2. Academic Validation
  3. Duvelisib upregulates p27 expression and leads to intestinal damage via the NEDD4L/CK1ε axis

Duvelisib upregulates p27 expression and leads to intestinal damage via the NEDD4L/CK1ε axis

  • Biochem Pharmacol. 2026 Aug;250(Pt 1):117939. doi: 10.1016/j.bcp.2026.117939.
Hao Yan 1,  Binshu Chai 1,  Miaomiao Yu 1,  Jiajia Chen 1,  Yonghai Wang 2,  Zixuan Zhang 1,  Wendong Yang 1,  Jiabin Lu 3,  Bo Yang 4,  Qiaojun He 5,  Peihua Luo 6,  Xiaochun Yang 7
Affiliations

Affiliations

  • 1 Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2 Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 3 Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 4 Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; School of Medicine, Hangzhou City University, Hangzhou 310015, China.
  • 5 Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 6 Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
  • 7 Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
PMID: 41905427 DOI: 10.1016/j.bcp.2026.117939
Abstract

Duvelisib-induced enterotoxicity is one of the most noteworthy clinical concerns, yet due to its unclear mechanism, effective intervention strategies remain lacking. Here, we demonstrated that duvelisib increased the protein stability of Casein Kinase 1ε (CK1ε) by down-regulating the expression of NEDD4 like E3 ubiquitin protein Ligase (NEDD4L), which in turn induced p27-dependent G0/G1 cell cycle arrest in small intestinal epithelial cells and led to intestinal injury. Meanwhile, we found that β, β-dimethyl-acryl-alkannin (ALCAP2), which could upregulate the protein level of NEDD4L, had protective effect against the toxicity in vivo. Collectively, our findings identified the excessive accumulation of CK1ε as a key cause of duvelisib-induced enterotoxicity, and reduction in the protein stability of CK1ε represents a potential therapeutic strategy to prevent duvelisib-induced enterotoxicity.

Keywords

ALCAP2; CK1ε; Duvelisib; Enterotoxicity; NEDD4L; P27.

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