Identification of MEOX1 as a potential target in metabolic dysfunction-associated steatohepatitis-related liver fibrosis.

Abstract

BackgroundThe mechanisms underlying the occurrence and progression of metabolic dysfunction-associated steatohepatitis (MASH)-related liver fibrosis remains poorly understood. This study aims to identify key transcription factors involved in the development of liver fibrosis in MASH patients, thereby providing potential targets for drug discovery.MethodsMicroarray data were retrieved from liver biopsy specimens of MASH patients exhibiting varying stages of fibrosis via the Gene Expression Omnibus database. Differentially expressed transcription factors (DETFs) were identified through the application of Weighted Gene Co-expression Network Analysis. A set of in vitro and in vivo experiments were conducted to investigate the role of MEOX1 in MASH-related fibrosis. To delineate the potential mechanisms, the transcriptomic RNA sequencing (RNA-seq), Alphafold, and PyMOL were used.ResultsA total of six DETFs (MEOX1, SOX4, LEF1, SOX9, MYC, and CBX2) were identified as being positively correlated with the progression of MASH-related fibrosis. MEOX1 was increased in mouse model of MASH diet-induced liver fibrosis and hepatic stellate cells (HSCs) stimulated by transforming growth factor-β1. Knockdown of the MEOX1 markedly suppressed the activation, proliferation, and migration of HSCs. RNA-Seq analysis identified serine protease inhibitor family E member 1 (SERPINE1) as the critical target of MEOX1 within HSCs. The protein interaction sites of MEOX1 and SERPINE1 were predicted using Alphafold and PyMOL.ConclusionIn summary, as a pivotal transcription factor, MEOX1 activates HSCs via SERPINE1, thereby promoting liver fibrosis associated with MASH. Inhibition of the MEOX1-SERPINE1 pathway could offer a novel therapeutic avenue for treating MASH-related fibrosis.