PARP7 enhances doxorubicin-induced cardiomyocyte ferroptosis and cardiotoxicity by ADP-ribosylation-dependent suppression of GPX4 activity.

As the roles of poly-ADP-ribose polymerase 7 (PARP7) in tumor immune evasion become increasingly well defined, PARP7 inhibitors have emerged as a promising class of anticancer therapeutics. To date, phase I clinical trials of PARP7 inhibitors have reported no significant cardiovascular adverse events. However, PARP7's involvement in doxorubicin (DOX)-induced cardiotoxicity (DIC), a major clinical limitation of widely used chemotherapeutics, remains poorly understood. Elucidating the functional role of PARP7 in this pathological context is essential for evaluating the therapeutic safety of pharmacological PARP7 inhibition. This study aimed to define the functional role and molecular mechanism of PARP7 in DIC. We demonstrate that PARP7 is robustly and selectively upregulated in cardiomyocytes following DOX exposure. Genetic ablation of PARP7 markedly attenuates DIC. Mechanistically, we identify glutathione peroxidase 4 (GPX4) as a direct ADP-ribosylation substrate of PARP7. PARP7 catalyzes mono-ADP-ribosylation of GPX4, leading to its loss of enzymatic activity. In addition, this suppression of GPX4 is both necessary and sufficient for PARP7-driven ferroptosis in cardiomyocytes. Importantly, cardiomyocyte-specific PARP7 knockdown, achieved via AAV9-cTNT-mediated delivery of short hairpin RNA, effectively reverses established DIC, confirming its therapeutic relevance in clinical translation. Collectively, these findings establish PARP7 as a druggable, cardiomyocyte- specific regulator of ferroptosis and define the PARP7-GPX4 axis as a mechanistically grounded, therapeutically targetable pathway in cardio-oncology.