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Although SETDB2 functions as a regulator of macrophage inflammation, its specific role in macrophage polarization during KOA remains poorly understood. A KOA mouse model was induced via papain injection. Cartilage and synovium damage were assessed by Safranin O\/Fast Green and H&amp;E staining, as well as OARSI and synovitis scores. Immunofluorescence was employed to determine the co\u2010localization of synovium CD68 and SETDB2. M1\u2010like (iNOS\n                    <jats:sup>+<\/jats:sup>\n                    ) and M2\u2010like (CD206\n                    <jats:sup>+<\/jats:sup>\n                    ) macrophage markers were evaluated using immunohistochemistry and flow cytometry. Inflammatory cytokine concentrations were measured by ELISA. SETDB2, Collagen II, and MMP\u201013 expression were examined by Western blotting or qRT\u2010PCR. Mouse synovial macrophages were stimulated with LPS and co\u2010cultured with chondrocytes. Flow cytometry, EdU staining, CCK\u20108, and transwell assays were used to assess the impact of SETDB2\u2010mediated macrophage polarization on chondrocyte proliferation and migration. Furthermore, bulk RNA sequencing, Western blotting, and ChIP\u2010qPCR were employed for mechanistic exploration. The research results show that, SETDB2 expression was reduced in synovial macrophages of KOA mice compared to controls. SETDB2 deficiency in macrophages aggravated synovitis, cartilage damage, and extracellular matrix degradation in KOA mice, characterized by an increase in M1\u2010like macrophages and a decrease in M2\u2010like macrophages. In\u00a0vitro, SETDB2 overexpression promoted M2\u2010like macrophage polarization and alleviated LPS\u2010induced inflammation. Co\u2010culture experiments demonstrated that SETDB2\u2010overexpressing macrophages enhanced chondrocyte proliferation and migration while inhibiting apoptosis. Mechanistically, SETDB2 knockdown reduced H3K9me3 enrichment and upregulated ALPK1 expression in LPS\u2010stimulated macrophages. ALPK1 overexpression reversed the beneficial effects of SETDB2\u2010overexpressing macrophages on chondrocyte behaviors. SETDB2 drives M2\u2010like macrophage polarization through the down\u2010regulation of ALPK1, thereby mitigating the progression of KOA.\n                  <\/jats:p>","DOI":"10.1096\/fj.202501895rr","type":"journal-article","created":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T09:01:01Z","timestamp":1767430861000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["SETDB2 Alleviates Knee Osteoarthritis Progression by Promoting M2\u2010Like Macrophage Polarization via Targeting ALPK1"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-9639-9581","authenticated-orcid":false,"given":"Yibao","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Orthopedics and Traumatology, Affiliated Hospital of Nanjing University of Chinese Medicine Jiangsu Provincial Hospital of Traditional Chinese Medicine  Nanjing Jiangsu Province P. R. 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