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In this study, we found that HMGCR\n                    <jats:sup>+<\/jats:sup>\n                    fibroblasts (FLSs) were significantly increased in the knee synovium of OA patients and OA mice. Elevated expression of HMGCR in synovial FLSs was positively correlated with cellular senescence and OA progression. The inhibition of HMGCR reversed cellular senescence of FLSs induced by TNF\u2010\u03b1 in vitro. Additionally, the HMGCR\u2010mediated cholesterol biosynthetic pathway contributed to cellular senescence. Targeted inhibition of HMGCR in synovial FLSs via intra\u2010articular adeno\u2010associated virus delivery effectively reversed cellular senescence of FLSs and mitigated synovitis, cartilage degradation, and pain behaviors in OA mice. Mechanistically, the phosphorylation of AKT1 at Ser473 enhanced its binding to Lys140 of Insig1, facilitating AKT1\u2013Insig1 complex formation. The activation of AKT1 induced the phosphorylation of Insig1 at Ser189 and the dissociation of Insig1 from sterol regulatory element\u2011binding protein cleavage\u2011activating protein (SCAP), which contributed to HMGCR transcription and cellular senescence of FLSs. Collectively, our study reveals a novel mechanism of HMGCR\u2010driven cellular senescence of FLSs in OA, which highlights HMGCR as a promising therapeutic target for OA.\n                  <\/jats:p>","DOI":"10.1002\/advs.76498","type":"journal-article","created":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T12:17:11Z","timestamp":1783945031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HMGCR\u2010Driven Cholesterol Metabolism Promotes Osteoarthritis Progression by Accelerating Synovial Fibroblast Senescence"],"prefix":"10.1002","volume":"13","author":[{"given":"Xiaoqi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Rehabilitation Medicine Army Medical Center Daping Hospital Army Medical University of PLA Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siru","family":"Zhou","sequence":"additional","affiliation":[{"name":"War Trauma Medical 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