Upregulation of the ERR & gamma;-VDAC1 axis underlies the molecular pathogenesis of pancreatitis

Emerging evidence suggest that transcription factors play multiple roles in the development of pancreatitis, a necroinflammatory condition lacking specific therapy. Estrogen-related receptor ? (ERR?), a pleiotropic transcription factor, has been reported to play a vital role in pancreatic acinar cell (PAC) homeostasis. However, the role of ERR? in PAC dysfunction remains hitherto unknown. Here, we demonstrated in both mice models and human cohorts that pancreatitis is associated with an increase in ERR? gene expression via activation of STAT3. Acinar-specific ERR? haploinsufficiency or pharmacological inhibition of ERR? significantly impaired the progression of pancreatitis both in vitro and in vivo. Using systematic transcriptomic analysis, we identified that voltage-dependent anion channel 1 (VDAC1) acts as a molecular mediator of ERR?. Mechanistically, we showed that induction of ERR? in cultured acinar cells and mouse pancreata enhanced VDAC1 expression by directly binding to specific site of the Vdac1 gene promoter and resulted in VDAC1 oligomerization. Notably, VDAC1, whose expression and oligomerization were dependent on ERR?, modulates mitochondrial Ca2+ and ROS levels. Inhibition of the ERR?-VDAC1 axis could alleviate mitochondrial Ca2+ accumulation, ROS formation and inhibit progression of pancreatitis. Using two different mouse models of pancreatitis, we showed that pharmacological blockade of ERR?-VDAC1 pathway has therapeutic benefits in mitigating progression of pancreatitis. Likewise, using PRSS1R122H-Tg mice to mimic human hereditary pancreatitis, we demonstrated that ERR? inhibitor also alleviated pancreatitis. Our findings highlight the importance of ERR? in pancreatitis progression and suggests its therapeutic intervention for prevention and treatment of pancreatitis.