Fluoxetine disrupts cholesterol metabolism in endothelial cells via SREBP2 activation

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) widely prescribed for the treatment of depressive disorders. However, its long-term cardiovascular safety remains unknown. Here, we report an association between fluoxetine intake and an increased risk of cardiovascular diseases in the UK biobank cohort . In PCSK9-overexpression mouse model of atherosclerosis and primary human endothelial cells (ECs), we uncover that fluoxetine deregulates lipid and cholesterol metabolism. Fluoxetine triggered an upregulation of cholesterol metabolism genes in ECs, leading to accumulation of lipid droplets, with higher levels of cholesterol esters, ceramides, sphingolipids and fatty acids. The disruption of lipid homeostasis was associated with increased cholesterol biosynthesis, and low-density lipoprotein (LDL) uptake in ECs via the LDL receptor. Mechanistically, fluoxetine activates the SREBP2 transcription factor, and SREPB2 inhibition attenuates lipid accumulation in ECs. Our findings reveal a mechanism through which fluoxetine-induced reprogramming of lipid metabolism in ECs can contribute to cardiovascular diseases.