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. Mechanistically, G-ECD binding to RYK activated ERK1/2 signaling, resulting in transcriptional activation of PPARγ-CD36 and SREBP1C pathways that promote hepatic lipid uptake and lipogenesis. Multiple therapeutic strategies targeting the GPNMB–RYK axis—including vaccination, short hairpin RNA, neutralizing antibody and N-acetylgalactosamine small interfering RNA—effectively prevented and treated MASH in preclinical models. Our findings identify the GPNMB–RYK axis as a new pathogenic ligand–receptor pathway and a promising therapeutic target for MASH.
