酒精性肝病（ALD）占肝硬化和肝细胞癌患者的很大一部分。在本研究中，我们研究了Brahma相关基因1（Brg1）在ALD发病机制中的作用和在ALD干预中的意义。我们报告Brg1表达在ALD小鼠模型、暴露于酒精的肝细胞和人类ALD标本中升高。调节Brg1在肝细胞中的表达影响了小鼠ALD的发展。流式细胞术显示，Brg1缺陷特异性抑制了ALD小鼠肝内Ly6G+中性粒细胞的浸润。RNA测序鉴定了C-X-C基序趋化因子配体14（CXCL14）作为Brg1的一个潜在靶点。CXCL14沉默减轻了小鼠的ALD发病，而CXCL14过表达则增加了小鼠的ALD发病。重要的是，用小分子化合物PFI-3抑制Brg1或给CXCL14受体拮抗剂的小鼠口服，均改善了小鼠ALD的发病。最后，在ALD患者中检测到Brg1表达、CXCL14表达和中性粒细胞浸润之间的正相关性。总之，我们的数据提供了以Brg1-CXCL14轴为靶点进行ALD干预的理念证明。 © 2023该作者。根据CC BY 4.0许可证条款发布。

Alcoholic liver disease (ALD) accounts for a large fraction of patients with cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement of Brahma-related gene 1 (Brg1) in ALD pathogenesis and implication in ALD intervention. We report that Brg1 expression was elevated in mouse models of ALD, in hepatocyte exposed to alcohol, and in human ALD specimens. Manipulation of Brg1 expression in hepatocytes influenced the development of ALD in mice. Flow cytometry showed that Brg1 deficiency specifically attenuated hepatic infiltration of Ly6G+ neutrophils in the ALD mice. RNA-seq identified C-X-C motif chemokine ligand 14 (CXCL14) as a potential target for Brg1. CXCL14 knockdown alleviated whereas CXCL14 over-expression enhanced ALD pathogenesis in mice. Importantly, pharmaceutical inhibition of Brg1 with a small-molecule compound PFI-3 or administration of an antagonist to the CXCL14 receptor ameliorated ALD pathogenesis in mice. Finally, a positive correlation between Brg1 expression, CXCL14 expression, and neutrophil infiltration was detected in ALD patients. In conclusion, our data provide proof-of-concept for targeting the Brg1-CXCL14 axis in ALD intervention.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.