Metabolic-Epigenetic Reprogramming of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis: Perspectives for Traditional Chinese Medicine.

BACKGROUND

In rheumatoid arthritis (RA), persistent synovial inflammation and clinical relapse cannot be fully explained by immune activation alone, as fibroblast-like synoviocytes (FLS) can acquire stable pathogenic states that sustain synovitis and joint destruction. Metabolic reprogramming and epigenetic remodeling are functionally integrated in RA-FLS, thereby promoting hyperproliferation, invasiveness, apoptosis resistance, and inflammatory memory.

METHODS AND

RESULTS

In this review, we summarize the interplay between altered cellular metabolism and epigeneticmechanisms, including DNA methylation, histone modifications, non-coding RNAs, RNA modifications, and chromatin remodeling, and discuss how this interplay contributes tostabilizing pathogenic FLS phenotypes.We further discuss gut microbiota-associated metabolites, including short-chain fatty acids, bile acids, tryptophan derivatives, and one-carbon metabolites, as potential mediators linking systemic metabolic imbalance to FLS epigenetic states. These metabolites may act through histone deacetylase (HDAC) inhibition, modulation of methyl donor availability, and receptor-mediated inflammatory signaling. From the perspective of Traditional Chinese Medicine (TCM), we propose that TCM formulations and bioactive compounds may modulate this network through microbiota-dependent metabolic remodeling and direct suppression of FLS activation. Finally, we identify current evidence gaps and highlight emerging therapeutic strategies, including metabolomics-guided fecal microbiota transplantation and FLS-targeted epigenetic interventions.

CONCLUSION

This review highlights metabolic-epigenetic reprogramming as a key mechanism underlying persistent RA-FLS phenotypes. Interactions among thegut microbiota, microbial metabolites, and epigenetic regulation provide a promising framework for linking systemic metabolic disturbances to local joint damage. Future studies integrating multi-omics profiling, microbiome modulation, and FLS-targeted epigenetic interventions are needed to clarify causality and facilitate more precise therapeutic strategies.