{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:30:21Z","timestamp":1787315421840,"version":"build-2736575974"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Osteoarthritis (OA)\u2010associated pain, driven by M1 macrophage polarization and inflammation, lacks effective therapies. Tetrahydropalmatine (THP), known for its anti\u2010inflammatory and analgesic properties, was evaluated for its effects on OA\u2010induced pain and macrophage polarization. A destabilization of the medial meniscus (DMM)\u2010induced OA mouse model and lipopolysaccharide (LPS)\u2010stimulated RAW264.7 macrophages were used. Behavioral tests, histology, immunofluorescence, enzyme\u2010linked immunosorbent assay (ELISA), reverse transcription\u2010quantitative polymerase chain reaction (RT\u2010qPCR), Western blotting (WB), and immunohistochemistry (IHC) were used to assess pain, inflammation, and the expression of lysine demethylase 4A (KDM4A), murine double minute 2 (MDM2), and hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1). THP treatment alleviated OA\u2010induced pain and cartilage damage and reduced CD86 expression, and reduced the expression of pro\u2010inflammatory factors tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1), inducible nitric oxide synthase (iNOS), interleukin\u20106 (IL\u20106), and key signaling molecules (KDM4A, MDM2, and HIF\u20101\u03b1). Mechanistically, KDM4A directly bound to the MDM2 promoter and activated its transcription via H3K9me3 demethylation, whereas MDM2 enhanced HIF\u20101\u03b1 signaling to promote M1 polarization. Overexpression of KDM4A reversed the inhibitory effects of THP on MDM2\/HIF\u20101\u03b1 signaling and inflammation. These findings indicate that THP mitigates OA\u2010associated pain and inflammation by blocking KDM4A\u2010mediated MDM2 transcription and suppressing HIF\u20101\u03b1\u2010dependent M1 macrophage polarization, highlighting the KDM4A\u2010MDM2\u2010HIF\u20101\u03b1 axis as a potential therapeutic target.<\/jats:p>","DOI":"10.1111\/cbdd.70279","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T04:33:51Z","timestamp":1773981231000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Tetrahydropalmatine Alleviates Osteoarthritis\u2010Associated Pain and Inflammation by Suppressing\n                    <scp>KDM4A<\/scp>\n                    \/\n                    <scp>MDM2<\/scp>\n                    \/\n                    <scp>HIF<\/scp>\n                    \u20101\u03b1\u2010Mediated\n                    <scp>M1<\/scp>\n                    Macrophage Polarization"],"prefix":"10.1111","volume":"107","author":[{"given":"Xiaobo","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Rehabilitation The Second Affiliated Hospital of Gannan Medical University  Ganzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyong","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Medicine The First Affiliated Hospital of Gannan Medical University  Ganzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuming","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The Second Affiliated Hospital of Gannan Medical University  Ganzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxia","family":"Gan","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation The Second Affiliated Hospital of Gannan Medical University  Ganzhou 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