Key result
TGF-β, RAAS, and mitochondrial dysfunction drive cardiac fibrosis, highlighting SIRT3 as a key regulatory target.
Why the study?
Cardiac fibrosis drives heart failure progression through complex cellular and molecular mechanisms that require better definition for precise antifibrotic strategies.
This review provides a comprehensive framework for understanding disease-specific fibrotic remodeling and highlights SIRT3 as a potential target for antifibrotic interventions.
SIRT3-targeted antifibrotic strategies remain investigational; review leaves open disease-specific validation in prospective trials.
Cardiac fibrosis is a critical pathological process driving the progression of heart failure, characterized by excessive extracellular matrix deposition, collagen network remodeling, and expansion of the myocardial interstitium. While fibrosis may reflect a reparative response to tissue injury, it can also signify a maladaptive remodeling process that progressively impairs cardiac structure and function. Cardiac fibroblasts and myofibroblasts serve as the principal effector cells responsible for matrix accumulation, whereas cardiomyocytes and immune cells contribute to fibrotic expansion through inflammatory signaling, paracrine communication, and microenvironmental regulation. Transforming growth factor-β, the renin–angiotensin–aldosterone system, inflammatory cytokines, mechanical stress, and metabolic disturbances collectively orchestrate a profibrotic signaling network. By regulating extracellular matrix synthesis, degradation, and crosslinking, these pathways promote myocardial stiffening and functional decompensation. In this review, we discuss the histopathological patterns of cardiac fibrosis across various pathological contexts, the major cellular contributors, and the core molecular mechanisms involved, while summarizing current advances in diagnostic evaluation and translational therapeutic strategies. We further discuss the context-dependent role of sirtuin 3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase, in linking mitochondrial homeostasis, oxidative stress, metabolic adaptation, and profibrotic signaling. More precise antifibrotic strategies require better definition of fibroblast states, fibrosis activity, and disease-specific remodeling patterns.
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Xie et al. (2026) conducted a review in Cardiac fibrosis. Cardiac fibrosis is a complex, context-dependent process driven by multiple signaling networks, including TGF-β, RAAS, and mitochondrial dysfunction, with SIRT3 emerging as a key regulatory target.
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