S-Nitrosothiol Signaling Regulates Liver Development and Improves Outcome following Toxic Liver Injury

摘要: Summary Toxic liver injury is a leading cause of failure and death because the organ's inability to regenerate amidst massive cell death, few therapeutic options exist. The mechanisms coordinating damage protection repair are poorly understood. Here, we show that S-nitrosothiols regulate growth during development after in vivo; in zebrafish, nitric-oxide (NO) enhanced formation independently cGMP-mediated vasoactive effects. After acetaminophen (APAP) exposure, inhibition enzymatic regulator S-nitrosoglutathione reductase (GSNOR) minimized toxic damage, increased proliferation, improved survival through sustained activation cytoprotective Nrf2 pathway. Preclinical studies APAP GSNOR-deficient mice confirmed conservation hepatoprotective properties S-nitrosothiol signaling across vertebrates; GSNOR-specific inhibitor histology acted with approved therapy N-acetylcysteine expand time window improve outcome. These demonstrate GSNOR inhibitors will be beneficial candidates for treating injury.