The FOXA2-BNIP3 axis alleviates acute necrotizing pancreatitis by promoting mitophagy in pancreatic acinar cells to inhibit mtDNA-Mediated AIM2 inflammasome activation

Acute necrotizing pancreatitis (ANP) is a severe inflammatory pancreatic disease characterized by pancreatic necrosis and systemic inflammation, with complex pathogenesis, rapid progression, and poor prognosis. Mitochondrial dysfunction in pancreatic acinar cells represents a pivotal early event in ANP; however, mitophagy, a central component of mitochondrial quality control, remains poorly characterized in terms of its role, regulatory networks, and therapeutic potential in ANP. In this study, we demonstrated that BNIP3 (BCL2 interacting protein 3) expression was significantly downregulated in patients with ANP and negatively correlated with inflammatory severity. Consistently, BNIP3-mediated mitophagy was impaired in the pancreatic tissue of ANP mouse models. Notably, restoration of BNIP3 expression using a novel adeno-associated virus targeting pancreatic tissue (AAV-PAN)-Bnip3 gene therapy vector alleviated pancreatic necrosis and systemic inflammatory injury, promoted mitophagy, and inhibited mitochondrial dysfunction and oxidative stress. Mechanistically, BNIP3-dependent mitophagy facilitated the clearance of damaged mitochondria and prevented mitochondrial DNA (mtDNA) release into the cytosol, thereby suppressing AIM2 (absent in melanoma 2) inflammasome activation and subsequent acinar cell pyroptosis. Furthermore, we identified the transcription factor FOXA2 (forkhead box A2) as a direct upstream regulator that bound to the Bnip3 promoter and positively regulated its expression. FOXA2 was downregulated in ANP, whereas pancreas-specific FOXA2 overexpression activated BNIP3-mediated mitophagy and conferred protection against inflammatory injury. Together, these findings uncovered a previously unrecognized mechanism whereby the FOXA2-BNIP3-AIM2 axis mitigated pancreatic and systemic inflammatory injury in ANP by enhancing mitophagy to restrain mtDNA-dependent AIM2 inflammasome activation, highlighting the FOXA2-BNIP3-AIM2 axis as a promising target for gene therapy.