Cardiac fibrosis is a key physiopathological process underlying the progression of virtually all heart diseases and related conditions, including myocardial infarction, pressure overload, and heart failure. Once regarded as a homogeneous and passive population, cardiac fibroblasts are now recognized as highly heterogeneous and dynamic, comprising distinct subpopulations with specialized molecular and functional identities. These subpopulations include resident fibroblasts, activated myofibroblasts, matrifibrocytes, inflammatory fibroblasts, and senescent fibroblasts, each contributing uniquely to extracellular matrix (ECM) remodeling, cytokine secretion, and intercellular crosstalk. Recent advances in single-cell transcriptomics, lineage tracing, and epigenetic profiling have revealed the plasticity and phenotypic transitions of cardiac fibroblasts in both physiological and pathological contexts. This review synthesizes current knowledge on fibroblast diversity in the adult heart, including their embryological origins and anatomical distribution, and explores how these insights could guide the development of precision anti-fibrotic therapies. We discuss a selection of emerging therapeutic strategies, including subtype-specific targeting (e.g., anti-POSTN, anti-IL1β), modulation of key signaling pathways (e.g., TGF-β, Wnt, Notch), with a brief mention also of novel approaches based on non-coding RNAs and epigenetic regulators. A better understanding of cardiac fibroblast heterogeneity holds significant potential for the design of more specific cell-type and context-tailored interventions, moving toward more effective and personalized treatments for cardiac fibrosis and its sequelae.

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.

Cardiac fibrosis is a complex and dynamic pathological process, central for cardiac repair, characterised by continuous cell–cell and cell–matrix interactions. Three-dimensional (3D) models are gaining increasing relevance, compared with traditional two-dimensional (2D) cellular setups, due to their ability to recapitulate key features of the fibrotic microenvironment at different levels of complexity, including cellular heterogeneity, spatial organisation and tissue mechanical properties. These systems have enabled a deeper investigation of fibrosis mechanobiology and the mechanosensitive pathways involved in disease progression, contributing to the identification of potential therapeutic targets for cardiac repair. Increasing biological complexity can reveal therapeutic responses that remain undetected in conventional models; however, the predictive value of 3D systems has so far been confirmed in vivo only for a limited number of platforms and compounds. The role of 3D models is therefore expanding beyond disease modelling towards platforms for the screening and evaluation of antifibrotic strategies, pointing to increasingly functional cardiac reparative strategies. Here, we distinguish model complexity, biological fidelity and demonstrated predictive value, compare current platforms according to their validation level and limitations, and discuss the benchmarks and standards required for their routine use in antifibrotic drug discovery. From this perspective, the development of systems that are not necessarily more sophisticated, but progressively more informative and predictive, may help bridge the gap between conventional 2D in vitro models and animal studies, ultimately improving the translational relevance of preclinical evaluation.