Ferroptosis in Anthracycline Cardiotoxicity: Mechanisms, the Cardioprotection Paradox and the Limits of Single-Pathway Thinking.

Anthracyclines remain among the most effective cytotoxic drugs, but their cumulative cardiotoxicity limits dosing and threatens survivors with heart failure. The discovery that doxorubicin kills cardiomyocytes substantially through ferroptosis-an iron-dependent, lipid-peroxidation-driven cell death-has reframed the mechanism and identified a defined target, and the field has rapidly populated with iron chelators, radical-trapping inhibitors and Nrf2/GPX4-activating natural products reported to protect the heart. This review argues that the prevailing enthusiasm is mismatched to the biology in two respects. First, doxorubicin engages several regulated cell-death programmes at once, and ferroptosis operates within a multilayered defence network (GPX4, the FSP1-coenzyme-Q10 axis, mitochondrial DHODH and GTP-cyclohydrolase-1/tetrahydrobiopterin); blocking one node redistributes death and helps explain why ferroptosis inhibitors have failed, and even worsened outcomes, in some doxorubicin models. Second, and more fundamentally, ferroptosis is tumour-suppressive and contributes to the anticancer efficacy of chemotherapy, radiotherapy and immunotherapy, so systemic ferroptosis inhibition to protect the heart risks shielding the tumour-a paradox the cardioprotection literature largely ignores. The single approved agent, dexrazoxane, is acceptable precisely because evidence indicates it spares antitumour efficacy. The path to translatable cardioprotection therefore runs not through broad ferroptosis blockade but through cardiac- and mitochondria-selective, appropriately timed reinforcement of iron handling and lipid-peroxidation defence, validated against hard cardiac endpoints and preserved tumour control. Ferroptosis is a genuine and central mechanism of anthracycline cardiotoxicity; converting that mechanism into safe therapy is a harder problem than the current literature acknowledges.