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In metabolic dysfunction-associated steatohepatitis (MASH), we find EphB2 becomes strongly overexpressed and overactive in hepatic stellate cells (HSCs) from humans with the disease and from mice fed liver-injuring high fat diets. Genetic deletion of EphB2 or inactivation of its tyrosine kinase catalytic domain suppressed diet-induced MASH fibrosis, while a kinase overactive point mutant displayed exacerbated steatosis and hepatic damage. Silencing EphB2 in primary HSCs dampened the ability of TGF-\u03b2\/SMAD signals to stimulate the transdifferentiation of stellate cells into profibrotic myofibroblasts, and HSC-specific deletion of the receptor, but not hepatocyte deletion, reduced liver scarring in multiple mouse models, even after fibrosis was established. Finally, a newly developed small molecule tetramerization inhibitor that targets EphB2-Ephrin receptor-ligand interactions effectively blunts inflammation and fibrosis in chemical and diet-induced liver injury models, demonstrating that therapeutically targeting EphB2 can counter MASH fibrosis.<\/jats:p>","DOI":"10.1101\/2025.11.19.688968","type":"posted-content","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T17:15:27Z","timestamp":1763658927000},"source":"Crossref","is-referenced-by-count":0,"title":["Diet-induced MASH liver fibrosis promoted by EphB2 can be targeted by small molecule tetramerization inhibitors"],"prefix":"10.64898","author":[{"given":"Masaaki","family":"Yoshigi","sequence":"first","affiliation":[{"name":"Department of Dermatology, Indiana University School of Medicine, Indianapolis IN 46202, USA"},{"name":"Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN46202, 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