The role of the resveratrol-sirtuin axis in the treatment of metabolic dysfunction-associated diseases

Abstract

Obesity, diabetes mellitus (DM), metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiovascular diseases (CVDs) share pathogenic mechanisms like oxidative stress and inflammation. Resveratrol (RSV) offers therapeutic potential by activating the sirtuin (SIRT) signaling network. This review synthesizes RSV’s pharmacological impacts on adipose, pancreatic, hepatic, and cardiovascular tissues, focusing on the AMPK/SIRT1/PGC-1α axis, PI3K/AKT pathways, and epigenetic modulations. Despite robust preclinical data, a significant translational gap exists. Clinical evidence is heterogeneous, often contradicting animal studies due to varying dosages, durations, and population characteristics. RSV acts as a pan-SIRT activator, though its precise SIRT1 activation mechanism, direct or via NAD⁺ modulation, remains debated. In obesity, RSV promotes adipose beiging and thermogenesis, yet clinical weight loss is modest. For DM, it preserves β-cell function and improves insulin sensitivity, primarily benefiting diabetic populations with variable glycemic outcomes. In MASLD, RSV ameliorates steatosis and fibrosis in models, but large-scale human trials confirming histological benefits are lacking. Regarding CVDs, RSV protects against endothelial dysfunction and inflammation, showing minor improvements in biomarkers like blood pressure, though hard endpoints need validation. Major limitations hinder clinical efficacy, such as poor oral bioavailability, rapid metabolism, and significant interindividual pharmacokinetic variability. The lack of standardized formulations further complicates systemic exposure. Nevertheless, the RSV-SIRT axis remains a unified metabolic and epigenetic modulator, stabilizing cellular microenvironments across organ systems. It represents a promising target for complex metabolic syndromes. Future research should prioritize overcoming bioavailability challenges through novel delivery systems and investigating synergistic combinatorial therapies to bridge the gap between preclinical promise and clinical reality.

Keywords

resveratrol / sirtuin / NAD⁺ / obesity / diabetes mellitus / metabolic dysfunction-associated steatotic liver disease / cardiovascular diseases

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