Evidence mapPaperPMID 41327279Full record

ArticleStem cell research & therapy2025

FFAR4 drives stem cell fate toward lipid- and iron-storing enterocytes protecting human enteroids from ferroptosis.

Mona Farhadipour, Hui Leng, Theo Thijs, Antoine Dubois, Ellen Deleus, Bart Van der Schueren, Matthias Lannoo, Laurens J Ceulemans, Marc Ferrante, Inge Depoortere

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Article in Stem cell research & therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

10 authors.

Mona FarhadipourGut Peptide Research Lab, Translational Research for Gastrointestinal Disorders (TARGID), KU Leuven, Gasthuisberg O&N1, P. O. Box 701, Leuven, 3000, Belgium.
Hui LengGut Peptide Research Lab, Translational Research for Gastrointestinal Disorders (TARGID), KU Leuven, Gasthuisberg O&N1, P. O. Box 701, Leuven, 3000, Belgium.
Theo ThijsGut Peptide Research Lab, Translational Research for Gastrointestinal Disorders (TARGID), KU Leuven, Gasthuisberg O&N1, P. O. Box 701, Leuven, 3000, Belgium.
Antoine DuboisLeuven Intestinal Failure and Transplantation (LIFT) Center, University Hospitals Leuven, Leuven, 3000, Belgium.
Ellen DeleusDepartment of Abdominal Surgery, University Hospitals Leuven, Leuven, 3000, Belgium.
Bart Van der SchuerenClinical and Experimental Endocrinology, University Hospitals Leuven, Leuven, Belgium.
Matthias LannooDepartment of Abdominal Surgery, University Hospitals Leuven, Leuven, 3000, Belgium.
Laurens J CeulemansLeuven Intestinal Failure and Transplantation (LIFT) Center, University Hospitals Leuven, Leuven, 3000, Belgium.
Marc FerranteTranslational Research for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
Inge DepoortereGut Peptide Research Lab, Translational Research for Gastrointestinal Disorders (TARGID), KU Leuven, Gasthuisberg O&N1, P. O. Box 701, Leuven, 3000, Belgium. inge.depoortere@kuleuven.be.

Funding

Methusalem KU Leuven NA
6 · The paper itself

Abstract

backgroundIntestinal stem cell (ISC) fate is directed by microenvironmental cues, partly regulated through surface receptors, many of which remain incompletely characterized. Here, we investigated the functional role of the lipid-sensing receptor free fatty acid receptor 4 (FFAR4) in regulating ISC fate in normal-weight individuals, and hypothesized that its function may be affected in the lipid-rich environment of patients with obesity.

methodsHuman-derived small intestinal organoids (enteroids) were developed from normal-weight multi-organ donors and from patients with obesity who underwent a Roux-en Y gastric bypass.

resultsIn enteroids derived from normal-weight individuals, FFAR4 activation in ISCs promoted differentiation toward lipid-processing absorptive enterocytes while reducing secretory goblet cell formation. Functionally, mucin production was not affected but lipid droplet formation and iron storage were increased and blocked by a MEK1/2 inhibitor. This crosstalk reduced lipid peroxidation and hence the susceptibility to ferroptosis in the presence of environmental stressors. In contrast, FFAR4 activation in enteroids from patients with obesity failed to rewire the composition and function of the enteroid epithelium, suggesting impaired FFAR4 signaling in the obese ISC compartment.

conclusionsAltogether, our findings show that chemosensory receptors on stem cells play a more influential role than previously appreciated in modulating gut epithelial composition and function in response to environmental cues.

Indexed as

EnterocytesFerroptosisIronReceptors, G-Protein-CoupledStem CellsCell DifferentiationHumansMaleObesityOrganoidsFFAR4 protein, humanIronReceptors, G-Protein-CoupledFerroptosisFFAR4Intestinal stem cell differentiationLipid metabolismObesity

Identifiers

PMID41327279
PMCPMC12772055

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LicenceCC BY-NC-ND
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.