NCOA4-mediated ferritinophagy exacerbates heart failure by releasing free iron to promote GPX4-mediated ferroptosis

Heart failure (HF) is typically characterized by high mortality and disability rates. The pathogenesis of HF is complex and multifactorial,the exact pathophysiology of HF remains to be fully elucidated. In our research group, we have discovered that autophagy is a crucial mechanism underlying the development of heart failure, and abnormal iron metabolism (such as ferroptosis) is closely associated with the occurrence and progression of cardiovascular diseases.Thus, through the construction of a rat model of heart failure following myocardial infarction and an H/R H9C2 cell model, we have conducted studies and found that NCOA4, through the classical autophagy pathway mediated by ATG5/ATG7 and in association with LC3B, plays a role in mediating ferritinophagy, controlling the degradation of ferritin. This modulation regulates the concentrations of cellular free iron and labile iron pool, suppresses GPX4 expression, promotes lipid peroxidation and oxidative stress, induces ferroptosis, and exacerbates the severity of heart failure. Our proposed hypothesis elucidates the mechanisms by which autophagy, NCOA4-mediated ferritinophagy, and GPX4-mediated ferroptosis contribute to the development of heart failure under conditions of myocardial ischemia and hypoxia. It helps reconcile many previously contradictory viewpoints and provides a viable pathway for the treatment of post-myocardial infarction heart failure.