A redox homeostasis-modulating protective strategy for pancreatitis: Selenoprotein W modulates Keap1/Nrf2/PPARγ/NF-κB interaction to alleviate pancreatic injury.

Pancreatitis is a severe digestive disorder that poses a serious threat to human health, with a continuously increasing mortality rate. Clinical treatment options remain limited, and the key therapeutic targets are still unclear. Selenoprotein W (SelW), a redox-related protein, has shown anti-inflammatory and antioxidant potential. However, its specific role in pancreatic tissue remains unknown. In this study, animal and cellular models of pancreatic injury were established to investigate the function of SelW. Histopathological examinations showed that selenium (Se) supplementation significantly alleviated pancreatic structural damage and islet atrophy. Mechanistic and Western blot analyses revealed that SelW deficiency elevated oxidative stress, decreased the expression of the anti-inflammatory cytokine IL-10, and increased levels of pro-inflammatory factors, including IL-1β, TNF-α, and IL-6. Mechanistic studies showed that SelW mitigates oxidative stress by activating the Keap1/Nrf2 pathway, enhances PPARγ expression, and markedly decreases the phosphorylation of IκBα and p65, thereby suppressing NF-κB-mediated inflammatory signaling. Overall, SelW protects against pancreatic injury by modulating the interconnected Keap1/Nrf2/PPARγ/NF-κB network, reducing oxidative damage, restraining inflammation, and preventing cell death. These results offer a novel mechanistic rationale for clinical prevention and targeted treatment of pancreatitis.