Fibrosis is a fundamental pathological process driving heart failure progression by promoting extracellular matrix deposition and impairing myocardial compliance. In recent years, the sirtuin family of NAD⁺-dependent deacetylases, traditionally linked to aging and metabolism, has emerged as a key regulator of cardiac fibrotic remodeling. This review investigates the roles of sirtuins in mitigating cardiac fibrosis, with emphasis on mechanisms such as mitochondrial preservation and the therapeutic potential of their modulation. Sirtuin signaling attenuates fibrosis by regulating intracellular pathways that control fibroblast activation. In particular, sirtuin-mediated deacetylation modulates pro-fibrotic mediators, including the TGF-β/Smad pathway, thereby reducing collagen synthesis and fibrotic gene expression. However, their effects are isoform- and context-dependent: SIRT1, SIRT3, SIRT6, and SIRT7 generally exert protective roles, whereas SIRT2 and SIRT5 may display neutral or even pro-fibrotic actions depending on the cell type, disease stage, and experimental context. Recognizing this complexity is essential to evaluate their therapeutic relevance. Building on these mechanistic insights, the review explores the preclinical development of sirtuin-targeted therapies. Strategies include NAD⁺ precursors, natural compounds, novel small-molecule activators with enhanced specificity, and agents that indirectly stimulate sirtuins through metabolic modulation. Such approaches highlight the potential of pharmacologically enhancing sirtuin activity to counteract maladaptive cardiac remodeling and improve outcomes in heart failure. By integrating molecular insights with advances in pharmacology, this review synthesizes the most recent mechanistic findings from the past three years with a dedicated focus on the translational challenges and opportunities of pharmacologically targeting sirtuins for anti-fibrotic therapy.
