Pharmacological inhibition of the Src homology phosphatase 2 confers partial protection in a mouse model of alcohol-associated liver disease

Ming-Fo Hsu; Shinichiro Koike; Chang-Shan Chen; Sonia M Najjar; Tzu-Ching Meng; Fawaz G Haj

doi:10.1016/j.biopha.2024.116590

Pharmacological inhibition of the Src homology phosphatase 2 confers partial protection in a mouse model of alcohol-associated liver disease

Biomed Pharmacother. 2024 Apr 22:175:116590. doi: 10.1016/j.biopha.2024.116590. Online ahead of print.

Authors

Ming-Fo Hsu¹, Shinichiro Koike², Chang-Shan Chen³, Sonia M Najjar⁴, Tzu-Ching Meng³, Fawaz G Haj⁵

Affiliations

¹ Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA 95616, USA. Electronic address: mfhsu@ucdavis.edu.
² Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA 95616, USA.
³ Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei, Taiwan.
⁴ Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA.
⁵ Department of Nutrition, University of California Davis, One Shields Ave, Davis, CA 95616, USA; Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA; Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, University of California Davis, Sacramento, CA 95817, USA. Electronic address: fghaj@ucdavis.edu.

PMID: 38653109
DOI: 10.1016/j.biopha.2024.116590

Abstract

Alcohol-associated liver disease (ALD) is a leading factor of liver-related death worldwide. ALD has various manifestations that include steatosis, hepatitis, and cirrhosis and is currently without approved pharmacotherapies. The Src homology phosphatase 2 (Shp2) is a drug target in some cancers due to its positive regulation of Ras-mitogen-activated protein kinase signaling and cell proliferation. Shp2 pharmacological inhibition yields beneficial outcomes in animal disease models, but its impact on ALD remains unexplored. This study aims to investigate the effects of Shp2 inhibition and its validity using a preclinical mouse model of ALD. We report that the administration of SHP099, a potent and selective allosteric inhibitor of Shp2, partially ameliorated ethanol-induced hepatic injury, inflammation, and steatosis in mice. Additionally, Shp2 inhibition was associated with reduced ethanol-evoked activation of extracellular signal-regulated kinase (ERK), oxidative, and endoplasmic reticulum (ER) stress in the liver. Besides the liver, excessive alcohol consumption induces multi-organ injury and dysfunction, including the intestine. Notably, Shp2 inhibition diminished ethanol-induced intestinal inflammation and permeability, abrogated the reduction in tight junction protein expression, and the activation of ERK and stress signaling in the ileum. Collectively, Shp2 pharmacological inhibition mitigates the deleterious effects of ethanol in the liver and intestine in a mouse model of ALD. Given the multifactorial aspects underlying ALD pathogenesis, additional studies are needed to decipher the utility of Shp2 inhibition alone or as a component in a multitherapeutic regimen to combat this deadly malady.

Keywords: Alcohol-associated liver disease; ERK signaling; Intestine permeability; Shp2 pharmacological inhibition; Stress signaling; Tight junction.