Lipid peroxidation intrinsically induces mitochondrial iron overload via Bach1-HO-1 signaling to promote cardiac ferroptosis.

Background: Lipid peroxidation and iron accumulation are hallmarks of ferroptosis, a form of cell death characterized by iron-dependent oxidative damage to cellular membranes. However, the molecular link between lipid peroxidation and iron overload in the execution of ferroptosis remains elusive. Moreover, the pathophysiological implications of the interaction between lipid peroxidation and iron overload in cardiac homeostasis and remodeling are also unknown. Methods: We assessed the role of lipid peroxidation in mediating cardiac iron overload and ferroptosis using genetic mouse models. We also performed molecular and cellular biology studies to elucidate the mechanisms by which lipid peroxidation regulates iron homeostasis and ferroptosis signaling in cardiomyocytes. Results: Cardiomyocyte-specific ablation of Gpx4 (glutathione peroxidase 4), a key suppressor of lipid peroxidation, promoted iron overload and ferroptosis in the heart, leading to dilated cardiomyopathy. Mice with heterozygous Gpx4 knockout were also predisposed to adverse cardiac remodeling and dysfunction following pressure overload. Mechanistically, elevated lipid peroxidation due to GPX4 inactivation intrinsically induced iron overload by promoting the nuclear export of Bach1 and subsequent induction of heme oxygenase-1 (HO-1). Genetic and pharmacologic inhibition of HO-1 markedly attenuated iron overload and ferroptosis in cardiomyocytes and rescued dilated cardiomyopathy associated with Gpx4 deficiency. Moreover, we identified HO-1 mitochondrial translocation as a key mechanism driving mitochondrial iron overload and ferroptosis. Targeted inhibition of mitochondrial iron overload or lipid peroxidation abrogated cardiac ferroptosis and pathological remodeling induced by Gpx4 deficiency. Conclusions: These findings identified a mechanistic link between lipid peroxidation and iron overload via the Bach1-HO-1 signaling pathway, revealing new regulators and molecular targets for cardiac ferroptosis.