LARP4B inhibits ferroptosis and accelerates the progression of pancreatic cancer by activating WNK1-induced NRF2/GCH1/BH4 pathway.

Abstract

Ferroptosis plays a crucial role in inhibiting tumor progression. La Ribonucleoprotein 4B (LARP4B) is known to function as a pro-oncogenic factor in digestive tumors, but its specific role and potential mechanisms remain unclear in pancreatic cancer (PC). In this study, we found that LARP4B was upregulated in PC tissues and cells. Overexpression of LARP4B promoted PC cell proliferation and invasion, while knockdown of LARP4B inhibited PC cell proliferation and invasion. Furthermore, knockdown of LARP4B was associated with intracellular iron overload, increased levels of reactive oxygen species (ROS) and malondialdehyde (MDA), and decreased glutathione (GSH) content and superoxide dismutase (SOD) activity in PC cells. Mechanistically, LARP4B binds to mRNA of with-no-lysine kinase 1 (WNK1) and promotes its stability, and WNK1 competitively binds to the partial Kelch domain of Kelch-like ECH-associated protein 1 (Keap1) to promote the nuclear translocation of nuclear factor erythroid-2-related factor 2 (NRF2), thereby activating the NRF2/GCH1/BH4 pathway and inhibiting ferroptosis in PC cells. ML385, a NRF2 nuclear translocation inhibitor, partially rescued the inhibitory effect of WNK1 on ferroptosis in PC cells. Finally, in vivo experiments showed that knockdown of LARP4B suppressed tumor growth in PC xenograft mice. In conclusion, our study demonstrated that LARP4B inhibited ferroptosis by activating the WNK1-mediated NRF2/GCH1/BH4 pathway, thereby promoting PC progression. Insight Box This work provides evidence for LARP4B as a pro-oncogenic factor in pancreatic cancer, while also offers new insights into the further understanding of the biological functions of LARP4B and the oncological mechanisms of pancreatic cancer. We found that LARP4B is upregulated in PC tissues and cells, and its overexpression promotes the proliferation and invasion of PC cells. Additionally, we discovered that LARP4B binds to WNK1 mRNA and enhances its stability. WNK1 competitively binds to Keap1 to facilitate NRF2 nuclear translocation, thereby activating the NRF2/GCH1/BH4 pathway and inhibiting ferroptosis in PC cells. These findings provide significant insights for further research on PC and the development of therapeutic strategies.