Hepatic protein tyrosine phosphatase Shp2 disruption mitigates the adverse effects of ethanol in the liver by modulating oxidative stress and ERK signaling.

Aims: Chronic excessive alcohol intake is a significant cause of alcohol-associated liver disease (ALD), a leading contributor to liver-related morbidity and mortality. The Src homology phosphatase 2 (Shp2; encoded by Ptpn11) is a widely expressed protein tyrosine phosphatase that modulates hepatic functions, but its role in ALD is mostly uncharted.

Main Methods: Herein, we explore the effects of liver-specific Shp2 genetic disruption using the established chronic-plus-binge mouse model of ALD.

Key Findings: We report that the hepatic Shp2 disruption had beneficial effects and partially ameliorated ethanol-induced injury, inflammation, and steatosis in the liver. Consistently, Shp2 deficiency was associated with decreased ethanol-evoked activation of extracellular signal-regulated kinase (ERK) and oxidative stress in the liver. Moreover, primary hepatocytes with Shp2 deficiency exhibited similar outcomes to those observed upon Shp2 disruption in vivo, including diminished ethanol-induced ERK activation, inflammation, and oxidative stress. Furthermore, pharmacological inhibition of ERK in primary hepatocytes mimicked the effects of Shp2 deficiency and attenuated oxidative stress caused by ethanol.

Significance: Collectively, these findings highlight Shp2 as a modulator of hepatic oxidative stress upon ethanol challenge and suggest the evaluation of this phosphatase as a potential therapeutic target for ALD.