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In this study, the interplay between epigenetic modifications and metabolic reprogramming during the activation of fibrocartilage cells in osteoarthritis was investigated. The findings demonstrate that FSTL1 markedly upregulates key glycolytic enzymes, including LDHA, HK2, and PKM, in chondrocytes, triggering a \u201cglycolytic burst\u201d that results in elevated intracellular lactate levels. This accumulated lactate acts as a precursor for epigenetic modifications, specifically promoting the lactylation of histone H3 lysine 18 (H3K18la) in fibrocartilage cells, thereby facilitating the transcriptional activation of critical fibrosis\u2010related genes such as Itga6, Cxcl10, and Parp16. Notably, pharmacological inhibition of the PI3K\/mTOR pathway or lactate dehydrogenase significantly diminishes H3K18la levels and markers of chondrocyte fibrosis, while exogenous lactate supplementation can counteract this effect. In summary, this study unveils the core mechanism by which FSTL1 reshapes the epigenetic landscape of chondrocytes and drives the fibrotic process through the activation of the \u201cglycolysis\u2010lactate\u2010H3K18la\u201d cascade axis, offering a dual\u2010target intervention strategy for OA involving metabolic reprogramming and epigenetic modification.<\/jats:p>","DOI":"10.1002\/advs.202512002","type":"journal-article","created":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T11:05:42Z","timestamp":1764155142000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["FSTL1 Orchestrates Metabolic\u2010Epigenetic Crosstalk: Glycolysis\u2010Dependent H3K18 Lactylation Drives Cartilage Fibrosis in Osteoarthritis"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5341-0746","authenticated-orcid":false,"given":"Feng","family":"Lu","sequence":"first","affiliation":[{"name":"Department of\u00a0Orthopedics The Third Affiliated Hospital of Nanjing Medical University (Changzhou No. 2 People's Hospital)  Changzhou Jiangsu 213003 P. 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