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M\u00fcller cells can acquire myofibroblast-like features during retinal fibroproliferative remodeling, yet the metabolic mechanisms governing these phenotypic changes remain poorly understood. Here, we report that lactate is a metabolic regulator of myofibroblast-like remodeling in M\u00fcller cells. Metabolomic profiling revealed elevated vitreous lactate levels in patients with PDR. Consistently, lactate concentrations were increased in the vitreous and retinal tissues of diabetic rats, whereas high-glucose exposure promoted lactate accumulation in primary M\u00fcller cells. Increased lactate availability enhanced M\u00fcller cell proliferative activity and migration, as well as the expression of myofibroblast-associated proteins, including \u03b1-smooth muscle actin, smooth muscle protein 22, and collagen I, whereas oxamate, an inhibitor of lactate dehydrogenase, attenuated these responses. Lactylome profiling and molecular validation revealed K186 of methyl-CpG-binding domain protein 2 (MBD2) as a functionally relevant lactylation site. RNA sequencing of high-glucose-treated M\u00fcller cells expressing MBD2-K186R versus MBD2-WT revealed reduced YAP1 expression in the K186R group, suggesting that YAP1 is a downstream effector of MBD2 K186 lactylation. Mechanistically, increased lactate availability enhanced MBD2 K186 lactylation and YAP1 activation, as evidenced by reduced inhibitory phosphorylation of YAP1 and increased nuclear accumulation of YAP1. MBD2 K186R attenuated YAP1 activation and myofibroblast-like changes, whereas YAP1 overexpression partially reversed these effects. Collectively, these findings reveal a lactate\u2013MBD2 K186 lactylation\u2013YAP1 signaling axis that promotes myofibroblast-like remodeling of M\u00fcller cells and may contribute to fibroproliferative pathology in PDR.<\/jats:p>","DOI":"10.1186\/s43556-026-00605-2","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:02:56Z","timestamp":1791241376000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lactate-induced MBD2 K186 lactylation promotes YAP1-dependent myofibroblast-like remodeling of M\u00fcller cells in diabetic retinopathy"],"prefix":"10.1186","volume":"7","author":[{"given":"Xindan","family":"Xing","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junwei","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinchen","family":"shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanying","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangjia","family":"Lv","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingtong","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hancong","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0377-3151","authenticated-orcid":false,"given":"Tian","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0115-7160","authenticated-orcid":false,"given":"Kun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"issue":"2","key":"605_CR1","doi-asserted-by":"publisher","first-page":"e130","DOI":"10.1016\/S2214-109X(20)30425-3","volume":"9","author":"GBD 2019 Blindness and Vision Impairment Collaborators","year":"2021","unstructured":"GBD 2019 Blindness and Vision Impairment Collaborators, Vision Loss Expert Group of the Global Burden of Disease Study. 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