Inhibiting CD36 palmitoylation improves cardiac function post-infarction by regulating lipid metabolic homeostasis and autophagy.

Alterations in myocardial energy substrate metabolism and mitochondrial injury following myocardial infarction (MI) lead to structural and functional abnormalities of the heart. The fatty acid translocase CD36 (CD36) plays a pivotal role in regulating lipid homeostasis and mitochondrial metabolism. Here, we demonstrate that inhibiting the palmitoylation of CD36 and the resulting alteration in its subcellular localization alleviates lipid metabolism disorders and mitochondrial dysfunction in cardiomyocytes of male mice post-MI. Mechanistically, the inhibition of CD36 palmitoylation enhances cardiac function through a dual mechanism: first, by alleviating fatty acid overload mediated by plasma membrane CD36, thereby restoring lipid metabolic balance; second, by augmenting the activity of the mitochondrial CD36-PGAM5 signaling axis and modulating Fundc1 and Drp1 Dephosphorylation, which subsequently improves mitophagy efficiency. Overall, our study highlights the significant role of CD36 palmitoylation in preserving heart function by regulating downstream metabolic signaling pathways, suggesting that targeting CD36 palmitoylation could be a promising therapeutic strategy for MI.