Discovery of Novel STING Inhibitors for the Treatment of Severe Acute Pancreatitis

Abstract Stimulator of interferon genes (STING) is a promising therapeutic target for severe acute pancreatitis (SAP), but effective small-molecule inhibitors remain limited. Here, structure−activity relationship studies identified compound D4 as a potent STING inhibitor with favorable cellular activity and safety. D4 directly engaged STING, inhibited its oligomerization and downstream TBK1/IRF3 signaling, and restored macrophage phagocytosis, autophagic flux, and mitochondrial function while suppressing NOD-like receptor family pyrin domain containing 3(NLRP3)-associated pyroptosis. D4 showed oral exposure with 24.70% bioavailability and no overt toxicity at 1000 mg/kg. In a caerulein/LPS-induced SAP model, D4 markedly reduced pancreatic injury, acinar cell necrosis, inflammatory infiltration, and serum amylase and lipase levels. STING knockdown produced similar protective effects. These findings identify D4 as a promising STING-targeting lead compound for SAP treatment.