Notopterol attenuates synovitis via α7nAChR-dependent metabolic reprogramming of macrophage polarisation

Synovitis, a characteristic feature of inflammatory arthritis (IA), is often driven by an aberrant macrophage-mediated inflammatory response that promotes irreversible joint damage. The α7 nicotinic acetylcholine receptor (α7nAChR) is a key regulator of the cholinergic anti-inflammatory pathway. Despite its therapeutic potential, how α7nAChR coordinates macrophage metabolic reprogramming to resolve synovitis remains underexplored. This study aims to elucidate the therapeutic effects of Notopterol, a bioactive constituent derived from the rhizome of Notopterygium incisum Ting ex H.T. Chang, a traditional Chinese medicine known for its potent anti-inflammatory and antioxidant properties, in treating inflammatory arthritis and the molecular mechanisms by which α7nAChR modulates macrophage reprogramming in synovitis. An in vivo mouse model of IA was established through complete Freund's adjuvant (CFA)-induced, Notopterol administration significantly attenuated synovitis progression, reduced joint swelling, and enhanced mechanical pain thresholds as well as suppressed the production of pro-inflammatory cytokines (IL-1β, TNF-α, and IFN-γ) while promoting anti-inflammatory IL-4 secretion. Complementary in vitro models employing lipopolysaccharide (LPS)-stimulated macrophages demonstrated that Notopterol exerts anti-inflammatory effects, restores mitochondrial function while shifting energy metabolism towards oxidative phosphorylation, a transition mechanistically linked to M1/M2 polarisation. Mechanistically, Notopterol promotes a shift from glycolysis to oxidative phosphorylation in macrophages, restoring mitochondrial function and enhancing their polarizing capacity through α7nAChR activation, thus revealing this receptor's pivotal role in macrophage metabolic regulation. Furthermore, biophysical validation confirms the high-affinity binding of Notopterol to α7nAChR, supporting its therapeutic potential in anti-inflammatory treatment. These findings highlight the innovative prospect of targeting macrophage metabolic pathways as a novel strategy for treating inflammatory arthritis.