Extracellular SQSTM1 exacerbates acute pancreatitis by activating autophagy-dependent ferroptosis

Acute pancreatitis (AP) is an abdominal inflammatory disease initiated by damaged pancreatic acinar cells and developed by systemic inflammation. SQSTM1 (sequestosome 1) has an intracellular function in mediating substrate degradation during macroautophagy/autophagy, and it can be released by macrophages and monocytes to trigger lethal inflammation during bacterial infection. Here, we report that extracellular SQSTM1 acts as a mediator of AP by enhancing the sensitivity to autophagy-dependent ferroptotic cell death. Serum SQSTM1 is elevated in AP patients as well as in mice that have cerulein-induced AP. The administration of SQSTM1-neutralizing antibodies protects against experimental AP in mice. Mechanistically, recombinant SQSTM1 protein (rSQSTM1) increases AGER (advanced glycosylation end-product specific receptor)-dependent ACSL4 (acyl-CoA synthetase long chain family member 4) expression, leading to polyunsaturated fatty acid production for autophagosome formation and subsequent ferroptosis. The rSQSTM1-elicited pathological responses during AP are attenuated in mice with the conditional deletion of Ager in the pancreas. These findings may provide not only new insights into the mechanism of autophagy-dependent cell death, but also suggest that targeting the extracellular SQSTM1 pathway is a potential strategy for the treatment of AP. Abbreviations: 5-HETE, 5-hydroxyeicosatetraenoic acid; ACSL4, acyl-CoA synthetase long chain family member 4; AP, acute pancreatitis; ATG, autophagy related; AGER, advanced glycosylation end-product specific receptor; DAMPs, danger/damage-associated molecular patterns; FTH1, ferritin heavy chain 1; GPX4, glutathione peroxidase 4; IL, interleukin; INSR, insulin receptor; MAP1LC3B, microtubule associated protein 1 light chain 3 beta; MDA, malondialdehyde; MPO, myeloperoxidase; PRRs, pattern recognition receptors; PUFA, polyunsaturated fatty acid; RNAi, RNA interference; SQSTM1, sequestosome 1; TNF, tumor necrosis factor; TLR, toll like receptor.