A novel mTORC1-NPC2 axis suppresses lipophagy and drives atherosclerotic plaque progression

Endothelial dysfunction is a critical initiating factor in atherosclerosis (AS), with NPC2 and mTORC1 playing key roles in the regulation of endothelial lipophagy.

To reveal that hypercholesterolemia disrupts endothelial lipophagy via the mTORC1-NPC2 axis and to explore its role in atherosclerotic progression.

Thirty AS patients and 30 healthy controls were enrolled. Lipophagy markers in endothelial cells isolated from plaque and non-plaque regions were assessed. Exosomes were characterized and their effects on endothelial viability were evaluated. Multi-omics analyses identified key differentially expressed pathways, which were validated in a high-cholesterol diet mouse model and in human aortic endothelial cells (HAoECs) using pharmacological activation, knockout, and molecular interaction assays.

AS patients showed significantly elevated serum cholesterol and suppressed lipophagy in plaque-derived endothelial cells. Plaque-derived exosomes inhibited endothelial cell viability and promoted injury marker expression. mTOR signaling was identified as a candidate activated pathway in plaque endothelium, and pharmacological activation of mTOR in HAoECs was associated with impaired lipophagy. Rapamycin attenuated HCD-induced mTOR activation and lipid accumulation in mice. GST pull-down and molecular docking supported a potential association between mTOR and NPC2, while NPC2 deficiency attenuated the rapamycin-associated restoration of lipophagy and lipid homeostasis.

Hypercholesterolemia disrupts endothelial lipophagy through the mTORC1-NPC2 signaling axis, promoting lipid accumulation and accelerating atherosclerosis. Targeting this pathway may offer a novel therapeutic strategy for AS.