RYK is a GPNMB receptor that drives MASH

Area of Science:

• Hepatology
• Molecular Biology
• Biochemistry

Background:

• Metabolic-dysfunction-associated steatohepatitis (MASH) prevalence is increasing globally, with limited effective treatment options.
• Glycoprotein non-metastatic melanoma protein B (GPNMB) is upregulated in MASH-protected mice.

Purpose of the Study:

• To investigate the role of GPNMB in MASH pathogenesis.
• To identify the receptor for GPNMB ectodomain (G-ECD) and elucidate the underlying molecular mechanisms.
• To explore therapeutic strategies targeting the GPNMB-RYK axis for MASH treatment.

Main Methods:

• Systemic or hepatocyte-specific Gpnmb ablation in diet-induced MASH mouse models.
• Identification of G-ECD receptor using a cell-surface-displayed transmembrane protein library.
• Hepatocyte-specific Ryk ablation and assessment of MASH progression.
• Analysis of downstream signaling pathways including ERK1/2, PPARγ-CD36, and SREBP1C.
• Evaluation of therapeutic interventions targeting the GPNMB-RYK axis.

Main Results:

• GPNMB ablation protected against diet-induced MASH.
• MASH progression was driven by the secreted GPNMB ectodomain (G-ECD), not full-length GPNMB.
• Serum G-ECD levels correlated positively with MASH severity in human patients.
• Receptor tyrosine kinase (RYK) was identified as the functional receptor for G-ECD.
• Hepatocyte-specific Ryk ablation ameliorated MASH and blocked G-ECD's pathogenic effects.
• G-ECD/RYK interaction activated ERK1/2 signaling, promoting hepatic lipid uptake and lipogenesis via PPARγ-CD36 and SREBP1C.
• Therapeutic strategies targeting the GPNMB-RYK axis showed efficacy in preclinical MASH models.

Conclusions:

• The GPNMB-RYK axis represents a novel ligand-receptor pathway implicated in MASH pathogenesis.
• Targeting the GPNMB-RYK axis is a promising therapeutic strategy for treating MASH.