2. Academic Validation
  3. Fluoxetine disrupts cholesterol metabolism in endothelial cells via SREBP2 activation

Fluoxetine disrupts cholesterol metabolism in endothelial cells via SREBP2 activation

  • Transl Psychiatry. 2026 Jun 23;16(1):318. doi: 10.1038/s41398-026-04197-x.
Fabiana Oliveira 1 2,  Christina Papa 1,  Tobias Hagemann 1,  Ruby Schipper 3 4,  Florian Geier 1,  Tino Röxe 5,  Faiqa Zulfqar 1,  Christoph Prönnecke 6,  Lisa Schmidt 6,  Hryhoriy Stryhanyuk 6,  Anne Hoffmann 1,  Anastasia Kyselova 7,  Christina Karantanou 7,  Yuli Buckley 1,  Muhammad Asad Farhan 8,  Jesús Rafael Rodríguez-Aguilera 1,  Saira Ambreen 8,  He Yao 1,  Amna Arif 8,  Hugo N G Martin 1,  Thomas Ebert 9,  Nora Klöting 1,  Matthias Blüher 1 9,  Khurrum Shahzad 8,  Jes-Niels Boeckel 5,  Carolina E Hagberg 3 4,  Rima Chakaroun 9 10,  Sofia-Iris Bibli 7 11 12,  Bilal N Sheikh 13 14 15 16
Affiliations

Affiliations

  • 1 Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich, Leipzig, Germany.
  • 2 Faculty of Medicine, University of Leipzig, Leipzig, Germany.
  • 3 Department of Medicine Solna, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden.
  • 4 Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
  • 5 Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig, Germany.
  • 6 Department of Technical Biogeochemistry, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany.
  • 7 European Center for Angioscience, Department of Vascular Dysfunction, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
  • 8 Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.
  • 9 Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.
  • 10 Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
  • 11 German Centre for Cardiovascular Research (DZHK), Berlin, Germany.
  • 12 Helmholtz-Institute for Translational AngioCardioScience (HI-TAC) of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Heidelberg University, Heidelberg, Germany.
  • 13 Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Center Munich, Leipzig, Germany. [email protected].
  • 14 Faculty of Medicine, University of Leipzig, Leipzig, Germany. [email protected].
  • 15 German Centre for Cardiovascular Research (DZHK), Berlin, Germany. [email protected].
  • 16 German Centre for Diabetes Research (DZD), Neuherberg, Germany. [email protected].
PMID: 42337263 DOI: 10.1038/s41398-026-04197-x
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.

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