SIRT1/STAT3 Axis Proposed as Central Regulator of Immune, Inflammatory, and Lipid Dysregulation in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by severe synovial inflammation, joint destruction, and significant systemic comorbidities, notably cardiovascular disease (CVD) linked to dyslipidemia. While the interplay between immune-inflammatory processes and lipid metabolic disturbances is crucial for RA pathogenesis, the precise molecular mechanisms integrating these domains remain poorly understood. Understanding this crosstalk is vital for developing therapies that address both inflammatory and metabolic aspects of the disease, moving beyond traditional siloed approaches.

This review synthesizes current evidence to propose the Sirtuin 1 (SIRT1)/signal transducer and activator of transcription 3 (STAT3) axis as a central regulator in rheumatoid arthritis (RA). Researchers analyzed existing literature on the bidirectional crosstalk between immune-inflammatory processes and lipid metabolic disturbances, focusing on identifying molecular mechanisms that integrate these domains. The review specifically examined the roles of SIRT1 and STAT3 and their interactions in RA pathogenesis.

The review proposes that the SIRT1/STAT3 axis acts as a central regulator of immune, inflammatory, and lipid metabolic dysregulation in rheumatoid arthritis. SIRT1, an NAD+-dependent deacetylase, functions as a metabolic sensor with inherent anti-inflammatory and lipid-regulating properties. Conversely, STAT3 is identified as a potent proinflammatory transcription factor, driving Th17 differentiation, promoting synovial hyperplasia, and contributing to metabolic reprogramming within the disease context. A critical finding is the antagonistic 'yin-yang' relationship between these two factors: > SIRT1 directly deacetylates and inactivates STAT3, thereby establishing a crucial regulatory checkpoint. In RA, chronic inflammation and metabolic stress are posited to suppress SIRT1 activity while simultaneously hyperactivating STAT3. This imbalance creates a detrimental positive feedback loop that perpetuates both immune dysfunction and lipid metabolic abnormalities, exacerbating disease progression.