Advanced Cellular Models for Drug Testing and Discovery to Target Cardiac Fibrosis Progression

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.