• Abstract The prevalence of metabolic-dysfunction-associated steatohepatitis (MASH) is rising globally, yet effective treatments remain limited1. • Here we found that systemic or hepatocyte-specific ablation of the gene encoding glycoprotein non-metastatic melanoma protein B (Gpnmb)-a top upregulated gene in MASH-protected mice from diet-induced MASH. • Notably, MASH progression was driven specifically by the secreted GPNMB ectodomain (G-ECD), rather than full-length GPNMB. • Serum G-ECD levels showed a strong positive correlation with MASH severity in human patients. • Using an unbiased screen of a cell-surface-displayed transmembrane protein library, we identified related to receptor tyrosine kinase (RYK) as a functional receptor for G-ECD. • Hepatocyte-specific Ryk ablation protected mice against MASH and abolished the pathogenic effects of G-ECD.
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