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.
摘要：
酒精相关性肝病（ALD）是全球肝脏相关死亡的主要因素。ALD有各种表现，包括脂肪变性，肝炎，和肝硬化，目前没有批准的药物疗法。Src同源磷酸酶2(Shp2)由于其对Ras-丝裂原活化蛋白激酶信号传导和细胞增殖的正调节而在一些癌症中是药物靶标。Shp2药理学抑制在动物疾病模型中产生有益的结果，但它对ALD的影响仍有待探索。本研究旨在使用ALD的临床前小鼠模型研究Shp2抑制作用及其有效性。我们报告说，SHP099，一种有效和选择性的Shp2变构抑制剂的给药，部分改善了乙醇诱导的肝损伤，炎症,和小鼠的脂肪变性。此外,Shp2抑制与乙醇诱发的细胞外信号调节激酶（ERK）激活减少有关，氧化，肝脏内质网（ER）应激。除了肝脏,过量饮酒会导致多器官损伤和功能障碍，包括肠道.值得注意的是,Shp2抑制减少乙醇诱导的肠道炎症和通透性，取消了紧密连接蛋白表达的减少，回肠ERK和应激信号的激活。总的来说，在ALD的小鼠模型中,Shp2药理学抑制减轻乙醇在肝脏和肠道中的有害作用。鉴于ALD发病机制的多因素方面，需要更多的研究来破译Shp2抑制单独使用或作为多种治疗方案的组成部分来对抗这种致命疾病的效用.
