2. Academic Validation
  3. Targeting PAK4 promotes Gemcitabine-induced pyroptosis in pancreatic cancer via NLRP1/caspase-3/GSDME axis

Targeting PAK4 promotes Gemcitabine-induced pyroptosis in pancreatic cancer via NLRP1/caspase-3/GSDME axis

  • Commun Biol. 2026 Jan 16;9(1):260. doi: 10.1038/s42003-026-09538-6.
Tianqi Lu 1 2,  Yongqi Song 1,  Keke Liang 3,  Zhongbo Zhang 4,  Yang Li 1,  Xiaodong Tan 5,  Xiaodong Li 6,  Feng Li 7
Affiliations

Affiliations

  • 1 Department of Cell Biology, Key Laboratory of Cell Biology, National Health Commission of the PRC and Key Laboratory of Medical Cell Biology, Ministry of Education of the PRC, School of Life Sciences, China Medical University, Shenyang, Liaoning, China.
  • 2 Department of Pharmaceutical Neuroendocrinology, School of Pharmacy, China Medical University, Shenyang, Liaoning, China.
  • 3 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China.
  • 4 Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
  • 5 Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China. [email protected].
  • 6 Department of Cell Biology, Key Laboratory of Cell Biology, National Health Commission of the PRC and Key Laboratory of Medical Cell Biology, Ministry of Education of the PRC, School of Life Sciences, China Medical University, Shenyang, Liaoning, China. [email protected].
  • 7 Department of Cell Biology, Key Laboratory of Cell Biology, National Health Commission of the PRC and Key Laboratory of Medical Cell Biology, Ministry of Education of the PRC, School of Life Sciences, China Medical University, Shenyang, Liaoning, China. [email protected].
PMID: 41540224 DOI: 10.1038/s42003-026-09538-6
Abstract

Pancreatic Cancer remains a highly lethal disease, underscoring the continued importance of chemotherapy. The first-line chemotherapeutic agent Gemcitabine (GEM) exerts its effect by inducing tumor cell Apoptosis, a process which can subsequently convert to Pyroptosis via GSDME expression. Nevertheless, the emergence of drug resistance has prompted extensive research to identify novel therapeutic targets. p21-activated kinase 4 (PAK4) plays important roles in various tumors, including the inhibition of tumor cell Apoptosis. Here, we show that PAK4 inhibits Pyroptosis in pancreatic Cancer through the NAcht leucinerich-repeat protein-1 (NLRP1)/caspase-9/Caspase-3/GSDME axis. PAK4 phosphorylates the E3 ubiquitin Ligase mouse double minute 2 homolog (MDM2) to promote the degradation of NLRP1, thereby inhibiting Pyroptosis. Furthermore, inhibition of PAK4 kinase activity promotes GEM-induced suppression of pancreatic Cancer growth both in vitro and in vivo. Our study suggests that targeting PAK4 to promote GEM-induced Pyroptosis may provide a new therapeutic approach for the treatment of pancreatic Cancer.

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