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

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.