GalNAc-GPNMB small molecule RNA treats MASH.

A study led by Professor Song Baoliang's team at Wuhan University has been published in the journal Nature, uncovering a novel ligand-receptor pathway, GPNMB-RYK.

The study, RYK is a GPNMB receptor that drives MASH, highlights the pivotal role of the regulatory molecule GPNMB in reprogramming lipid metabolism in hepatocytes. Researchers identified the single-pass transmembrane protein RYK as the functional receptor for the GPNMB extracellular domain (G-ECD), which enhances hepatic lipid uptake and synthesis, thereby driving the progression of MASLD/MASH.

The team explored various therapeutic strategies targeting the GPNMB-RYK signaling axis, including G-ECD vaccines, neutralizing antibodies, AAV-shRNA, and GalNAc-siRNA, all of which demonstrated efficacy in preventing or treating MASLD/MASH.

The researchers identified GPNMB as a key molecule that was significantly upregulated in MASH mice livers via transcriptome sequencing across different diets.

Mice with systemic or hepatocyte-specific knockout of GPNMB showed significant resistance to diet-induced MASH phenotypes, underscoring the critical role of hepatocyte-derived GPNMB in MASH pathogenesis.

The study confirmed that extracellular G-ECD, produced by proteolytic cleavage of GPNMB, is the functional form that mediates MASH development. Clinical data further revealed a positive correlation between plasma G-ECD levels and the progression of MASLD/MASH in patients.

The team also employed a cell-surface display library from Novo Nordisk for receptor screening, identifying 13 candidate receptors with GPNMB binding activity from 3,330 human transmembrane protein sequences.

Among these, RYK was identified as the key receptor. In RYK knockout mice, researchers observed complete resistance to the MASH-promoting effects mediated by G-ECD. The binding of G-ECD to RYK activates ERK1/2, which in turn upregulates the PPARγ-CD36 and SREBP1C pathways, promoting hepatic fatty acid uptake and lipid synthesis, thereby accelerating MASH.

Further evaluation of intervention strategies targeting the GPNMB-RYK signaling pathway, including vaccination, AAV-shRNA knockdown, neutralizing antibodies, and GalNAc-siRNA, demonstrated significant preventive and therapeutic effects across multiple MASH mouse models.