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

Abstract

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.