Abstract
Drug-induced cardiotoxicity (DICT) severely hampers drug development and threatens patient safety. Together with the growing global burden of cardiovascular disease, there is an urgent need to establish more predictive preclinical models. Recently, human pluripotent stem cell-derived cardiac organoids (hCOs) have emerged as a promising three-dimensional in vitro model, achieving significant progress in simulating the complex structure and function of the human heart. However, existing reviews predominantly focus on technical construction or specific applications, lacking an integrated discussion of pathological model construction and their use under evolving regulatory frameworks. This review distinguishes itself by proposing a novel, holistic framework that bridges "construction technology," "pathological modeling," and "application evaluation." We systematically categorize and summarize three major strategies for building hCO-based pathological models: patient-specific, gene-edited, and microenvironment-modulated approaches. Furthermore, we highlight the unique advantages of hCOs in preclinical drug assessment and detail their cutting-edge applications in early DICT warning, metabolism-related safety evaluation, and personalized drug evaluation. Finally, we address current challenges, including maturation and standardization, and outline future directions involving integration with organ-on-a-chip technology and artificial intelligence. This review aims to provide a theoretical foundation and roadmap toward more reliable and human-relevant drug development paradigms.