Metformin aggravates pancreatitis by regulating the release of oxidised mitochondrial DNA via the frataxin (FXN)/ninjurin 1 (NINJ1) signalling pathway

Background and Purpose Patients with diabetes are at a higher risk of developing acute pancreatitis compared to those without diabetes. Therefore, it is essential to investigate the effects of metformin, a primary treatment for type 2 diabetes, on the progression of pancreatitis. Experimental Approach Network pharmacology was employed to investigate the potential effects of metformin on pancreatitis and to predict its underlying molecular mechanisms. Pharmacological and mechanistic studies of metformin were conducted utilising mtDNA depletion (ρ0) of 266‐6 acinar cells, knockout mouse models and experimental models of both acute and chronic pancreatitis. The mitochondrial homeostasis and plasma membrane integrity were examined through phase‐contrast microscopy and time‐lapse video imaging. Key Results Network pharmacology analysis revealed that metformin possesses significant potential to modulate the pathogenesis of pancreatitis, likely through its regulation of mitochondrial function and cell membrane morphology. Further, the results revealed that metformin augmented the release of oxidised mitochondrial DNA (Ox‐mtDNA) by enhancing NINJ1‐mediated plasma membrane rupture, which subsequently ignited a cascade of acinar cell necrosis. Metformin exacerbated mitochondrial iron imbalance by suppressing Frataxin, thereby worsening mitochondrial homeostasis disruption and Ox‐mtDNA generation. NINJ1 knockout eliminated the metformin‐induced acinar cell necrosis and elevation of Ox‐mtDNA levels, and mtDNA depletion reversed the effect of metformin on acinar cell death. Conclusion and Implications Metformin exacerbates both acute and chronic pancreatitis, possibly because of increased release of Ox‐mtDNA via modulation of mitochondrial iron homeostasis and NINJ1‐mediated plasma membrane rupture, suggesting that extreme caution should be exercised when using metformin in diabetic patients with pancreatitis.