4-octyl itaconate attenuate experimental acute pancreatitis via inhibiting Sting signaling pathway and activating Nrf2 pathway in macrophages

Acute pancreatitis (AP) is a common and severe inflammatory disease of the abdomen. Recent studies have shown that macrophages play a crucial role in AP. 4-octyl itaconate (4OI), a derivative of the cell metabolism intermediate itaconate (ITA), has demonstrated significant anti-inflammatory effects in various cell and disease models. In this study, we investigated the potential role and mechanism of 4OI in both in vivo and in vitro models of AP.After administering 25 mg/kg of 4OI to mice and inducing AP with caerulein or L-Arg, we found that 4OI significantly alleviated the severity of AP: serum amylase and lipase levels were significantly reduced, histopathological scores decreased, and levels of inflammatory factors were notably lower. Additionally, macrophage infiltration and M1 polarization were significantly reduced. Through in vitro experiments, we further explored the molecular mechanism by which 4OI inhibits the inflammatory response in macrophages. We discovered that 4OI reduces macrophage polarization to the pro-inflammatory M1 type and decreases the expression of inflammation-related genes. We also found that 4OI exerts its anti-inflammatory effects by promoting the Nrf2 signaling pathway and inhibiting the Sting signaling pathway. In conclusion, this study reveals the anti-inflammatory effects of 4OI in AP and its potential clinical therapeutic value.