Capsaicin alleviates rheumatoid arthritis by regulating macrophage M1 polarization through HIF-1α-mediated effects on mitochondrial autophagy and glycolysis

Capsaicin (CAP), the pungent compound in chili peppers, is well-known for its anti-inflammatory properties, yet its role in autoimmune immunometabolism remains unexplored. In a murine model of Collagen-Induced Arthritis,CAP markedly attenuated joint swelling, cartilage damage, and bone erosion. Mechanistically, CAP targeted HIF-1α, leading to a coordinated suppression of both BNIP3-mediated mitophagy and the characteristic glycolytic shift in M1 macrophages. This dual metabolic suppression was recapitulated in human THP-1-derived M1-like macrophages, where it inhibited M1 polarization and reduced pro-inflammatory cytokine secretion. Collectively, these data identify CAP as a food-derived immunometabolic modulator that alleviates rheumatoid arthritis (RA) by concurrently disrupting mitophagy and glycolysis in M1 macrophages via HIF-1α.