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

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.