PSAP Protects Against Acute Myocardial Ischemia-Reperfusion Injury by Promoting ASAH1-Mediated Ceramide Metabolism.

Myocardial ischemia-reperfusion (I/R) injury remains a leading cause of cardiovascular morbidity. However, due to the unclear underlying molecular mechanisms, effective therapeutic approaches are still lacking. This study aims to investigate the function and downstream mechanism of the lysosomal protein prosaposin (PSAP) in regulating ceramide homeostasis and cardiomyocyte apoptosis during acute I/R injury. In our study, we found that PSAP expression was significantly downregulated in the heart subjected to acute I/R surgery. Restoration of PSAP protein via AAV9-PSAP-OE in vivo significantly reduced infarct size and attenuated cardiomyocyte apoptosis. Similarly, PSAP overexpression in OGD/R-treated primary cardiomyocytes (NRCMs) decreased apoptosis, while PSAP knockdown exacerbated apoptosis. Mechanistically, PSAP accelerates the ceramide degradation pathway by rescuing the expression of the lysosomal N-acylsphingosine amidohydrolase 1 (ASAH1), thereby attenuating I/R-induced ceramide accumulation and cardiomyocyte apoptosis. Our results reveal a novel mechanism of PSAP function and highlight its potential as a therapeutic target for acute myocardial I/R injury.