ABSTRACT Osteoarthritis (OA)‐associated pain, driven by M1 macrophage polarization and inflammation, lacks effective therapies. Tetrahydropalmatine (THP), known for its anti‐inflammatory and analgesic properties, was evaluated for its effects on OA‐induced pain and macrophage polarization. A destabilization of the medial meniscus (DMM)‐induced OA mouse model and lipopolysaccharide (LPS)‐stimulated RAW264.7 macrophages were used. Behavioral tests, histology, immunofluorescence, enzyme‐linked immunosorbent assay (ELISA), reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR), 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‐inducible factor‐1α (HIF‐1α). THP treatment alleviated OA‐induced pain and cartilage damage and reduced CD86 expression, and reduced the expression of pro‐inflammatory factors tumor necrosis factor‐α (TNF‐α), inducible nitric oxide synthase (iNOS), interleukin‐6 (IL‐6), and key signaling molecules (KDM4A, MDM2, and HIF‐1α). Mechanistically, KDM4A directly bound to the MDM2 promoter and activated its transcription via H3K9me3 demethylation, whereas MDM2 enhanced HIF‐1α signaling to promote M1 polarization. Overexpression of KDM4A reversed the inhibitory effects of THP on MDM2/HIF‐1α signaling and inflammation. These findings indicate that THP mitigates OA‐associated pain and inflammation by blocking KDM4A‐mediated MDM2 transcription and suppressing HIF‐1α‐dependent M1 macrophage polarization, highlighting the KDM4A‐MDM2‐HIF‐1α axis as a potential therapeutic target.
Chen et al. (2026) studied this question.