Genetic and pharmacologic modulations elucidate NRF2 protective role in acute pancreatitis.

Acute pancreatitis (AP) is a potentially fatal disease of the exocrine pancreas. The disease pathogenesis remains obscure, and no effective treatment is available. Uncontrolled, deregulated inflammation is a major cause of systemic complications in AP; however, approaches to reduce inflammation in human disease by inhibiting inflammatory mediators have encountered multiple challenges and have not been successful. Oxidative stress drives inflammation in many diseases but its role in AP remains poorly understood. This study evaluates the role of nuclear factor erythroid 2-related factor 2 (NRF2), the master antioxidant defense transcription factor, in the inflammatory response and severity of experimental AP in mouse and cellular (ex vivo) models. Pancreas-specific genetic ablation of NRF2 worsened nonalcoholic and alcohol-mediated AP by downregulating antioxidant gene expression and upregulating inflammatory mediators, as shown by RNA-Seq analysis. Pancreatic NRF2 was activated in the experimental AP models; however, this activation was insufficient to prevent oxidative stress and inflammation. Additional pharmacologic NRF2 activation with sulforaphane markedly reduced oxidative stress, inflammation, and other pancreatitis responses; importantly, it ameliorated a recurrent episode of AP. The results highlight a major role of NRF2 in protecting against oxidative stress and inflammation in AP and suggest pharmacologic activation of NRF2 as a promising therapeutic strategy to mitigate inflammation and reduce the severity of pancreatitis.NEW & NOTEWORTHY Nonresolving inflammation is a major cause of acute pancreatitis (AP) mortality. Oxidative stress drives inflammation in various diseases, but its role in AP remains poorly understood, and targeted therapies are lacking. We show that acinar cell nuclear factor erythroid 2-related factor 2 (NRF2) activation in experimental AP was insufficient to prevent oxidative stress; however, additional NRF2 activation with sulforaphane markedly reduced oxidative stress, the inflammatory response, and disease severity. The results highlight pharmacologic NRF2 activators as a promising therapeutic approach for pancreatitis.