Liver X receptor unlinks intestinal regeneration and tumorigenesis

Srustidhar Das (), S. Martina Parigi, Xinxin Luo, Jennifer Fransson, Bianca C. Kern, Ali Okhovat, Oscar E. Diaz, Chiara Sorini, Paulo Czarnewski, Anna T. Webb, Rodrigo A. Morales, Sacha Lebon, Gustavo Monasterio, Francisca Castillo, Kumar P. Tripathi, Ning He, Penelope Pelczar, Nicola Schaltenberg, Marjorie Fuente, Francisco López-Köstner, Susanne Nylén, Hjalte List Larsen, Raoul Kuiper, Per Antonson, Marcela A. Hermoso, Samuel Huber, Moshe Biton, Sandra Scharaw, Jan-Åke Gustafsson, Pekka Katajisto and Eduardo J. Villablanca ()
Additional contact information
Srustidhar Das: Karolinska Institutet and University Hospital
S. Martina Parigi: Karolinska Institutet and University Hospital
Xinxin Luo: Karolinska Institutet and University Hospital
Jennifer Fransson: Karolinska Institutet and University Hospital
Bianca C. Kern: Karolinska Institutet and University Hospital
Ali Okhovat: Karolinska Institutet and University Hospital
Oscar E. Diaz: Karolinska Institutet and University Hospital
Chiara Sorini: Karolinska Institutet and University Hospital
Paulo Czarnewski: Karolinska Institutet and University Hospital
Anna T. Webb: Karolinska Institutet
Rodrigo A. Morales: Karolinska Institutet and University Hospital
Sacha Lebon: Weizmann Institute of Science
Gustavo Monasterio: Karolinska Institutet and University Hospital
Francisca Castillo: Karolinska Institutet and University Hospital
Kumar P. Tripathi: Karolinska Institutet and University Hospital
Ning He: Karolinska Institutet and University Hospital
Penelope Pelczar: Universitätsklinikum Hamburg-Eppendorf
Nicola Schaltenberg: Universitätsklinikum Hamburg-Eppendorf
Marjorie Fuente: Universidad Finis Terrae
Francisco López-Köstner: Universidad de Los Andes
Susanne Nylén: Karolinska Institutet
Hjalte List Larsen: University of Copenhagen
Raoul Kuiper: Norwegian Veterinary Institute
Per Antonson: Karolinska Institutet
Marcela A. Hermoso: Universidad de Chile
Samuel Huber: Universitätsklinikum Hamburg-Eppendorf
Moshe Biton: Weizmann Institute of Science
Sandra Scharaw: Karolinska Institutet
Jan-Åke Gustafsson: Karolinska Institutet
Pekka Katajisto: Karolinska Institutet
Eduardo J. Villablanca: Karolinska Institutet and University Hospital

Nature, 2025, vol. 637, issue 8048, 1198-1206

Abstract: Abstract Uncontrolled regeneration leads to neoplastic transformation1–3. The intestinal epithelium requires precise regulation during continuous homeostatic and damage-induced tissue renewal to prevent neoplastic transformation, suggesting that pathways unlinking tumour growth from regenerative processes must exist. Here, by mining RNA-sequencing datasets from two intestinal damage models4,5 and using pharmacological, transcriptomics and genetic tools, we identified liver X receptor (LXR) pathway activation as a tissue adaptation to damage that reciprocally regulates intestinal regeneration and tumorigenesis. Using single-cell RNA sequencing, intestinal organoids, and gain- and loss-of-function experiments, we demonstrate that LXR activation in intestinal epithelial cells induces amphiregulin (Areg), enhancing regenerative responses. This response is coordinated by the LXR-ligand-producing enzyme CYP27A1, which was upregulated in damaged intestinal crypt niches. Deletion of Cyp27a1 impaired intestinal regeneration, which was rescued by exogenous LXR agonists. Notably, in tumour models, Cyp27a1 deficiency led to increased tumour growth, whereas LXR activation elicited anti-tumour responses dependent on adaptive immunity. Consistently, human colorectal cancer specimens exhibited reduced levels of CYP27A1, LXR target genes, and B and CD8 T cell gene signatures. We therefore identify an epithelial adaptation mechanism to damage, whereby LXR functions as a rheostat, promoting tissue repair while limiting tumorigenesis.

Date: 2025
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DOI: 10.1038/s41586-024-08247-6

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