Cardiac Fibrosis as a Dynamic Therapeutic Target: Overcoming Translational Barriers to Antifibrotic Therapy.

Cardiac fibrosis is a central feature of many cardiovascular diseases, contributing to myocardial stiffening, electrical dysfunction, and progression to heart failure. Despite its clinical importance, no therapy directly targeting myocardial fibrosis is currently established in practice. Advances in the understanding of cardiac fibroblast biology and profibrotic signaling pathways, including transforming growth factor-β and neurohormonal activation, have driven the development of multiple antifibrotic strategies in preclinical models, ranging from small molecules to gene- and cell-based approaches. However, translation into clinical benefit has remained limited, with existing evidence largely derived from early-phase studies that rely on indirect imaging or biomarker-based assessments. This review examines the mechanisms underpinning cardiac fibrosis and evaluates current antifibrotic strategies across key cardiovascular conditions from a translational perspective. We argue that translational failure arises not simply from ineffective therapies, but from a mismatch between the biological complexity of human fibrotic remodeling and the simplified paradigms underpinning current therapeutic development. We highlight key barriers to translation, including limitations of experimental models, fibroblast heterogeneity, temporal dependence of therapeutic efficacy, challenges in fibrosis assessment, and constraints in trial design. We further outline emerging strategies to bridge the translational gap.