Cardiac fibroblasts in extracellular matrix homeostasis and remodeling

Resident cardiac fibroblasts are indispensable regulators of myocardial homeostasis and key effectors of pathological cardiac remodeling. Formerly viewed as passive structural support cells, activated fibroblasts are now recognized as dynamic mediators of extracellular matrix (ECM) turnover, paracrine signaling, and electromechanical coupling within the heart. Fibroblast heterogeneity, defined by developmental origin and microenvironmental cues, further amplifies the complexity of their roles across physiological and pathological contexts. In response to stress or injury, cardiac fibroblasts undergo activation and transition into myofibroblasts, orchestrating wound repair but also driving maladaptive fibrosis when persistently stimulated. This activation is governed by an intricate network of signaling pathways, including transforming growth factor (TGF)-β/SMAD, renin-angiotensin-aldosterone system (RAAS), endothelin-1, RhoA-MRTF (Myocardin-Related Transcription Factor)-SRF (serum response factor), integrins, and inflammatory cytokine cascades, which collectively determine fibroblast phenotype and ECM remodeling outcomes. Their pleiotropic functions encompass ECM synthesis and degradation, regulation of angiogenesis, secretion of cytokines and growth factors, and modulation of cardiomyocyte electrophysiology. In this review, we synthesize current insights into the molecular and cellular mechanisms by which resident naive cardiac fibroblasts regulate cardiac ECM dynamics, with an emphasis on profibrotic signaling networks, transcriptional and developmental regulators, and intercellular cross talk. We also describe how recent lineage-tracing and transcriptomic studies redefine resident cardiac fibroblasts as the dominant drivers of ECM remodeling and fibrosis. We further identify unresolved questions surrounding fibroblast plasticity, their contributions to arrhythmogenesis, and cardiometabolic remodeling. Understanding the context-dependent functions of cardiac fibroblasts is essential to developing targeted antifibrotic interventions that preserve reparative processes while preventing adverse remodeling, ultimately improving outcomes in cardiovascular disease.