2. Academic Validation
  3. Epithelial MST1 deficiency promotes pyroptosis and aggravates inflammatory bowel disease via the YAP/p73 signaling pathway

Epithelial MST1 deficiency promotes pyroptosis and aggravates inflammatory bowel disease via the YAP/p73 signaling pathway

  • Cell Death Differ. 2025 Sep 26. doi: 10.1038/s41418-025-01588-3.
Jiali Lu # 1 2,  Fei Li # 3,  Hailin Wang # 1 2,  Yali Yu 1 2,  Yuan Yuan 1 2,  Yukang Zhang 1 2,  Pule Liu 1 2,  Qiu Zhao 1 2,  Min Wu 4,  Mei Ye 5 6
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China.
  • 2 Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China.
  • 3 Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
  • 4 Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, College of Life Sciences, Taikang Center for Life and Medical Sciences of Wuhan University, Wuhan, Hubei, China.
  • 5 Department of Gastroenterology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China. wumeiye08@163.com.
  • 6 Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China. wumeiye08@163.com.
  • # Contributed equally.
PMID: 41006633 DOI: 10.1038/s41418-025-01588-3
Abstract

The Hippo pathway has been implicated in the onset and pathogenesis of inflammatory bowel disease (IBD), with Mammalian STE20-like kinase 1 (MST1), a core kinase in this pathway, playing significant roles in inflammation and immune regulation. However, the specific role of MST1 in IBD remains largely undefined. In this study, we observed that MST1 expression was significantly decreased in IBD patients and acute colitis mice. Intestinal epithelial cell-specific MST1 knockout mice exhibited heightened susceptibility to dextran sodium sulfate (DSS)-induced colitis, characterized by severe disruption of intestinal epithelial barrier and markedly increased epithelial cell Pyroptosis, thus exacerbating intestinal inflammation. Pharmacological inhibition of Caspase-1/GSDMD-mediated Pyroptosis ameliorated the detrimental effects of MST1 deficiency in colitis. Consistently, MST1 deficiency exacerbated intestinal barrier disruption and Pyroptosis in both in vivo and in vitro models under TNFα-induced inflammation and DNA damage. Mechanistically, MST1 depletion promoted YAP nuclear translocation and enhances its interaction with p73 in intestinal epithelial cells, leading to increased p73 stability and transcriptional activity. This, in turn, facilitated the recruitment of p73 to the Caspase-1 promoter, upregulating Caspase-1 expression and translating into increased Pyroptosis under TNFα-induced inflammatory conditions. Altogether, our findings highlight the critical role of MST1 in maintaining intestinal mucosal barrier homeostasis by regulating epithelial cell Pyroptosis via the YAP/p73 signaling pathway. Reduced MST1 expression may correlate with a better response to anti-TNF therapy in IBD patients. Consequently, MST1 could serve as a promising predictive biomarker for anti-TNF therapy responsiveness and a potential therapeutic target for IBD, offering valuable insights for personalized treatment strategies.

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