Xue-Fu-Zhu-Yu decoction attenuates synovial apoptosis via MAPK signaling in Knee Osteoarthritis

Knee osteoarthritis (KOA) lacks disease-modifying non-surgical treatments. This study evaluated whether Xue-Fu-Zhu-Yu (XFZY) decoction attenuates KOA-related synovial inflammation and apoptosis through MAPK signaling. UPLC-MS/MS profiling identified phenylpropanoids/polyketides, benzenoids, lipid-like compounds, and representative bioactive constituents including formononetin. Network pharmacology was combined with LPS-treated human synovial cells and a Freund's complete adjuvant-induced rat KOA model. XFZY reduced LPS-induced IL-6 and TNF-alpha, restored mitochondrial membrane potential, increased Bcl-2, reduced Caspase-3, and improved SOD and GSH levels. In silico analyses highlighted overlapping KOA-XFZY targets enriched in MAPK-related pathways; experimentally, XFZY decreased phosphorylation of p38, ERK, and JNK, whereas anisomycin weakened and SB203580 enhanced its anti-apoptotic effects. In rats, oral XFZY reduced inflammatory indices, improved synovial tissue integrity, and suppressed p38-MAPK activation. These findings extend known anti-inflammatory actions of XFZY to KOA synovial apoptosis and suggest MAPK suppression as a functional mediator, although validation in primary joint cells and clinical studies remains necessary.