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Here we show that MAT-derived complement factor D (CFD) and component 3 (C3) derived from steatotic liver coordinately drive excessive alternative complement activation, resulting in cartilage damage in mice during aging and metabolic disorders. Mechanistically, estrogen-related receptor \u03b1 (ESRRA) transcriptionally upregulates CFD responding to bone marrow adipocytes (BMAds) expansion. Inhibition of ESRRA\/CFD signaling in BMAds blocks the chondrocyte senescence and catabolism triggered by C3 that is released from steatotic hepatocyte, interrupting C3-CFD-MAC cascade, thereby suppressing ERK1\/2 phosphorylation and mitochondrial dysfunction. Adipocyte-specific ablation or pharmacological inhibition of ESRRA reduces CFD levels particularly in adipocyte-rich bone marrow, attenuating osteoarthritis progression in aged mice. Our findings highlight a key liver-MAT-cartilage axis bridged by C3-CFD-MAC pathway, raising the potential for adipocyte ESRRA-targeting therapies for aging-related metabolic osteoarthritis.<\/jats:p>","DOI":"10.1038\/s41413-026-00527-3","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T08:28:13Z","timestamp":1777451293000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting adipocyte ESRRA alleviates osteoarthritis via interrupting inter-organelle crosstalk of complement C3-CFD-MAC cascade"],"prefix":"10.1038","volume":"14","author":[{"given":"Tongling","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaocheng","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengda","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chon Him","family":"Choy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuolei","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanting","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-An","family":"Geng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaiyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0887-088X","authenticated-orcid":false,"given":"Kelvin W. 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