Tilianin counteracts doxorubicin-induced myocardial injury by downregulating mitophagy-dependent ferroptosis

Doxorubicin (DOX)-induced cardiotoxicity (DIC) remains a major clinical limitation of this widely used chemotherapeutic agent. Dracocephalum moldavica L., a traditional Uyghur medicinal herb used for cardiovascular disorders, contains the flavonoid Tilianin (Til). Although Til exhibits reported cardioprotective properties, whether and how it mitigates DIC remains incompletely understood. In this study, we established DIC models in H9c2 cardiomyocytes and C57BL/6N mice and performed transcriptomic profiling to identify underlying mechanisms. Pharmacological interrogation using mitochondrial modulators (carbonyl cyanide m-chlorophenylhydrazone and cyclosporin A) and a ferroptosis inhibitor (ferrostatin-1) revealed that DOX triggers excessive mitophagy, leading to mitochondrial iron release and lipid peroxidation, ultimately driving mitophagy-dependent ferroptosis in cardiomyocytes. Til intervention attenuated DOX-induced cardiac dysfunction and myocardial injury in vivo and protected H9c2 cells from cytotoxicity in vitro by suppressing overactivated mitophagy and partially restoring iron homeostasis. These findings demonstrate that Til confers cardioprotection against DIC through modulation of the mitophagy-ferroptosis axis, supporting its potential as a candidate agent for managing chemotherapy-related cardiac injury.