4-octyl Itaconate Attenuates Acute Pancreatitis and Associated Lung Injury by Suppressing Ferroptosis in Mice.

Acute pancreatitis (AP) is a common gastrointestinal emergency requiring hospitalization. In recent years, several studies have demonstrated a role for 4-octyl itaconate (4-OI) in anti-inflammatory and oxidative stress injury. However, the potential effects of 4-OI in AP have not been investigated. Caerulein and LPS were used to induce experimental AP models in mice and AR42J cells and then studied by histopathology, biochemical, and molecular analysis. Ferroptosis inhibitor ferrostatin-1 effectively improves pancreatic injury and reduces lipid peroxidation products in experimental AP mice. 4-OI treatment significantly alleviated pancreatic and AP-associated lung injury and inflammation in experimental AP mice by inhibiting ferroptosis. The ferroptosis activator Erastin blocked the protective effect of 4-OI against pancreatic injury in AP, validating that 4-OI alleviates pancreatitis injury through ferroptosis. In vitro experiments further confirmed that 4-OI treatment ameliorated AP-induced pancreatic injury by inhibiting ferroptosis. Our study, for the first time, found that 4-OI ameliorates AP and AP-related lung injury by inhibiting ferroptosis in experimental AP mice, providing a new therapeutic target for alleviating AP.