Cross-modal integration of metabolomics and cardiac functionality captures dynamic metabotoxic effects of doxorubicin in engineered heart tissues

Functional stem cell-derived heart models offer new avenues for preclinical, animal-free physiological assessment of drug cardiotoxicity. Yet, comprehensive molecular profiling in these models remains limited, leaving key metabolic drivers of cardiotoxicity unexplored. Here, we leveraged an innovative platform and a topology-guided integration framework to unveil the complex dose- and time-dependent metabolic rewiring of the central carbon metabolism caused by doxorubicin-induced cardiotoxicity (DiC) in human heart tissue. Through cross-modal integration of cardiac functionality and metabolomics in 3D engineered heart tissues, we identified 20 metabolites linked to cardiac contraction and differentially affected by doxorubicin exposure. Nine of them, including carnitine esters and uridine 5'-diphosphate (UDP)-glucuronic acid, were never before implicated in DiC and may represent promising candidates for DiC metabolic rescue. By yielding high-resolution insights into complex biological mechanisms, our platform and mathematical framework enable metabolic and functional assessment of cardiotoxicity in engineered heart models, paving the way for innovative advances in preclinical drug development.