Cardiac organoids bridge translational gaps in 3R-compliant safety testing

Cardiotoxicity remains a leading cause of late-stage drug attrition and post-marketing withdrawal, underscoring persistent limitations in current preclinical safety assessment paradigms. Traditional animal models are constrained by interspecies differences in electrophysiology, ion channel composition, myocardial remodeling, and pharmacokinetics, while two-dimensional human induced pluripotent stem cel-derived cardiomyocytes (hiPSC-CMs) lack tissue-level, functional maturity, organization and multicellular complexity. These limitations create a translational gap between cellular assays and whole-organ physiology. Human cardiac organoids represent an emerging mesoscopic platform that bridges this gap by integrating three-dimensional architecture, electromechanical coupling, and multicellular interactions within a human genetic context. Unlike isolated cardiomyocytes, cardiac organoids support coordinated conduction, arrhythmic susceptibility, force generation, extracellular matrix remodeling, and emerging neurocardiac crosstalk. These properties position them as promising tools for implementing the 3Rs (Replacement, Reduction, Refinement) in early-stage cardiovascular drug development. This review critically evaluates the biological fidelity, functional capabilities, and disease modeling relevance of human cardiac organoids, and examines their potential integration into safety pharmacology frameworks. We propose that cardiac organoids constitute a critical intermediate layer between reductionist cellular systems and whole-organ models. Finally, we delineate the scientific and regulatory steps, including standardization and validation against established frameworks, required to transition them from exploratory research tools to robust platforms for predictive and ethically aligned cardiovascular safety assessments.