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Background <p>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.</p> Aim <p>This study aimed to investigate whether kaempferol alleviates FC by modulating autophagy in ICCs through the p53/AMPK/mTOR signaling pathway.</p> Methods <p>A mouse model of FC was established using loperamide (10&#xa0;mg/kg/day) for 14 d. Animals received kaempferol (15, 30, or 60&#xa0;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.</p> Results <p>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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年11月15日

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  • Huilin Xiong,
  • Taohong He,
  • Juan Tang,
  • Jie Chu,
  • Ping He

摘要

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.