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

Qingwei Zhang, Jiamin Li, Xin Liu, Ximing Chen, Liwei Zhu, Zhen Zhang, Yingying Hu, Tong Zhao, Han Lou, Henghui Xu, Wenjie Zhao, Xinxin Dong, Zeqi Sun, Xiuxiu Sun, Baofeng Yang () and Yong Zhang ()
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Qingwei Zhang: Harbin Medical University
Jiamin Li: College of Pharmacy, Harbin Medical University
Xin Liu: College of Pharmacy, Harbin Medical University
Ximing Chen: Harbin Medical University
Liwei Zhu: Harbin Medical University
Zhen Zhang: Harbin Medical University
Yingying Hu: Harbin Medical University
Tong Zhao: Harbin Medical University
Han Lou: Harbin Medical University
Henghui Xu: Harbin Medical University
Wenjie Zhao: Harbin Medical University
Xinxin Dong: Harbin Medical University
Zeqi Sun: Harbin Medical University
Xiuxiu Sun: Harbin Medical University
Baofeng Yang: College of Pharmacy, Harbin Medical University
Yong Zhang: Harbin Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61875-y

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