Moxibustion Modulates ALOX15-Mediated Lipid Peroxidation to Inhibit Ferroptosis in Synovial Inflammatory Injury of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by synovial, cartilage, and bone damage. Emerging research evidence has linked its pathogenesis to ferroptosis, arachidonic acid (ARA) metabolism, and lipid peroxidation. Lipid peroxidation serves as the final executor of ferroptosis, and arachidonate lipoxygenase (ALOX)-mediated oxidative reactions enzymatically promote lipid peroxidation. Moxibustion (MOX), a traditional therapeutic modality in Chinese medicine, has demonstrated significant efficacy in our study. Specifically, MOX applied at the Zusanli (ST36) and Shenshu (BL23) acupoints effectively ameliorated paw swelling in Freund's complete adjuvant (FCA)-induced RA model rats, significantly reduced arthritis scores, and corrected ARA metabolic dysregulation. Furthermore, MOX treatment markedly decreased the expression levels of arachidonate 15-lipoxygenase (ALOX15), acyl-CoA synthetase long-chain family member 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and reactive oxygen species (ROS) in the synovial tissues of RA model rats while increasing the expression of ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4). Serum analyses revealed significant reductions in malondialdehyde (MDA), lipid peroxide (LPO), interleukin-12 (IL-12), and tumor necrosis factor-alpha (TNF-α) levels, alongside elevated glutathione (GSH) and superoxide dismutase (SOD) levels. The underlying mechanism involves the modulation of ALOX15-mediated lipid peroxidation to inhibit ferroptosis, thereby alleviating RA-associated inflammatory damage. These findings highlight the substantial therapeutic potential of MOX in mitigating RA-related inflammation and provide a novel theoretical basis for its clinical application in RA management.