P62/Sequestosome1 deficiency disrupts antioxidant and stress homeostasis during acute pancreatitis without exacerbating inflammation

Abstract

Backgrounds

Acute pancreatitis (AP) is a common inflammatory disease of the pancreas, characterized by complex pathogenesis and limited specific treatment options. The selective autophagy adapter protein p62/sequestosome1 emerged as a key player in cellular stress responses, with emerging evidence suggesting its role in modulating both infection-driven and sterile inflammation. However, the role of p62 in the pathogenesis of AP remains unclear.

Methods

To investigate the role of p62 in AP, we generated pancreas-specific conditional knockout mice (p62^ff; Ptf1a^cre/+) and induced AP by 12 repeated intraperitoneal cerulein injections. Mice were sacrificed either 1 h or 8 h after the final injection. Pancreatic damage was assessed along with serum amylase levels, intrapancreatic trypsin activity, proinflammatory cytokines, antioxidant genes, ER stress and cell death markers using immunohistochemistry, qRT-PCR, and western blotting.

Results

p62^ff; Ptf1a^cre/+ mice showed normal growth and pancreatic development. Upon cerulein challenge, both p62 knockout and control mice developed comparable pancreatic injury, without significant differences in histological scores, amylase, or trypsin activity. However, p62-deficient mice displayed significantly impaired antioxidant responses. Notably, Nqo1 expression was reduced and Keap1 accumulated, indicating disrupted Nrf2 signaling. Ferroptosis markers also showed genotype- and time-dependent changes: GPX4 was reduced at 1 h, while FTH1 without significant differences in p62-deficient mice. Periodic acid–Schiff staining further revealed increased glycogen depletion in knockout mice, suggesting elevated metabolic stress.

Conclusions

These findings suggest that while p62 deletion does not affect overall AP severity, it compromises redox homeostasis and metabolic recovery, highlighting a protective role for p62 during pancreatic injury.