SIRT1 as a Key Regulator in Rheumatic Diseases: Integrating Molecular Insights with Traditional Chinese Medicine...

Rheumatic diseases are characterized by chronic inflammation and immune dysregulation that profoundly impair patients' quality of life, yet their underlying pathogenic mechanisms remain incompletely elucidated. Sirtuin 1 (SIRT1), an NAD⁺-dependent deacetylase, has emerged as a pivotal regulatory hub that integrates inflammatory signaling, cellular stress responses, metabolic reprogramming, and epigenetic control. Through key pathways (e.g. NF-κB and AMPK), SIRT1 modulates immune activation, synovial pathology, cartilage degeneration, and systemic inflammatory phenotypes across a spectrum of major rheumatic diseases, including rheumatoid arthritis (RA), osteoarthritis (OA), systemic lupus erythematosus (SLE), and gout. To summarize the current body of evidence, we conducted a targeted literature search across major databases (e.g. PubMed and Web of Science) for publications published up to 2025. We included peer-reviewed original studies and reviews that investigated (a) SIRT1 expression/activity and its downstream mechanisms in rheumatic diseases, or (b) traditional Chinese medicine (TCM) compounds or formulations with experimental or clinical evidence of SIRT1 modulation. We synthesized mechanistic insights spanning immunometabolism, inflammasome regulation, autophagy/ferroptosis, and non-coding (nc)RNA-mediated epigenetic networks. Additionally, we critically discussed context-dependent-and at times conflicting-observations across experimental models and human studies. Furthermore, we evaluated the current landscape of TCM-based SIRT1 modulation and found that most evidence remains preclinical; translational efforts are constrained by bioavailability, standardization, dosing, and reproducibility. Taken together, this integrative review highlights SIRT1 as a biologically important but context-dependent regulatory node in rheumatic diseases. It also emphasizes that SIRT1-targeted interventions (including TCM-derived modulators) require biomarker-guided stratification, pharmacological validation, and rigorously designed clinical studies before they can be translated into clinical practice.