Ferroptosis as a Master Regulator of Anthracycline-Induced Cardiotoxicity: Mechanistic Insights, Biomarkers, and Emerging Cardioprotective Strategies
Author(s):
Afrah Thiab Hlail
Date: 09/10/2026
doi: https://doi.org/10.5281/zenodo.8425890
Abstract
Background: Anthracyclines, especially doxorubicin, are a key element of curative chemotherapy but are
associated with dose-limiting and sometimes permanent cardiotoxicity. For decades, the prevailing
theories have been oxidative stress and topoisomerase IIβ-mediated DNA damage, but neither fully
explains cardiomyocyte sensitivity. Much of this injury occurs via ferroptosis, a type of iron-dependent
programmed cell death involving lipid peroxidation. This discovery has changed the field and opened new
therapeutic avenues. Doxorubicin forms redox-active complexes with intracellular iron, resulting in heme
oxygenase-1-mediated free iron release, intercalates into mitochondrial DNA to interfere with heme
synthesis, and downregulates glutathione peroxidase 4, causing mitochondrial lipid peroxidation and
cardiomyocyte death. Iron chelation with dexrazoxane and ferroptosis inhibitors such as ferrostatin-1 and
liproxstatin-1 ameliorated this injury in rodent models, but a landmark study showed that these inhibitors
did not protect human induced pluripotent stem cell-derived cardiomyocytes, indicating a species
dependent translational gap. Statins and sodium-glucose co-transporter-2 inhibitors provide modest,
mechanistically distinct cardioprotection in clinical cohorts. Troponin, natriuretic peptides, and growth
differentiation factor-15 provide complementary, but imperfect, early detection. Ferroptosis as a shared
injury pathway reinterprets anthracycline cardiotoxicity as a pharmacologically tractable process rather
than an unavoidable trade-off, informing cardio-oncology risk stratification, biomarker-guided
monitoring, and rational combination cardioprotective strategies. The priorities include closing the
murine-to-human translational gap in the efficacy of ferroptosis inhibitors, developing clinically validated
biomarkers, and testing iron-directed and systemic cardioprotective combination regimens in adequately
powered, biomarker-stratified clinical trials.
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