GIPC1 remodels lipid metabolism by transporting DECR1 into mitochondria against ferroptosis during dilated cardiomyopathy (DCM)

Abstract Dilated cardiomyopathy (DCM) is a globally prevalent heart muscle disease with high morbidity and mortality. The scaffolding protein GIPC1 plays a key role in the trafficking and regulation of transmembrane receptors. However, the potential role of GIPC1 in DCM remain obscure. In this study, we discovered that the expression of GIPC1 was decreased in DCM patients and DOX-induced mice DCM. Knockout of GIPC1 further deteriorated DOX-induced DCM. While overexpression of GIPC1 mitigated DCM-induced cardiac dysfunction. Furthermore, knockdown of GIPC1 inhibited FAO and mitochondrial metabolism, which led to the PUFAs accumulation-induced ferroptosis. Conversely, overexpression of GIPC1 protected DCM against ferroptosis. Mechanistically, GIPC1 regulated the actin-based transport of DECR1 into mitochondria for lipid metabolism. This study suggested that GIPC1 remodels lipid metabolism by transporting DECR1 into mitochondria, which may protect cardiac myocytes against ferroptosis in DCM.