Abstract Ferroptosis is the form of regulated cell death driven by iron-induced lipid peroxidation, implicated in different cardiovascular diseases and especially heart failure. It is an abundant form of regulated cell death in the myocardium of many heart failure animal models, including the chronic ischemic, pressure overload, diabetic, septic, obesity-related and doxorubicin-induced cardiomyopathy models. Across these models, disordered iron handling, antioxidant failure, enzymatic phospholipid peroxidation, and mitochondrial stress converge on ferroptosis, leading to contractile dysfunction and adverse remodelling. Although definitive causality between ferroptosis and heart failure has not yet been established, emerging evidence suggests that ferroptosis contributes to heart failure progression, supported by multi-layer rescue with classic inhibitors (ferrostatin-1, liproxstatin-1, iron chelators) and by cardiometabolic drugs with clinical efficacy in heart failure (Sodium–Glucose Cotransporter 2 inhibitors, sacubitril/valsartan, finerenone, levosimendan, nicorandil) as well as polyphenols, which restore systolic and/or diastolic indices and reverse remodelling. Early human evidence aligns, showing that human failing myocardial and epicardial adipose tissue exhibit ferroptosis-specific transcriptional and lipidomic signatures, while circulating biomarkers and tissue profiles of patients receiving SGLT2 inhibitors indicate reduced ferroptosis activity. In this review, through critical synthesis of existing evidence, we analyse current literature, discuss translational barriers and propose a new conceptual mechanistic framework – “the ferroptosis nexus” - wherein iron mobilization, antioxidant collapse, lipid priming, and mitochondrial/calcium amplifiers form a self-reinforcing loop culminating in pump failure. Standardized ferroptosis signatures, single cell and spatial transcriptomics analysis, and mechanism-driven clinical trials are needed to identify responsive heart failure phenotypes and translate ferroptosis modulation into precision cardioprotection.
Karampinos et al. (2026) studied this question.