Saikosaponin d protects pancreatic acinar cells against cerulein-induced pyroptosis through alleviating mitochondrial damage and inhibiting cGAS-STING pathway

Acute pancreatitis represents an inflammatory disease featuring pancreatic necrosis and inflammation. Inflammatory injury of pancreatic acinar cells (PACs) is critically involved in the initiation and progression of acute pancreatitis. Pyroptosis, a new kind of programmed cell death concomitant with a low-grade inflammatory reaction, plays a function in acute pancreatitis pathology. It is unclear whether saikosaponin d (SSd), a pharmacologically active natural product, could protect PACs by regulating pyroptosis. Here, we established a PAC injury model in vitro using cerulein to treat AR42J cells. SSd restored viability and proliferation and lowered the release of pancreatic enzymes and inflammatory interleukins in cerulein-treated AR42J cells. Cerulein-induced pyroptosis was evidenced by typical ultrastructural changes and NLRP3/caspase-1 activation in AR42J cells, but SSd attenuated cerulein-induced pyroptosis and inhibited NLRP3/caspase-1 pathway. Mechanically, SSd reduced mitochondrial damage and mtDNA release, and blocked cGAS-STING signaling in AR42J cells treated with cerulein, contributing to the inhibition of NLRP3-mediated pyroptosis. Furthermore, SSd abolished cerulein-elevated oxidative stress in AR42J cells, leading to the mitigation of mitochondrial damage and inhibition of cGAS-STING signaling and pyroptosis. In conclusion, SSd protected PACs against cerulein-induced pyroptosis by alleviating mitochondrial damage and inhibiting the cGAS-STING pathway, and it could be a therapeutic candidate for acute pancreatitis. Acute pancreatitis is a non-infectious inflammatory disease and these are no effective drugs for this disease. Here, we found that Saikosaponin d (SSd) alleviated NLRP3-mediated pyroptosis and inflammatory injury by blocking cGAS-STNG signaling pathway in pancreatic acinar cells (PACs) treated with cerulein. These actions were attributed to SSd suppression of oxidative stress and mitigation of mitochondrial damage. Regulating pyroptosis of PACs could be a promising strategy for combating acute pancreatitis, and SSd could be a potent candidate for further development.