Journal Article

Fluoxetine disrupts cholesterol metabolism in endothelial cells via SREBP2 activation

Oliveira, Fabiana, Farhan, Muhammad Asad, Karantanou, Christina, Hoffmann, Anne, Sheikh, Bilal N., Arif, Amna, Chakaroun, Rima, Blüher, Matthias, Kyselova, Anastasia, Rodríguez-Aguilera, Jesús Rafael, Martin, Hugo N. G., Hagberg, Carolina E., Klöting, Nora, Yao, He, Geier, Florian, Ambreen, Saira, Ebert, Thomas, Hagemann, Tobias, Stryhanyuk, Hryhoriy, Boeckel, Jes-Niels, Röxe, Tino, Prönnecke, Christoph, Schmidt, Lisa, Papa, Christina, Schipper, Ruby, Shahzad, Khurrum, Buckley, Yuli, Bibli, Sofia-Iris, Zulfqar, Faiqa

2026

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 14/1 / 14/19 / 38/39 / 42/89 / 45/90 / 631/443 / 692/420 / 692/699 / 82/58 / 96/106 / 96/31 / Atherosclerosis / Behavioral Sciences / Biological Psychology / Cell and Molecular Biology / Cell growth / Cell- och molekylärbiologi / Cells, Cultured / Cholesterol / Cholesterol - metabolism / Endoplasmic Reticulum - drug effects / Endoplasmic Reticulum - metabolism / Endothelial Cells - drug effects / Endothelial Cells - metabolism / Fluoxetine - adverse effects / Fluoxetine - pharmacology / Gene expression / Heart attacks / Humans / Lipid Metabolism - drug effects / Lipids / Medicine / Medicine & Public Health / Metabolism / Metabolites / Neurosciences / Pharmacotherapy / Psychiatry / Receptors, LDL - drug effects / Receptors, LDL - metabolism / Selective Serotonin Reuptake Inhibitors - adverse effects / Selective Serotonin Reuptake Inhibitors - pharmacology / Software / Sterol Regulatory Element Binding Protein 2 - drug effects / Sterol Regulatory Element Binding Protein 2 - metabolism / Transcription factors / Up-Regulation - drug effects