Mechanisms of the RGS12-GPX4-ACSL4 signaling axis in regulating ferroptosis during myocardial ischemia-reperfusion injury.

Abstract

Acute myocardial infarction (AMI) is one of the leading causes of death worldwide. Timely reperfusion therapy following AMI can effectively salvage ischemic cardiomyocytes. However, myocardial ischemia-reperfusion injury (MIRI), which inevitably occurs during the process of blood supply recovery, may affect the therapeutic outcome. During MIRI, various forms of cell death, such as apoptosis, autophagy and pyroptosis, are involved. Ferroptosis is a recently discovered form of programmed cell death. Studies have shown that ferroptosis is closely related to the progression of MIRI. In the regulation of ferroptosis, GPX4 inhibits ferroptosis by clearing lipid peroxides, whereas ACSL4 promotes lipid peroxidation and drives ferroptosis. In addition to known regulatory factors, recent studies have found that Regulator of RGS12, a key protein in the RGS family, plays an important role in ischemia-reperfusion injury. The deletion of Regulator of RGS12 significantly reduces the incidence of ferroptosis in cardiomyocytes, whereas its overexpression exacerbates ferroptosis. This phenomenon may be related to the regulation of iron metabolism-related signaling pathways by RGS12. This review aims to summarize the molecular mechanisms by which RGS12 influences the progression of ferroptosis through regulating GPX4 and ACSL4 expression, thereby contributing to MIRI.