Advances in traditional Chinese medicine for modulating macrophage polarization in the treatment of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent synovitis and progressive joint destruction, wherein macrophage polarization constitutes a critical pathogenic mechanism governing both the initiation and perpetuation of synovial inflammation. The conventional M1 and M2 dichotomy has evolved into a continuum model encompassing disease-stage-specific synovial subsets, including remission-associated MerTK-positive populations and pro-inflammatory clusters, reflecting the functional heterogeneity of macrophages in the rheumatoid microenvironment. Modulating macrophage polarization accordingly represents a promising therapeutic strategy; however, pharmacological agents specifically designed to target macrophage phenotypes remain in nascent stages of development. Traditional Chinese medicine (TCM) has emerged as a potential avenue for addressing this therapeutic gap. Extensive experimental evidence has demonstrated that diverse multi-botanical drug formulations and purified bioactive metabolites, including sinomenine, icariin, and curcumin, can effectively modulate macrophage polarization through interconnected pathways involving NF-κB, JAK-STAT, and PI3K-Akt signaling. These interventions further act through metabolic reprogramming between glycolysis and oxidative phosphorylation, operating via metabolite-driven epigenetic modifications such as histone lactylation and the IRG1-itaconate-TET2 axis, alongside NLRP3 inflammasome restriction and autophagic regulation, all of which collectively promote the rebalancing of inflammatory and reparative macrophage phenotypes. This review systematically consolidates current mechanistic understanding and critically assesses translational gaps, including the predominance of rodent collagen-induced arthritis (CIA) models, the scarcity of human synovial macrophage validation, undefined pharmacokinetics of active metabolites, and the need for patient stratification by synovial subset markers. It aims to establish a theoretical framework facilitating future investigations into precise molecular targets and supporting the rational development of macrophage-targeted, clinically viable interventions for RA.