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  3. Aging-related peroxisomal dysregulation disrupts intestinal stem cell differentiation through alterations of very long-chain fatty acid oxidation

Aging-related peroxisomal dysregulation disrupts intestinal stem cell differentiation through alterations of very long-chain fatty acid oxidation

  • PLoS Biol. 2025 Dec 19;23(12):e3003552. doi: 10.1371/journal.pbio.3003552.
Xiaoxin Guo 1 2,  Gang Du 3 4,  Juanyu Zhou 1,  Fang Fu 1,  Yu Yuan 1,  Xingzhu Liu 1,  Haiou Chen 1,  Qianyi Wan 1 5,  Bo Gong 2,  Haiyang Chen 1
Affiliations

Affiliations

  • 1 West China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging Research, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
  • 2 Genetic Diseases Key Laboratory of Sichuan Province, Department of Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
  • 3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
  • 4 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, United States of America.
  • 5 Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
PMID: 41417787 DOI: 10.1371/journal.pbio.3003552
Abstract

Aging disrupts intestinal stem cell (ISC) lineage fidelity, impairing epithelial barrier function and then promoting systemic health decline. In this study, we identify peroxisomal dysfunction as a critical driver of age-associated ISC mis-differentiation. Using Drosophila and mouse colonic organoids, we demonstrate that reduced PEX5 expression in aged ISCs impairs peroxisomal matrix protein import, leading to very long-chain fatty acids (VLCFAs) accumulation. In addition, we found that RAB7-dependent late endosome maturation and SOX21A were downstream of the peroxisome in controlling aged ISC differentiation. Aspirin, a classic anti-inflammatory drug, restores ISC lineage fidelity by enhancing PEX5-mediated peroxisomal β-oxidation of VLCFAs. Taken together, these findings highlight peroxisomal dysfunction and VLCFA metabolism as pivotal regulators of ISC aging and suggest new therapeutic strategies for combating age-related intestinal decline.

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