SIRT1 in Cardiac Diseases: Molecular Mechanisms, Therapeutic Potential, and Future Directions

Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD⁺)-dependent class III histone deacetylase, functions as a central metabolic sensor and stress-responsive regulator in the cardiovascular system. Unlike its well-characterized role in atherosclerosis, SIRT1 exerts multifaceted protective effects directly on cardiac tissue. This review synthesizes recent advances in understanding SIRT1-mediated cardioprotection across a spectrum of heart diseases, including myocardial ischemia/reperfusion (I/R) injury, heart failure (HF), diabetic cardiomyopathy (DCM), cardiac hypertrophy, aging-related cardiac dysfunction and circadian rhythm disruption. Mechanistically, SIRT1 orchestrates antioxidant defense through nuclear factor erythroid 2-related factor 2 (Nrf2) and Forkhead box O (FoxO) transcription factors activation, suppresses inflammatory signaling via nuclear factor kappa B (NF-κB) deacetylation, inhibits apoptosis by targeting p53, promotes autophagic flux and mitophagy, regulates mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and controls ferroptosis via the Nrf2/glutathione peroxidase 4 (GPX4) axis. Preclinical studies demonstrate that natural compounds (resveratrol, quercetin, curcumin, ginsenosides, tanshinone IIA, bergenin, swietenine) and synthetic SIRT1 activators (SRT1720, anilinopyridine derivatives) attenuate cardiac injury and improve function. Moreover, SIRT1 serves as a prognostic biomarker in HF and diabetic patients. However, context-dependent dual roles, where excessive SIRT1 expression may be detrimental, underscore the need for precise modulation. Challenges remain in achieving cardiac-specific targeting, optimizing NAD⁺ availability, and translating preclinical findings into clinical practice. Future research should integrate multi-omics approaches, single-cell transcriptomics, and precision medicine strategies to unlock the therapeutic potential of SIRT1 in cardiac diseases.