Ferroptosis regulation in doxorubicin-induced cardiotoxicity: multi-mechanism interventions and translational...

Doxorubicin (DOX), a highly effective anthracycline chemotherapy drug, has its clinical application severely restricted by dose-dependent doxorubicin-induced cardiotoxicity (DIC). Ferroptosis, an iron-dependent, lipid peroxidation-driven regulated cell death, has been confirmed as a core pathological mechanism in DIC, where it synergistically participates with multiple cell death modalities in myocardial injury. This review systematically elaborates the multidimensional molecular mechanisms underlying DOX-induced myocardial ferroptosis, including: lipid peroxidation cascade self-amplification, bidirectional regulation by selective autophagy, multilayered GPX4 modification and stability regulation, and involvement of the gut microbiota-heart axis. Concurrently, we summarize evidence for natural phytochemicals-including flavonoids, polyphenols, terpenoids, and traditional Chinese medicine compounds-that inhibit myocardial ferroptosis via multi-target mechanisms, providing theoretical support for phytochemical-based DIC intervention. Critically, this review addresses the clinical translation dilemmas in ferroptosis regulation and proposes three innovative strategies: (1) time-decoupling strategy based on IFN-γ signaling; (2) cardiac-targeted nanodrug delivery system employing the OGF/OGFR axis; (3) cross-regulation between ferroptosis and other regulated cell death pathways. These strategies aim to achieve tissue-selective ferroptosis intervention, simultaneously protecting myocardium while maintaining DOX anti-tumor efficacy, thereby providing molecular mechanistic basis and clinical translational directions for constructing precision ferroptosis-targeted cardioprotective strategies.