Obesity impairs gut repair via AFABP-mediated iron overload in intestinal stem cells

  • Nat Metab. 2026 Jan;8(1):74-95. doi: 10.1038/s42255-025-01425-4.
Zhiming Liu  #  1 ,  Yi Chen  #  2 ,  Jinhua Yan  #  1 ,  Yu Yuan  #  1 ,  Qianyi Wan  #  1  2 ,  Rui Zhao  #  2 ,  Fang Fu  1 ,  Xinxin Fan  1 ,  Yawen Deng  1 ,  Xiaoxin Guo  1 ,  Haiou Chen  1 ,  Xingzhu Liu  1 ,  Jinbao Ye  1 ,  Haiyang Chen  3
Affiliations
  • 1. West China Centre of Excellence for Pancreatitis, and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
  • 2. Division of Gastrointestinal Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China.
  • 3. West China Centre of Excellence for Pancreatitis, and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China. [email protected].
  • # Contributed equally.
PMID: 41507665 DOI: 10.1038/s42255-025-01425-4
Abstract

Obesity impairs the function of multiple organs, but its effect on gut regeneration remains poorly defined. Here, we show that adipocyte fatty acid-binding protein (AFABP), an adipokine involved in fatty acid transport, impedes intestinal repair by disrupting iron homeostasis in intestinal stem cells (ISCs). Mechanistically, elevated AFABP secretion in obesity binds to plasma transferrin, leading to iron accumulation in ISCs. This accumulation disrupts peroxisome-mediated ISC differentiation, which is essential for intestinal repair following injury. Notably, AFABP overexpression in adipocytes of lean mice impedes ISC differentiation and gut repair. Conversely, AFABP depletion or the administration of AFABP inhibitors, iron chelators or peroxisome activators effectively mitigates colitis in obese Animals. Overall, our findings reveal a mechanistic link between obesity and intestinal repair, and identify the adipose-gut axis as a therapeutic target for obesity-associated intestinal disorders.

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