits NLRP3 inflammasome activation-mediated pyroptosis in diabetic cardiomyopathy by targeting miR-34b-3p/AHR. Cell Cycle 19, 3054–3065 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, Y. et al. Knockdown of MALAT1 attenuates high-glucose-induced angiogenesis and inflammation via endoplasmic reticulum stress in human retinal vascular endothelial cells. Biomed. Pharmacother. 124, 109699 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wu, M. et al. Oxidative and endoplasmic reticulum stresses mediate apoptosis induced by modified LDL in human retinal Müller cells. Invest. Ophthalmol. Vis. Sci. 53, 4595–4604 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Miyata, Y. et al. Regulation of endothelium-reticulum-stress-mediated apoptotic cell death by a polymethoxylated flavone, nobiletin, through the inhibition of nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase in retinal Müller cells. Cells 10, 669 (2021).

  • Anitha, R. E., Janani, R., Peethambaran, D. & Baskaran, V. Lactucaxanthin protects retinal pigment epithelium from hyperglycemia-regulated hypoxia/ER stress/VEGF pathway mediated angiogenesis in ARPE-19 cell and rat model. Eur. J. Pharmacol. 899, 174014 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ménard, C. et al. miR-106b suppresses pathological retinal angiogenesis. Aging 12, 24836–24852 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Adachi, T. et al. Contribution of p38 MAPK, NF-κB and glucocorticoid signaling pathways to ER stress-induced increase in retinal endothelial permeability. Arch. Biochem. Biophys. 520, 30–35 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chung, Y. R., Choi, J. A., Koh, J. Y. & Yoon, Y. H. Ursodeoxycholic acid attenuates endoplasmic reticulum stress-related retinal pericyte loss in streptozotocin-induced diabetic mice. J. Diabetes Res. 2017, 1763292 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jia, M. et al. Redox homeostasis maintained by GPX4 facilitates STING activation. Nat. Immunol. 21, 727–735 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wen, Z. et al. Hyperlipidemia induces proinflammatory responses by activating STING pathway through IRE1α-XBP1 in retinal endothelial cells. J. Nutr. Biochem. 112, 109213 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, Y. et al. GRP75 modulates endoplasmic reticulum-mitochondria coupling and accelerates Ca(2+)-dependent endothelial cell apoptosis in diabetic retinopathy. Biomolecules 12, 1778 (2022).

  • Fu, D. et al. Survival or death: a dual role for autophagy in stress-induced pericyte loss in diabetic retinopathy. Diabetologia 59, 2251–2261 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chan, C. M. et al. Methylglyoxal induces cell death through endoplasmic reticulum stress-associated ROS production and mitochondrial dysfunction. J. Cell Mol. Med. 20, 1749–1760 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, K. et al. TCF7L2 promotes ER stress signaling in diabetic retinopathy. Exp. Eye Res. 221, 109142 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Luo, J. et al. TCF7L2 variation and proliferative diabetic retinopathy. Diabetes 62, 2613–2617 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sankrityayan, H. et al. ER stress response mediates diabetic microvascular complications. Drug Discov. Today 24, 2247–2257 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cheung, N., Mitchell, P. & Wong, T. Y. Diabetic retinopathy. Lancet 376, 124–136 (2010).

    Article 
    PubMed 

    Google Scholar
     

  • Zhang, J., Chen, X., Zhang, L. & Peng, Y. IGF1 gene polymorphisms associated with diabetic retinopathy risk in Chinese Han population. Oncotarget 8, 88034–88042 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, Z. et al. Single-cell transcriptome analyses reveal microglia types associated with proliferative retinopathy. JCI Insight 7, e160940 (2022).

  • Marwarha, G. et al. Palmitate-induced endoplasmic reticulum stress and subsequent C/EBPα homologous protein activation attenuates leptin and Insulin-like growth factor 1 expression in the brain. Cell. Signal. 28, 1789–1805 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Abhary, S. et al. Common sequence variation in the VEGFA gene predicts risk of diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 50, 5552–5558 (2009).

    Article 
    PubMed 

    Google Scholar
     

  • Beránek, M. et al. Polymorphism R25P in the gene encoding transforming growth factor-beta (TGF-beta1) is a newly identified risk factor for proliferative diabetic retinopathy. Am. J. Med. Genet. 109, 278–283 (2002).

    Article 
    PubMed 

    Google Scholar
     

  • Yadav, H. et al. Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling. Cell Metab. 14, 67–79 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, C. & Morris, J. R. Genes, genetics, and epigenetics: a correspondence. Science 293, 1103–1105 (2001).

    Article 
    CAS 

    Google Scholar
     

  • Nilsson, E. E., Sadler-Riggleman, I. & Skinner, M. K. Environmentally induced epigenetic transgenerational inheritance of disease. Environ. Epigenet. 4, dvy016 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kwak, S. H. & Park, K. S. Recent progress in genetic and epigenetic research on type 2 diabetes. Exp. Mol. Med. 48, e220 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, P. et al. LncRNA-MALAT1 promotes neovascularization in diabetic retinopathy through regulating miR-125b/VE-cadherin axis. Biosci. Rep. 39, BSR20181469 (2019).

  • Nandini, H. S. & Naik, P. R. Antidiabetic, antihyperlipidemic and antioxidant effect of Vincamine, in streptozotocin-induced diabetic rats. Eur. J. Pharmacol. 843, 233–239 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ghosh, R. et al. Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PLoS ONE 5, e9575 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rani, E. A., Janani, R., Chonche, M. J. & Vallikannan, B. Lactucaxanthin regulates the cascade of retinal oxidative stress, endoplasmic reticulum stress and inflammatory signaling in diabetic rats. Ocul. Immunol. Inflamm. 31, 320–328 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, Y. et al. Blocking the interaction between interleukin-17A and endoplasmic reticulum stress in macrophage attenuates retinal neovascularization in oxygen-induced retinopathy. Cell Biosci. 11, 82 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lai, D. W. et al. TPL2 (therapeutic targeting tumor progression locus-2)/ATF4 (activating transcription factor-4)/SDF1α (chemokine stromal cell-derived factor-α) axis suppresses diabetic retinopathy. Circ. Res. 121, e37–e52 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Feit-Leichman, R. A. et al. Vascular damage in a mouse model of diabetic retinopathy: relation to neuronal and glial changes. Invest. Ophthalmol. Vis. Sci. 46, 4281–4287 (2005).

    Article 
    PubMed 

    Google Scholar
     

  • Ahmad, I., Del Debbio, C. B., Das, A. V. & Parameswaran, S. Müller glia: a promising target for therapeutic regeneration. Invest. Ophthalmol. Vis. Sci. 52, 5758–5764 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mills, S. A. et al. Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy. Proc. Natl Acad. Sci. USA 118, e2112561118 (2021).

  • Bringmann, A. et al. Cellular signaling and factors involved in Müller cell gliosis: neuroprotective and detrimental effects. Prog. Retin. Eye Res. 28, 423–451 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, M. et al. Semaphorin 3A inhibits endoplasmic reticulum stress induced by high glucose in Müller cells. Curr. Eye Res. 48, 70–79 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Oshitari, T., Yoshida-Hata, N. & Yamamoto, S. Effect of neurotrophin-4 on endoplasmic reticulum stress-related neuronal apoptosis in diabetic and high glucose exposed rat retinas. Neurosci. Lett. 501, 102–106 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sharma, I., Yadav, K. S. & Mugale, M. N. Redoxisome and diabetic retinopathy: pathophysiology and therapeutic interventions. Pharm. Res. 182, 106292 (2022).

    Article 
    CAS 

    Google Scholar
     

  • Kaneko, M. & Nomura, Y. ER signaling in unfolded protein response. Life Sci. 74, 199–205 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Guo, L., Bai, S. P., Zhao, L. & Wang, X. H. Astragalus polysaccharide injection integrated with vinorelbine and cisplatin for patients with advanced non-small cell lung cancer: effects on quality of life and survival. Med. Oncol. 29, 1656–1662 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Deng, S., Yang, L., Ma, K. & Bian, W. Astragalus polysaccharide improve the proliferation and insulin secretion of mouse pancreatic β cells induced by high glucose and palmitic acid partially through promoting miR-136-5p and miR-149-5p expression. Bioengineered 12, 9872–9884 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Khachik, F., Bernstein, P. S. & Garland, D. L. Identification of lutein and zeaxanthin oxidation products in human and monkey retinas. Invest. Ophthalmol. Vis. Sci. 38, 1802–1811 (1997).

    CAS 
    PubMed 

    Google Scholar
     

  • Gopal, S. S. et al. Lactucaxanthin – a potential anti-diabetic carotenoid from lettuce (Lactuca sativa) inhibits α-amylase and α-glucosidase activity in vitro and in diabetic rats. Food Funct. 8, 1124–1131 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Saini, R. K., Moon, S. H., Gansukh, E. & Keum, Y. S. An efficient one-step scheme for the purification of major xanthophyll carotenoids from lettuce, and assessment of their comparative anticancer potential. Food Chem. 266, 56–65 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lenin, R. et al. Tauroursodeoxycholic acid alleviates endoplasmic reticulum stress-mediated visual deficits in diabetic tie2-TNF transgenic mice via TGR5 signaling. J. Ocul. Pharm. Ther. 39, 159–174 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Yanagi, S., Sato, T., Kangawa, K. & Nakazato, M. The homeostatic force of ghrelin. Cell Metab. 27, 786–804 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yang, H. et al. Functional characterization of 58-kilodalton inhibitor of protein kinase in protecting against diabetic retinopathy via the endoplasmic reticulum stress pathway. Mol. Vis. 17, 78–84 (2011).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dąbkowska, M. et al. Electrostatic complex of neurotrophin 4 with dendrimer nanoparticles: controlled release of protein in vitro and in vivo. Int. J. Nanomed. 14, 6117–6131 (2019).

    Article 

    Google Scholar
     

  • Abdel-Ghaffar, A. et al. Effects of 4-phenylbutyric acid on the development of diabetic retinopathy in diabetic rats: regulation of endoplasmic reticulum stress-oxidative activation. Arch. Physiol. Biochem. 129, 964–974 (2021).

  • Lv, J. et al. Sulforaphane delays diabetes-induced retinal photoreceptor cell degeneration. Cell Tissue Res. 382, 477–486 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yoo, Y. M. & Joo, S. S. Melatonin can modulate neurodegenerative diseases by regulating endoplasmic reticulum stress. Int. J. Mol. Sci. 24, 2381 (2023).

  • Reda, S., Elsammak, G. A., Elsayed, T. G. & Mostafa, S. A. A comparative study between the possible protective role of melatonin versus its combination with adipose derived-mesenchymal stem cells on experimentally induced diabetic retinopathy in adult male albino rats (histological and immunohistochemical study). Ultrastruct. Pathol. 47, 131–145 (2023).

  • Lim, L. S. et al. Age-related macular degeneration. Lancet 379, 1728–1738 (2012).

    Article 
    PubMed 

    Google Scholar
     

  • Mitchell, P., Liew, G., Gopinath, B. & Wong, T. Y. Age-related macular degeneration. Lancet 392, 1147–1159 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Guymer, R. H. & Campbell, T. G. Age-related macular degeneration. Lancet 401, 1459–1472 (2023).

  • Wong, W. L. et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health 2, e106–e116 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Karthikeyan, B. et al. Insights on the involvement of (-)-epigallocatechin gallate in ER stress-mediated apoptosis in age-related macular degeneration. Apoptosis 22, 72–85 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bok, D. The retinal pigment epithelium: a versatile partner in vision. J. Cell Sci. Suppl. 17, 189–195 (1993).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Paraoan, L. et al. Secretory proteostasis of the retinal pigmented epithelium: impairment links to age-related macular degeneration. Prog. Retin. Eye Res. 79, 100859 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Johnson, L. V., Leitner, W. P., Staples, M. K. & Anderson, D. H. Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Exp. Eye Res. 73, 887–896 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lambert, N. G. et al. Risk factors and biomarkers of age-related macular degeneration. Prog. Retin. Eye Res. 54, 64–102 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kunchithapautham, K., Atkinson, C. & Rohrer, B. Smoke exposure causes endoplasmic reticulum stress and lipid accumulation in retinal pigment epithelium through oxidative stress and complement activation. J. Biol. Chem. 289, 14534–14546 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, C. et al. Role of unfolded protein response dysregulation in oxidative injury of retinal pigment epithelial cells. Antioxid. Redox Signal. 20, 2091–2106 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Song, J. Y. et al. Suppressing endoplasmic reticulum stress-related autophagy attenuates retinal light injury. Aging 12, 16579–16596 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chalour, N. et al. AβPP-induced UPR transcriptomic signature of glial cells to oxidative stress as an adaptive mechanism to preserve cell function and survival. Curr. Alzheimer Res. 15, 643–654 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ethen, C. M. et al. The proteome of central and peripheral retina with progression of age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 47, 2280–2290 (2006).

    Article 
    PubMed 

    Google Scholar
     

  • Decanini, A. et al. Changes in select redox proteins of the retinal pigment epithelium in age-related macular degeneration. Am. J. Ophthalmol. 143, 607–615 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, Z. et al. Genetic associations of anti-vascular endothelial growth factor therapy response in age-related macular degeneration: a systematic review and meta-analysis. Acta Ophthalmol. 100, e669–e680 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gerhardt, M. J. et al. ER stress-induced aggresome trafficking of HtrA1 protects against proteotoxicity. J. Mol. Cell Biol. 9, 516–532 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, W. et al. The P300/XBP1s/Herpud1 axis promotes macrophage M2 polarization and the development of choroidal neovascularization. J. Cell Mol. Med. 25, 6709–6720 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yasuda, H. et al. Role of activating transcription factor 4 in murine choroidal neovascularization model. Int. J. Mol. Sci. 22, 8890 (2021).

  • Zhang, S. X. et al. The unfolded protein response in retinal vascular diseases: implications and therapeutic potential beyond protein folding. Prog. Retin. Eye Res. 45, 111–131 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Matsui, A. et al. Expression of vascular endothelial growth factor by retinal pigment epithelial cells induced by amyloid-β is depressed by an endoplasmic reticulum stress inhibitor. Ophthalmic Res 55, 37–44 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Kheitan, S., Minuchehr, Z. & Soheili, Z. S. Exploring the cross talk between ER stress and inflammation in age-related macular degeneration. PLoS ONE 12, e0181667 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Allikmets, R. et al. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 277, 1805–1807 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • He, D. et al. eIF2α incites photoreceptor cell and retina damage by all-trans-retinal. J. Biol. Chem. 299, 104686, (2023).

  • Torrini, M. et al. Mutation analysis of oxisterol-binding-protein gene in patients with age-related macular degeneration. Genet. Test. 11, 421–426 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tuo, J. et al. The involvement of sequence variation and expression of CX3CR1 in the pathogenesis of age-related macular degeneration. FASEB J. 18, 1297–1299 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tuo, J. et al. Murine ccl2/cx3cr1 deficiency results in retinal lesions mimicking human age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 48, 3827–3836 (2007).

    Article 
    PubMed 

    Google Scholar
     

  • Xu, B. et al. Role of VEGFR2 in mediating endoplasmic reticulum stress under glucose deprivation and determining cell death, oxidative stress, and inflammatory factor expression. Front. Cell Dev. Biol. 9, 631413 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, C. et al. Regulation of Nrf2 by X box-binding protein 1 in retinal pigment epithelium. Front. Genet. 9, 658 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Feng, J. et al. Expression of endoplasmic reticulum stress markers GRP78 and CHOP induced by oxidative stress in blue light-mediated damage of A2E-containing retinal pigment epithelium cells. Ophthalmic Res. 52, 224–233 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu, Y. et al. CHAC1 as a novel contributor of ferroptosis in retinal pigment epithelial cells with oxidative damage. Int. J. Mol. Sci. 24, 1582 (2023).

  • Colgan, S. M., Hashimi, A. A. & Austin, R. C. Endoplasmic reticulum stress and lipid dysregulation. Expert Rev. Mol. Med. 13, e4 (2011).

    Article 
    PubMed 

    Google Scholar
     

  • Tan, L. X., Li, J., Germer, C. J. & Lakkaraju, A. Analysis of mitochondrial dynamics and function in the retinal pigment epithelium by high-speed high-resolution live imaging. Front. Cell Dev. Biol. 10, 1044672 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dou, G. et al. Deficiency of αB crystallin augments ER stress-induced apoptosis by enhancing mitochondrial dysfunction. Free Radic. Biol. Med. 53, 1111–1122 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Baek, A., Son, S., Baek, Y. M. & Kim, D. E. KRT8 (keratin 8) attenuates necrotic cell death by facilitating mitochondrial fission-mediated mitophagy through interaction with PLEC (plectin). Autophagy 17, 3939–3956 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Saptarshi, N., Porter, L. F. & Paraoan, L. PERK/EIF2AK3 integrates endoplasmic reticulum stress-induced apoptosis, oxidative stress and autophagy responses in immortalised retinal pigment epithelial cells. Sci. Rep. 12, 13324 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ha, J. H. et al. Ocular inflammation and endoplasmic reticulum stress are attenuated by supplementation with grape polyphenols in human retinal pigmented epithelium cells and in C57BL/6 mice. J. Nutr. 144, 799–806 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lin, Y. H. et al. Retinal protective effect of curcumin metabolite hexahydrocurcumin against blue light-induced RPE damage. Phytomedicine 110, 154606 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhu, X., Wang, K., Zhou, F. & Zhu, L. Paeoniflorin attenuates atRAL-induced oxidative stress, mitochondrial dysfunction and endoplasmic reticulum stress in retinal pigment epithelial cells via triggering Ca(2+)/CaMKII-dependent activation of AMPK. Arch. Pharm. Res. 41, 1009–1018 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhou, X. et al. Propofol decreases endoplasmic reticulum stress-mediated apoptosis in retinal pigment epithelial cells. PLoS ONE 11, e0157590 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sreekumar, P. G., Hinton, D. R. & Kannan, R. Endoplasmic reticulum-mitochondrial crosstalk: a novel role for the mitochondrial peptide humanin. Neural Regen. Res. 12, 35–38 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, Y. et al. Inhibition of starvation-triggered endoplasmic reticulum stress, autophagy, and apoptosis in ARPE-19 cells by taurine through modulating the expression of Calpain-1 and Calpain-2. Int. J. Mol. Sci. 18, 2146 (2017).

  • Li, D. et al. Human umbilical cord mesenchymal stem cell-derived exosomal miR-27b attenuates subretinal fibrosis via suppressing epithelial-mesenchymal transition by targeting HOXC6. Stem Cell Res. Ther. 12, 24 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yu, J. J. et al. Age-related macular degeneration (AMD) transmitochondrial cybrids protected from cellular damage and death by human retinal progenitor cells (hRPCs). Stem Cells Int. 2021, 6655372 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kannan, R., Sreekumar, P. G. & Hinton, D. R. Alpha crystallins in the retinal pigment epithelium and implications for the pathogenesis and treatment of age-related macular degeneration. Biochim. Biophys. Acta 1860, 258–268 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hartong, D. T., Berson, E. L. & Dryja, T. P. Retinitis pigmentosa. Lancet 368, 1795–1809 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Megaw, R. et al. Use of induced pluripotent stem-cell technology to understand photoreceptor cytoskeletal dynamics in retinitis pigmentosa. Lancet 385, S69 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Wang, Y. et al. Variants identified by next-generation sequencing cause endoplasmic reticulum stress in Rhodopsin-associated retinitis pigmentosa. BMC Ophthalmol. 21, 371 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Palu, R. A. S. & Chow, C. Y. Baldspot/ELOVL6 is a conserved modifier of disease and the ER stress response. PLoS Genet. 14, e1007557 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yu, Y. et al. A new rhodopsin R135W mutation induces endoplasmic reticulum stress and apoptosis in retinal pigment epithelial cells. J. Cell. Physiol. 234, 14100–14108 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xu, H. et al. Deletion of the Impg2 gene causes the degeneration of rod and cone cells in mice. Hum. Mol. Genet. 29, 1624–1634 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Athanasiou, D. et al. The role of the ER stress-response protein PERK in rhodopsin retinitis pigmentosa. Hum. Mol. Genet. 26, 4896–4905 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, S. et al. Secretory defect and cytotoxicity: the potential disease mechanisms for the retinitis pigmentosa (RP)-associated interphotoreceptor retinoid-binding protein (IRBP). J. Biol. Chem. 288, 11395–11406 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kang, M. J., Chung, J. & Ryoo, H. D. CDK5 and MEKK1 mediate pro-apoptotic signalling following endoplasmic reticulum stress in an autosomal dominant retinitis pigmentosa model. Nat. Cell Biol. 14, 409–415 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jiang, H., Xiong, S. & Xia, X. Retinitis pigmentosa‑associated rhodopsin mutant T17M induces endoplasmic reticulum (ER) stress and sensitizes cells to ER stress-induced cell death. Mol. Med. Rep. 9, 1737–1742 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Osada, H. et al. Neuroprotective effect of bilberry extract in a murine model of photo-stressed retina. PLoS ONE 12, e0178627 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bhootada, Y. et al. Limited ATF4 expression in degenerating retinas with ongoing ER stress promotes photoreceptor survival in a mouse model of autosomal dominant retinitis pigmentosa. PLoS ONE 11, e0154779 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yamoah, A. et al. Early alterations of RNA binding protein (RBP) homeostasis and ER stress-mediated autophagy contributes to progressive retinal degeneration in the rd10 mouse model of retinitis pigmentosa (RP). Cells 12, 1094 (2023).

  • Kunte, M. M. et al. ER stress is involved in T17M rhodopsin-induced retinal degeneration. Invest. Ophthalmol. Vis. Sci. 53, 3792–3800 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Viringipurampeer, I. A. et al. NLRP3 inflammasome activation drives bystander cone photoreceptor cell death in a P23H rhodopsin model of retinal degeneration. Hum. Mol. Genet. 25, 1501–1516 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Qiu, Y. et al. Shifting the balance of autophagy and proteasome activation reduces proteotoxic cell death: a novel therapeutic approach for restoring photoreceptor homeostasis. Cell Death Dis. 10, 547 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chiang, W. C. et al. Robust endoplasmic reticulum-associated degradation of rhodopsin precedes retinal degeneration. Mol. Neurobiol. 52, 679–695 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yao, J. et al. Inhibiting autophagy reduces retinal degeneration caused by protein misfolding. Autophagy 14, 1226–1238 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhao, N., Li, N. & Wang, T. PERK prevents rhodopsin degradation during retinitis pigmentosa by inhibiting IRE1-induced autophagy. J. Cell Biol. 222, e202208147 (2023).

  • Wang, J. et al. Landscape of pathogenic variants in six pre-mRNA processing factor genes for retinitis pigmentosa based on large in-house data sets and database comparisons. Acta Ophthalmol. 100, e1412–e1425 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Valdés-Sánchez, L. et al. Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins. Mol. Med. 26, 1 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Georgiou, M. et al. Activation of autophagy reverses progressive and deleterious protein aggregation in PRPF31 patient-induced pluripotent stem cell-derived retinal pigment epithelium cells. Clin. Transl. Med. 12, e759 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vang, S., Longley, K., Steer, C. J. & Low, W. C. The unexpected uses of urso- and tauroursodeoxycholic acid in the treatment of non-liver diseases. Glob. Adv. Health Med. 3, 58–69 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gorbatyuk, M. S. et al. Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78. Proc. Natl Acad. Sci. USA 107, 5961–5966 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ozawa, Y. et al. Effects of epigenetic modification of PGC-1α by a chemical chaperon on mitochondria biogenesis and visual function in retinitis pigmentosa. Cells 11, 1497 (2022).

  • Zheng, M., Mitra, R. N., Weiss, E. R. & Han, Z. Rhodopsin genomic loci DNA nanoparticles improve expression and rescue of retinal degeneration in a model for retinitis pigmentosa. Mol. Ther. 28, 523–535 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shahin, S. et al. AAV-CRISPR/Cas9 gene editing preserves long-term vision in the P23H rat model of autosomal dominant retinitis pigmentosa. Pharmaceutics 14, 824 (2022).

  • Shinohara, T., Mulhern, M. L. & Madson, C. J. Silencing gene therapy for mutant membrane, secretory, and lipid proteins in retinitis pigmentosa (RP). Med. Hypotheses 70, 378–380 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yoshida, T. et al. The use of induced pluripotent stem cells to reveal pathogenic gene mutations and explore treatments for retinitis pigmentosa. Mol. Brain 7, 45 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Duarri, A. et al. Transplantation of human induced pluripotent stem cell-derived retinal pigment epithelium in a swine model of geographic atrophy. Int. J. Mol. Sci. 22, 10497 (2021).

  • Lin, B. et al. Retina organoid transplants develop photoreceptors and improve visual function in RCS rats with RPE dysfunction. Invest. Ophthalmol. Vis. Sci. 61, 34 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Foltz, L. P., Howden, S. E., Thomson, J. A. & Clegg, D. O. Functional assessment of patient-derived retinal pigment epithelial cells edited by CRISPR/Cas9. Int. J. Mol. Sci. 19, 4127 (2018).

  • Klassen, H. J. et al. Multipotent retinal progenitors express developmental markers, differentiate into retinal neurons, and preserve light-mediated behavior. Invest. Ophthalmol. Vis. Sci. 45, 4167–4173 (2004).

    Article 
    PubMed 

    Google Scholar
     

  • Brown, C. et al. Human primitive mesenchymal stem cell-derived retinal progenitor cells improved neuroprotection, neurogenesis, and vision in rd12 mouse model of retinitis pigmentosa. Stem Cell Res. Ther. 13, 148 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pan, T. et al. Combined transplantation with human mesenchymal stem cells improves retinal rescue effect of human fetal RPE cells in retinal degeneration mouse model. Invest. Ophthalmol. Vis. Sci. 61, 9 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ma, M. et al. Therapeutic effects of mesenchymal stem cell-derived exosomes on retinal detachment. Exp. Eye Res. 191, 107899 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dezfuly, A. R. et al. Therapeutic effects of human adipose mesenchymal stem cells and their paracrine agents on sodium iodate induced retinal degeneration in rats. Life Sci. 300, 120570 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Knickelbein, J. E. et al. Modulation of immune responses by extracellular vesicles from retinal pigment epithelium. Invest. Ophthalmol. Vis. Sci. 57, 4101–4107 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, K. Y. et al. Retinitis pigmentosa: novel therapeutic targets and drug development. Pharmaceutics 15, 685 (2023).

  • Zhang, F. et al. The microbial opsin family of optogenetic tools. Cell 147, 1446–1457 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gaub, B. M. et al. Restoration of visual function by expression of a light-gated mammalian ion channel in retinal ganglion cells or ON-bipolar cells. Proc. Natl Acad. Sci. USA 111, E5574–5583 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Remmer, M. H., Rastogi, N., Ranka, M. P. & Ceisler, E. J. Achromatopsia: a review. Curr. Opin. Ophthalmol. 26, 333–340 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Wawrocka, A. et al. Five novel CNGB3 gene mutations in Polish patients with achromatopsia. Mol. Vis. 20, 1732–1739 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kohl, S. et al. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nat. Genet. 47, 757–765 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, E. J. et al. Multiexon deletion alleles of ATF6 linked to achromatopsia. JCI Insight 5, e136041 (2020).

  • Mastey, R. R. et al. Characterization of retinal structure in ATF6-associated achromatopsia. Invest. Ophthalmol. Vis. Sci. 60, 2631–2640 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, F., Ma, H., Butler, M. R. & Ding, X. Q. Potential contribution of ryanodine receptor 2 upregulation to cGMP/PKG signaling-induced cone degeneration in cyclic nucleotide-gated channel deficiency. FASEB J. 34, 6335–6350 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kroeger, H. et al. ATF6 is essential for human cone photoreceptor development. Proc. Natl Acad. Sci. USA 118, e2103196118 (2021).

  • Chiang, W. C. et al. Achromatopsia mutations target sequential steps of ATF6 activation. Proc. Natl Acad. Sci. USA 114, 400–405 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ma, H. et al. Loss of cone cyclic nucleotide-gated channel leads to alterations in light response modulating system and cellular stress response pathways: a gene expression profiling study. Hum. Mol. Genet. 22, 3906–3919 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, E. J. et al. Mitochondria and endoplasmic reticulum stress in retinal organoids from patients with vision loss. Am. J. Pathol. https://doi.org/10.1016/j.ajpath.2022.12.002 (2022).

  • Tam, A. B. et al. The UPR activator ATF6 responds to proteotoxic and lipotoxic stress by distinct mechanisms. Dev. Cell 46, 327.e7–343.e7 (2018).

    Article 

    Google Scholar
     

  • Reichel, F. F. et al. Three-year results of phase I retinal gene therapy trial for CNGA3-mutated achromatopsia: results of a non randomised controlled trial. Br. J. Ophthalmol. 106, 1567–1572 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Hassall, M. M., Barnard, A. R. & MacLaren, R. E. Gene therapy for color blindness. Yale J. Biol. Med. 90, 543–551 (2017).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Komáromy, A. M. et al. Transient photoreceptor deconstruction by CNTF enhances rAAV-mediated cone functional rescue in late stage CNGB3-achromatopsia. Mol. Ther. 21, 1131–1141 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Siles, L., Gaudó, P. & Pomares, E. High-efficiency CRISPR/Cas9-mediated correction of a homozygous mutation in achromatopsia-patient-derived iPSCs. Int. J. Mol. Sci. 24, 3655 (2023).

  • Liu, Y. C. et al. Cataracts. Lancet 390, 600–612 (2017).

    Article 
    PubMed 

    Google Scholar
     

  • Cicinelli, M. V. et al. Cataracts. Lancet 401, 377–389 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Zhang, H. et al. Association between polymorphisms of OGG1, EPHA2 and age-related cataract risk: a meta-analysis. BMC Ophthalmol. 16, 168 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, T. et al. Mutations of the EPHA2 receptor tyrosine kinase gene cause autosomal dominant congenital cataract. Hum. Mutat. 30, E603–611 (2009).

    Article 
    PubMed 

    Google Scholar
     

  • Dave, A. et al. Genotype, age, genetic background, and sex influence Epha2-related cataract development in mice. Invest. Ophthalmol. Vis. Sci. 62, 3 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Berthoud, V. M. et al. Connexin mutants compromise the lens circulation and cause cataracts through biomineralization. Int. J. Mol. Sci. 21, 5822 (2020).

  • Berthoud, V. M. et al. The cataract-linked mutant Connexin50D47A causes endoplasmic reticulum stress in mouse lenses. J. Biol. Chem. 291, 17569–17578 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Periyasamy, P. & Shinohara, T. Age-related cataracts: role of unfolded protein response, Ca(2+) mobilization, epigenetic DNA modifications, and loss of Nrf2/Keap1 dependent cytoprotection. Prog. Retin. Eye Res. 60, 1–19 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Palsamy, P. et al. Methylglyoxal induces endoplasmic reticulum stress and DNA demethylation in the Keap1 promoter of human lens epithelial cells and age-related cataracts. Free Radic. Biol. Med. 72, 134–148 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, S. P., Yang, X. Z. & Cao, G. P. Acetyl-l-carnitine prevents homocysteine-induced suppression of Nrf2/Keap1 mediated antioxidation in human lens epithelial cells. Mol. Med. Rep. 12, 1145–1150 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Palsamy, P., Bidasee, K. R. & Shinohara, T. Valproic acid suppresses Nrf2/Keap1 dependent antioxidant protection through induction of endoplasmic reticulum stress and Keap1 promoter DNA demethylation in human lens epithelial cells. Exp. Eye Res. 121, 26–34 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Palsamy, P., Bidasee, K. R. & Shinohara, T. Selenite cataracts: activation of endoplasmic reticulum stress and loss of Nrf2/Keap1-dependent stress protection. Biochim. Biophys. Acta 1842, 1794–1805 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liu, C. et al. Involvement of increased endoplasmic reticulum stress in the development of cataracts in BALB.NCT-Cpox(nct) mice. Exp. Eye Res. 215, 108905 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Elanchezhian, R. et al. Low glucose under hypoxic conditions induces unfolded protein response and produces reactive oxygen species in lens epithelial cells. Cell Death Dis. 3, e301 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ma, T. J. et al. Nrf2 protects human lens epithelial cells against H(2)O(2)-induced oxidative and ER stress: the ATF4 may be involved. Exp. Eye Res. 169, 28–37 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang, Y. et al. Cataract formation in transgenic HO-1 G143H mutant mice: Involvement of oxidative stress and endoplasmic reticulum stress. Biochem. Biophys. Res. Commun. 537, 43–49 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhou, S. et al. Endoplasmic reticulum stress regulates epithelial‑mesenchymal transition in human lens epithelial cells. Mol. Med. Rep. 21, 173–180 (2020).

    CAS 
    PubMed 

    Google Scholar
     

  • de Iongh, R. U., Wederell, E., Lovicu, F. J. & McAvoy, J. W. Transforming growth factor-beta-induced epithelial-mesenchymal transition in the lens: a model for cataract formation. Cells Tissues Organs 179, 43–55 (2005).

    Article 
    PubMed 

    Google Scholar
     

  • Liu, H. et al. Sulforaphane promotes ER stress, autophagy, and cell death: implications for cataract surgery. J. Mol. Med. 95, 553–564 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jara, O., Minogue, P. J., Berthoud, V. M. & Beyer, E. C. Chemical chaperone treatment improves levels and distributions of connexins in Cx50D47A mouse lenses. Exp. Eye Res. 175, 192–198 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, L. et al. Sigma 1 receptor stimulation protects against oxidative damage through suppression of the ER stress responses in the human lens. Mech. Ageing Dev. 133, 665–674 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wei, D. et al. Application of iontophoresis in ophthalmic practice: an innovative strategy to deliver drugs into the eye. Drug Deliv. 30, 2165736 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sfriso, P. et al. Blau syndrome, clinical and genetic aspects. Autoimmun. Rev. 12, 44–51 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Milman, N. & Byg, K. E. [Blau syndrome-a chronic granulomatous, genetic disease]. Ugeskr Laeger 168, 3612–3614 (2006).

    PubMed 

    Google Scholar
     

  • Ogura, Y. et al. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J. Biol. Chem. 276, 4812–4818 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pham, O. H. et al. NOD1/NOD2 and RIP2 regulate endoplasmic reticulum stress-induced inflammation during chlamydia infection. mBio 11, e00979-20 (2020).

  • Keestra-Gounder, A. M. et al. NOD1 and NOD2 signalling links ER stress with inflammation. Nature 532, 394–397 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, W. et al. Crosstalk between ER stress, NLRP3 inflammasome, and inflammation. Appl. Microbiol. Biotechnol. 104, 6129–6140 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lebeaupin, C. et al. ER stress induces NLRP3 inflammasome activation and hepatocyte death. Cell Death Dis. 6, e1879 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wert, K. J. et al. CAPN5 mutation in hereditary uveitis: the R243L mutation increases calpain catalytic activity and triggers intraocular inflammation in a mouse model. Hum. Mol. Genet. 24, 4584–4598 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kirectepe Aydin, A. et al. Peripheral blood mononuclear cell proteome profile in Behçet’s syndrome. Rheumatol. Int. 40, 65–74 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Smatlik, N. et al. Mesalazine suppresses proinflammatory cytokines in patients with acute anterior uveitis independently of HLA-B27. Ocul. Immunol. Inflamm. 30, 1369–1377 (2021).

  • Lee, H. J. et al. Proteomics-based functional studies reveal that galectin-3 plays a protective role in the pathogenesis of intestinal Behçet’s disease. Sci. Rep. 9, 11716 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sehgal, P., Colombel, J. F., Aboubakr, A. & Narula, N. Systematic review: safety of mesalazine in ulcerative colitis. Aliment. Pharmacol. Ther. 47, 1597–1609 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Krantz, B. A. et al. Uveal melanoma: epidemiology, etiology, and treatment of primary disease. Clin. Ophthalmol. 11, 279–289 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McLaughlin, C. C. et al. Incidence of noncutaneous melanomas in the U.S. Cancer 103, 1000–1007 (2005).

    Article 
    PubMed 

    Google Scholar
     

  • Damato, E. M. & Damato, B. E. Detection and time to treatment of uveal melanoma in the United Kingdom: an evaluation of 2,384 patients. Ophthalmology 119, 1582–1589 (2012).

    Article 
    PubMed 

    Google Scholar
     

  • Rietschel, P. et al. Variates of survival in metastatic uveal melanoma. J. Clin. Oncol. 23, 8076–8080 (2005).

    Article 
    PubMed 

    Google Scholar
     

  • Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell. 161, 1681–1696 (2015).

  • Van Raamsdonk, C. D. et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457, 599–602 (2009).

    Article 
    PubMed 

    Google Scholar
     

  • Robertson, A. G. et al. Integrative analysis identifies four molecular and clinical subsets in uveal melanoma. Cancer Cell 32, 204.e5–220.e5 (2017).

    Article 

    Google Scholar
     

  • Durante, M. A. et al. Single-cell analysis reveals new evolutionary complexity in uveal melanoma. Nat. Commun. 11, 496 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Smit, K. N., Jager, M. J., de Klein, A. & Kiliҫ, E. Uveal melanoma: towards a molecular understanding. Prog. Retin. Eye Res. 75, 100800 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Pandiani, C. et al. Single-cell RNA sequencing reveals intratumoral heterogeneity in primary uveal melanomas and identifies HES6 as a driver of the metastatic disease. Cell Death Differ. 28, 1990–2000 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, X. et al. Construction and verification of a hypoxia-related nine-gene prognostic model in uveal melanoma based on integrated single-cell and bulk RNA sequencing analyses. Exp. Eye Res. 223, 109214 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Asnaghi, L. et al. Hypoxia promotes uveal melanoma invasion through enhanced Notch and MAPK activation. PLoS ONE 9, e105372 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mahadevan, N. R. et al. Cell-extrinsic effects of tumor ER stress imprint myeloid dendritic cells and impair CD8+ T cell priming. PLoS ONE 7, e51845 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, T. et al. MMP1 and MMP9 are potential prognostic biomarkers and targets for uveal melanoma. BMC Cancer 21, 1068 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tan, B. et al. Matrix metalloproteinase-11 promotes early mouse mammary gland tumor growth through metabolic reprogramming and increased IGF1/AKT/FoxO1 signaling pathway, enhanced ER stress and alteration in mitochondrial UPR. Cancers 12, 2357 (2020).

  • Bellini, L. et al. Endoplasmic reticulum stress mediates resistance to BCL-2 inhibitor in uveal melanoma cells. Cell Death Discov. 6, 22 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Eigner, K. et al. The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone. Sci. Rep. 7, 17498 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shields, C. L. et al. Choroidal melanoma: clinical features, classification, and top 10 pseudomelanomas. Curr. Opin. Ophthalmol. 25, 177–185 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Zhao, X., Kong, F., Wang, L. & Zhang, H. c-FLIP and the NOXA/Mcl-1 axis participate in the synergistic effect of pemetrexed plus cisplatin in human choroidal melanoma cells. PLoS ONE 12, e0184135 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, Q. et al. LiCl induces apoptosis via CHOP/NOXA/Mcl-1 axis in human choroidal melanoma cells. Cancer Cell Int. 21, 96 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, W. et al. Targeting photodynamic and photothermal therapy to the endoplasmic reticulum enhances immunogenic cancer cell death. Nat. Commun. 10, 3349 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Katoh, Y. et al. Inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor T cell response through regulating β-catenin signaling in cancer cells and ER stress in T cells and synergizes with anti-PD-1 antibody. J. Immunother. Cancer 10, e004616 (2022).

  • Weiss, J. S. et al. IC3D classification of corneal dystrophies-edition 2. Cornea 34, 117–159 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Wang, L. et al. CHST6 mutation screening and endoplasmatic reticulum stress in macular corneal dystrophy. Oncotarget 8, 96301–96312 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shyam, R., Ogando, D. G. & Bonanno, J. A. Mitochondrial ROS in Slc4a11 KO corneal endothelial cells lead to ER stress. Front. Cell Dev. Biol. 10, 878395 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Okumura, N. et al. Activation of TGF-β signaling induces cell death via the unfolded protein response in Fuchs endothelial corneal dystrophy. Sci. Rep. 7, 6801 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Weiss, J. S. et al. The IC3D classification of the corneal dystrophies. Cornea 27, S1–83 (2008).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aggarwal, S., Peck, T., Golen, J. & Karcioglu, Z. A. Macular corneal dystrophy: a review. Surv. Ophthalmol. 63, 609–617 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Akama, T. O. et al. Macular corneal dystrophy type I and type II are caused by distinct mutations in a new sulphotransferase gene. Nat. Genet. 26, 237–241 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hao, X. D. et al. Association of macular corneal dystrophy with excessive cell senescence and apoptosis induced by the novel mutant CHST6. Exp. Eye Res. 214, 108862 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen, S. et al. Pathophysiological mechanisms of autosomal dominant congenital stromal corneal dystrophy: C-terminal-truncated decorin results in abnormal matrix assembly and altered expression of small leucine-rich proteoglycans. Am. J. Pathol. 179, 2409–2419 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, S. et al. Intracellularly-retained decorin lacking the C-terminal ear repeat causes ER stress: a cell-based etiological mechanism for congenital stromal corneal dystrophy. Am. J. Pathol. 183, 247–256 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Skonier, J. et al. cDNA cloning and sequence analysis of beta ig-h3, a novel gene induced in a human adenocarcinoma cell line after treatment with transforming growth factor-beta. DNA Cell Biol. 11, 511–522 (1992).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Klintworth, G. K. Advances in the molecular genetics of corneal dystrophies. Am. J. Ophthalmol. 128, 747–754 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Choi, S. I. et al. Lysosomal trafficking of TGFBIp via caveolae-mediated endocytosis. PLoS ONE 10, e0119561 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Choi, S. I. et al. 4-Phenylbutyric acid reduces mutant-TGFBIp levels and ER stress through activation of ERAD pathway in corneal fibroblasts of granular corneal dystrophy type 2. Biochem. Biophys. Res. Commun. 477, 841–846 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jun, A. S. et al. An alpha 2 collagen VIII transgenic knock-in mouse model of Fuchs endothelial corneal dystrophy shows early endothelial cell unfolded protein response and apoptosis. Hum. Mol. Genet. 21, 384–393 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Okumura, N. et al. Sustained activation of the unfolded protein response induces cell death in Fuchs’ endothelial corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 58, 3697–3707 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jun, D. J. et al. Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation. J. Lipid Res. 61, 746–757 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Choi, S. I. et al. Melatonin reduces endoplasmic reticulum stress and corneal dystrophy-associated TGFBIp through activation of endoplasmic reticulum-associated protein degradation. J. Pineal Res. https://doi.org/10.1111/jpi.12426 (2017).

  • Kim, E. C., Meng, H. & Jun, A. S. Lithium treatment increases endothelial cell survival and autophagy in a mouse model of Fuchs endothelial corneal dystrophy. Br. J. Ophthalmol. 97, 1068–1073 (2013).

    Article 
    PubMed 

    Google Scholar
     

  • Loganathan, S. K. & Casey, J. R. Corneal dystrophy-causing SLC4A11 mutants: suitability for folding-correction therapy. Hum. Mutat. 35, 1082–1091 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kim, E. C., Meng, H. & Jun, A. S. N-Acetylcysteine increases corneal endothelial cell survival in a mouse model of Fuchs endothelial corneal dystrophy. Exp. Eye Res. 127, 20–25 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chiu, A. M. et al. High throughput assay identifies glafenine as a corrector for the folding defect in corneal dystrophy-causing mutants of SLC4A11. Invest. Ophthalmol. Vis. Sci. 56, 7739–7753 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Buono, L. et al. Mesenchymal stem cell-derived extracellular vesicles protect human corneal endothelial cells from endoplasmic reticulum stress-mediated apoptosis. Int. J. Mol. Sci. 22, 4930 (2021).

  • Santodomingo-Rubido, J. et al. Keratoconus: an updated review. Cont. Lens Anterior Eye 45, 101559 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Flockerzi, E. et al. Keratoconus staging by decades: a baseline ABCD classification of 1000 patients in the Homburg Keratoconus Center. Br. J. Ophthalmol. 105, 1069–1075 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Hwang, S., Lim, D. H. & Chung, T. Y. Prevalence and incidence of keratoconus in South Korea: a nationwide population-based study. Am. J. Ophthalmol. 192, 56–64 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Shinde, V. et al. Mapping keratoconus molecular substrates by multiplexed high-resolution proteomics of unpooled corneas. Omics 23, 583–597 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Moschos, M. M. et al. Polymorphism analysis of VSX1 and SOD1 genes in Greek patients with keratoconus. Ophthalmic Genet. 36, 213–217 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Udar, N. et al. SOD1: a candidate gene for keratoconus. Invest. Ophthalmol. Vis. Sci. 47, 3345–3351 (2006).

    Article 
    PubMed 

    Google Scholar
     

  • Dickhout, J. G. et al. Peroxynitrite causes endoplasmic reticulum stress and apoptosis in human vascular endothelium: implications in atherogenesis. Arterioscler. Thromb. Vasc. Biol. 25, 2623–2629 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Collier, S. A. Is the corneal degradation in keratoconus caused by matrix-metalloproteinases? Clin. Exp. Ophthalmol. 29, 340–344 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nelson, K. K. et al. Elevated sod2 activity augments matrix metalloproteinase expression: evidence for the involvement of endogenous hydrogen peroxide in regulating metastasis. Clin. Cancer Res. 9, 424–432 (2003).

    CAS 
    PubMed 

    Google Scholar
     

  • Wang, G. et al. The role of autophagy in the pathogenesis of exposure keratitis. J. Cell Mol. Med. 23, 4217–4228 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Coursey, T. G. et al. Interferon-γ-induced unfolded protein response in conjunctival goblet cells as a cause of mucin deficiency in Sjögren syndrome. Am. J. Pathol. 186, 1547–1558 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cui, Y. et al. Mycobacterium bovis induces endoplasmic reticulum stress mediated-apoptosis by activating IRF3 in a murine macrophage cell line. Front. Cell Infect. Microbiol. 6, 182 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fangary, S. et al. Nanoparticle fraught liposomes: a platform for increased antibiotic selectivity in multidrug resistant bacteria. Mol. Pharm. 19, 3163–3177 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, P. et al. High osmotic pressure increases reactive oxygen species generation in rabbit corneal epithelial cells by endoplasmic reticulum. Am. J. Transl. Res. 8, 860–870 (2016).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cejka, C. & Cejkova, J. Oxidative stress to the cornea, changes in corneal optical properties, and advances in treatment of corneal oxidative injuries. Oxid. Med. Cell Longev. 2015, 591530 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Woodward, A. M., Di Zazzo, A., Bonini, S. & Argüeso, P. Endoplasmic reticulum stress promotes inflammation-mediated proteolytic activity at the ocular surface. Sci. Rep. 10, 2216 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Barrera, M. J. et al. Dysfunctional mitochondria as critical players in the inflammation of autoimmune diseases: potential role in Sjögren’s syndrome. Autoimmun. Rev. 20, 102867 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hu, S. et al. Lacrimal gland homeostasis is maintained by the AQP5 pathway by attenuating endoplasmic reticulum stress inflammation in the lacrimal gland of AQP5 knockout mice. Mol. Vis. 27, 679–690 (2021).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Krokowski, D. et al. GADD34 function in protein trafficking promotes adaptation to hyperosmotic stress in human corneal cells. Cell Rep. 21, 2895–2910 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Baird, P. N. et al. Myopia. Nat. Rev. Dis. Prim. 6, 99 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Holden, B. A. et al. Global prevalence of myopia and high myopia and temporal trends from 2000 through 2050. Ophthalmology 123, 1036–1042 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Young, T. L., Metlapally, R. & Shay, A. E. Complex trait genetics of refractive error. Arch. Ophthalmol. 125, 38–48 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ikeda, S. I. et al. Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes. Nat. Commun. 13, 5859 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, H. et al. Scleral hypoxia is a target for myopia control. Proc. Natl Acad. Sci. USA 115, E7091–e7100 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhao, F. et al. Scleral HIF-1α is a prominent regulatory candidate for genetic and environmental interactions in human myopia pathogenesis. EBioMedicine 57, 102878 (2020).

    Article 
    PubMed 
    PubMed Central