2. Academic Validation
  3. Kaempferol Ameliorates Functional Constipation in Mice by Regulating Autophagy of Interstitial Cells of Cajal via the p53/AMPK/mTOR Axis

Kaempferol Ameliorates Functional Constipation in Mice by Regulating Autophagy of Interstitial Cells of Cajal via the p53/AMPK/mTOR Axis

  • Dig Dis Sci. 2025 Nov 15. doi: 10.1007/s10620-025-09559-x.
Huilin Xiong 1,  Taohong He 2,  Juan Tang 3,  Jie Chu 4,  Ping He 5
Affiliations

Affiliations

  • 1 Department of TCM Anorectal, West China Hospital of Sichuan University-ZiyangHospital, Ziyang Central Hospital, Ziyang, 641300, China.
  • 2 Department of Proctology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
  • 3 Department of Endocrinology, West China Hospital of Sichuan University-ZiyangHospital, Ziyang Central Hospital, Ziyang, 641300, China.
  • 4 Department of Oncology, West China Hospital of Sichuan University-ZiyangHospital, Ziyang Central Hospital, Ziyang, 641300, China.
  • 5 Department of Proctology, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, China. [email protected].
PMID: 41240265 DOI: 10.1007/s10620-025-09559-x
Abstract

Background: Functional constipation (FC) is a prevalent gastrointestinal disorder, and abnormal Autophagy in interstitial cells of Cajal (ICCs) has been implicated in its pathogenesis. Kaempferol, a natural flavonoid, shows therapeutic potential for constipation, though its precise mechanism remains unclear.

Aim: This study aimed to investigate whether kaempferol alleviates FC by modulating Autophagy in ICCs through the p53/AMPK/mTOR signaling pathway.

Methods: A mouse model of FC was established using loperamide (10 mg/kg/day) for 14 d. Animals received kaempferol (15, 30, or 60 mg/kg) or mosapride for 7 d. Constipation symptoms were evaluated by measuring fecal water content and intestinal propulsion rate. Colon tissue damage was assessed histologically, and c-Kit expression was analyzed via qRT-PCR and immunohistochemistry. Autophagy activity and pathway protein expression were examined using transmission electron microscopy and Western blot. In vitro experiments utilized L-glutamate-stimulated ICCs with the mTOR agonist MHY1485 for mechanistic validation.

Results: Kaempferol significantly improved constipation symptoms, increased c-Kit expression, and alleviated colon tissue damage in FC mice. It effectively suppressed excessive Autophagy in ICCs, demonstrated by reduced autophagosome formation, decreased LC3-II/LC3-I ratio and Beclin1, and increased p62. Mechanistically, kaempferol activated the p53/AMPK/mTOR pathway both in vivo and in vitro, elevating p53 and p-mTOR while reducing p-AMPK expression. The anti-autophagic effect was enhanced by MHY1485.

Conclusion: Kaempferol ameliorates functional constipation by inhibiting excessive Autophagy in ICCs via activation of the p53/AMPK/mTOR pathway, providing new insights into its mechanism and supporting its potential as a therapeutic agent for FC.

Keywords

Autophagy; Functional constipation; Interstitial cells of Cajal; Kaempferol; p53/AMPK/mTOR axis.

Figures
Products