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Here, we identified the effect of a potent, selective NLRP3 inhibitor, MCC950, on autophagy and apoptosis under hypoxia. Neonatal mice were exposed to hyperoxia for 5\u2009days to establish oxygen\u2010induced retinopathy (OIR) model. Intravitreal injection of MCC950 was given, and then autophagy and apoptosis markers were assessed. Retinal autophagy, apoptosis, and related pathways were evaluated by western blot, immunofluorescent labeling, transmission electron microscopy, and TUNEL assay. Autophagic activity in M\u00fcller glia after NLRP3 inflammasome inhibition, together with its influence on photoreceptor death, was studied using western blot, immunofluorescence staining, mRFP\u2010GFP\u2010LC3 adenovirus transfection, cell viability, proliferation, and apoptosis assays. Results showed that activation of NLRP3 inflammasome in M\u00fcller glia was detected in OIR model. MCC950 could improve impaired retinal autophagic flux and attenuate retinal apoptosis while it regulated the retinal AMPK\/mTOR\/ULK\u20101 pathway. Suppressed autophagy and depressed proliferation capacity resulting from hypoxia was promoted after MCC950 treatment in M\u00fcller glia. Inhibition of AMPK and ULK\u20101 pathway significantly interfered with the MCC950\u2010induced autophagy activity, indicating MCC950 positively modulated autophagy through AMPK\/mTOR\/ULK\u20101 pathway in M\u00fcller cells. Furthermore, blockage of autophagy in M\u00fcller glia significantly induced apoptosis in the cocultured 661W photoreceptor cells, whereas MCC950 markedly preserved the density of photoreceptor cells. These findings substantiated the therapeutic potential of MCC950 against impaired autophagy and subsequent apoptosis under hypoxia. Such protective effect might involve the modulation of AMPK\/mTOR\/ULK\u20101 pathway. Targeting NLRP3 inflammasome in M\u00fcller glia could be beneficial for photoreceptor survival under hypoxic conditions.<\/jats:p>","DOI":"10.1096\/fj.202301922rr","type":"journal-article","created":{"date-parts":[[2024,5,16]],"date-time":"2024-05-16T07:04:52Z","timestamp":1715843092000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Inhibition of\n                    <scp>NLRP3<\/scp>\n                    inflammasome by\n                    <scp>MCC950<\/scp>\n                    under hypoxia alleviates photoreceptor apoptosis via inducing autophagy in M\u00fcller glia"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3626-326X","authenticated-orcid":false,"given":"Shuang","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Ruijin Hospital Affiliated Shanghai Jiaotong University School of Medicine  Shanghai 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