Authors
Fabiana Oliveira, Christina Papa, Tobias Hagemann, Ruby Schipper, Florian Geier, Tino Röxe, Faiqa Zulfqar, Christoph Prönnecke, Lisa Schmidt, Hryhoriy Stryhanyuk, Anne Hoffmann, Anastasia Kyselova, Christina Karantanou, Yuli Buckley, Muhammad Asad Farhan, Jesús Rafael Rodríguez-Aguilera, Saira Ambreen, He Yao, Amna Arif, Hugo N G Martin, Thomas Ebert, Nora Klöting, Matthias Blüher, Khurrum Shahzad, Jes-Niels Boeckel, Carolina E Hagberg, Rima Chakaroun, Sofia-Iris Bibli, Bilal N Sheikh
Published in
Translational psychiatry. Volume 16. Issue 1. Jun 23, 2026. Epub Jun 23, 2026.
Abstract
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) commonly prescribed for the treatment of depressive disorders. Recent clinical reports and studies in animal models have suggested that fluoxetine increases the risk of cardiovascular diseases, but the underlying mechanisms remain unknown. Here, we uncover that fluoxetine disrupts lipid and cholesterol metabolism in primary human endothelial cells (ECs). Fluoxetine triggered an upregulation of cholesterol metabolism genes, leading to the accumulation of lipid droplets in ECs. We find higher levels of cholesterol esters, ceramides, sphingolipids and fatty acids in ECs treated with fluoxetine. The disruption of lipid homeostasis was driven by increased cholesterol biosynthesis, as well as low-density lipoprotein (LDL) uptake and transcytosis via the LDL receptor. Fluoxetine accumulated in ECs in the endoplasmic reticulum (ER), caused ER expansion and reduced protein translation, without inducing ER stress markers. Mechanistically, fluoxetine activated the SREBP2 transcription factor in an INSIG-dependent manner. SREBP2 inhibition attenuated the fluoxetine-mediated upregulation of the LDL receptor and lipid accumulation. Our findings reveal that fluoxetine reprograms lipid metabolism and leads to endothelial dysfunction.
PMID:
42337263
Bibliographic data and abstract were imported from PubMed on 24 Jun 2026.
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