Bioactive Compounds from Traditional Chinese Medicine for Rheumatoid Arthritis: Exposure–Response Constraints, Causal Mechanisms, and Translational Evidence

Rheumatoid arthritis (RA) is a systemic autoimmune disease sustained by synovial immune–stromal circuits and progressive osteoclast-mediated structural damage. This critical narrative review evaluates 15 chemically defined TCM-derived constituents selected because they have recurrent RA-relevant pharmacology together with sufficient mechanistic, exposure, safety, or translational evidence for comparative appraisal. English-language PubMed and Web of Science searches (January 2010– 31 July 2026, with earlier landmark studies) were used; preclinical evidence was assessed separately from human evidence. Across the literature, reported effects converge on macrophages, RA fibroblast-like synoviocytes (RA-FLSs), T-cell programs, osteoclastogenesis, neutrophil extracellular trap (NET) formation, and recurrent signaling nodes including NF-κB/MAPK, JAK/STAT, PI3K–AKT–mTOR, ROS–Nrf2, NLRP3–caspase-1, RANKL–NFATc1, and HIF-1α–VEGF. However, most isolated compounds remain supported mainly by cell and animal studies, and downstream pathway changes often provide associative rather than causal mechanistic evidence. The strongest human signal concerns standardized Tripterygium wilfordii Hook F (TwHF) products, which must not be equated with isolated triptolide or celastrol. Small trials of formulation-specific curcumin and clinical use of sinomenine provide additional but less definitive signals. Translation is constrained by low or formulation-dependent exposure, active metabolites, product–constituent non-equivalence, toxicity, and limited target-engagement or rescue data. TCM-derived constituents should therefore be viewed as mechanistic leads or potential adjuncts rather than substitutes for guideline-directed DMARD therapy. The most credible development paths are standardized clinically studied botanical products, gut-restricted exposure-aware strategies such as berberine, and chemically defined leads with demonstrated target engagement, clinically achievable exposure, structural benefit, and combination safety.