Abstract
Ischemic heart disease is a leading cause of death worldwide. Myocardial infarction (MI) results in cardiac damage due to cell death and insufficient cardiomyocyte self-renewal. Ferroptosis, a novel type of cell death, has recently been shown as a key cause of cardiomyocyte death after MI. However, the complicated regulation mechanisms involved in ferroptosis, especially how ferroptosis is integrated into classical cell survival/death pathways, are still unclear. Here, we discovered that HIP-55, a novel adaptor protein, acts as a hub protein for the integration of the ferroptosis mechanism into the classical AKT cell survival and MAP4K1 cell death pathways for MI injury. The expression of HIP-55 is induced in MI. Genetic deletion of HIP-55 increased cardiomyocyte ferroptosis and MI injury, whereas cardiac-specific overexpression of HIP-55 significantly alleviated cardiomyocyte ferroptosis and MI injury. Mechanistically, HIP-55 was identified as a new AKT substrate. AKT phosphorylates HIP-55 at S269/T291 sites and further HIP-55 directs AKT signaling to negatively regulate the MAP4K1 pathway against MI injury in a site-specific manner. S269A/T291A-mutated HIP-55 (HIP-55AA), which is defective in AKT phosphorylation and significantly decreases the interaction between HIP-55 and MAP4K1, failed to inhibit the MAP4K1/GPX4 ferroptosis pathway. In line with this mechanism, cardiac-specific overexpression of HIP-55WT mice, but not cardiac-specific overexpression of HIP-55AA mice, protected cardiomyocytes against MI-induced ferroptosis and cardiac injury in vivo. These findings suggest that HIP-55 rewired the classical AKT (cell survival) and MAPK (cell death) pathways into ferroptosis mechanism in MI injury. HIP-55 may be a new therapeutic target for myocardial damage.