HDACs targeting from traditional Chinese medicine: mechanisms and therapeutic potential in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a complex autoimmune disease driven by dysregulated epigenetic mechanisms, with histone deacetylases (HDACs) playing isoform-specific pathogenic or protective roles by modulating histone acetylation, immune function, and bone metabolism. While HDAC modulators (inhibitors/activators) show therapeutic potential for RA, current single-target agents are limited by poor isoform selectivity, off-target toxicity, and inadequate attenuation of RA's multi-pathway pathology. In addition, the frequent occurrence of pan-assay interference compounds in natural-product space necessitates rigorous validation to reduce false-positive bioactivity claims. In this narrative review, we focus on Traditional Chinese Medicine (TCM)-derived metabolites as promising HDAC modulators, systematically summarizing recent progress in their development for RA. We highlight TCM-derived inhibitors, activators, and dual modulators, along with their isoform-specific mechanisms and structural basis of HDAC interaction. Notably, TCM-derived modulators exert synergistic effects by targeting multiple pathological links in RA, including synovial inflammation, fibroblast-like synoviocyte proliferation, immune imbalance, and bone destruction. However, their clinical translation is hindered by insufficient human clinical data, inconsistent TCM standardization, and limited pharmacokinetic/pharmacodynamic characterization. This review bridges traditional botanical medicine with modern epigenetic drug development, providing insights into RA therapies. Future research should prioritize clinical validation, standardized formulation, and mechanistic refinement to advance TCM-derived HDAC modulators toward clinical application.