Downregulation of NOX2 Expression Alleviates Severe Acute Pancreatitis by Restoring Autophagy and Inhibiting mtDNA-mediated Activation of the cGAS-STING Signalling Pathway

Severe acute pancreatitis (SAP) is characterized by intense inflammation and pancreatic tissue injury. However, the specific mechanism underlying the progression of the disease remains unclear. Here, the role of the cGAS-STING pathway in driving SAP was investigated in both in vivo and in vitro models. Robust activation of the cGAS-STING pathway in SAP was observed, as evidenced by increased expression of pathway markers and inflammatory cytokines. We reported that the excessive production of reactive oxygen species (ROS) exacerbates mitochondrial stress. Mitochondrial stress in acinar cells led to decreased mitochondrial membrane potential and increased mitochondrial morphological changes, thus resulting in the cytosolic leakage of mitochondrial DNA (mtDNA). Moreover, after mtDNA was released, the cGAS-STING pathway was activated. However, inhibition of ROS with N-acetylcysteine (NAC) attenuated mtDNA leakage, reduced inflammatory responses, and increased cell viability. Moreover, the restoration of autophagic flux with rapamycin alleviated mitochondrial stress, reduced mtDNA leakage, and protected against pancreatic injury. These findings demonstrated that NOX2-derived ROS exacerbated mitochondrial stress and inflammation in SAP. Collectively, by reducing NOX2-derived excessive ROS levels, autophagy is restored, and cGAS-STING activation driven by mtDNA leakage is alleviated, which correspondingly restrains the progression of SAP. Therefore, NOX2 may become a potential therapeutic target for treating SAP.