Scientists identify RYK as a GPNMB receptor driving MASH in mice

Scientists identify a key driver of fatty liver disease

Researchers have discovered a new molecular pathway that drives a severe form of fatty liver disease. Targeting this pathway with several different therapies successfully treated the condition in mice.

The study, published in Nature, focuses on metabolic-dysfunction-associated steatohepatitis (MASH), formerly known as NASH. The disease involves liver inflammation and scarring and has few effective treatments.

A protein fragment is the culprit

The team found that a protein called GPNMB is highly upregulated in MASH. In experiments, deleting the Gpnmb gene in mice protected them from diet-induced MASH.

Further work revealed the disease is driven specifically by a cleaved, secreted fragment of the protein, called the GPNMB ectodomain (G-ECD). The full-length protein did not have the same effect. In human patients, serum levels of G-ECD strongly correlated with MASH severity.

Finding the receptor and the mechanism

Using a screen of cell-surface proteins, the researchers identified the receptor tyrosine kinase RYK as the functional receptor for G-ECD. Deleting the Ryk gene in mouse hepatocytes also protected against MASH and blocked G-ECD's effects.

The study details the harmful cascade: when G-ECD binds to RYK, it activates ERK1/2 signaling. This leads to the activation of two key pathways:

• The PPARγ-CD36 pathway, which promotes fat uptake in the liver.
• The SREBP1C pathway, which drives the liver's internal production of fat.

Together, this dual action significantly worsens liver fat accumulation, a hallmark of MASH.

Multiple therapies show promise in mice

The researchers tested several strategies to disrupt the GPNMB-RYK axis, all of which showed efficacy in preclinical models. The successful approaches included:

• A vaccination against GPNMB.
• Short hairpin RNA (shRNA) to silence the gene.
• A neutralizing antibody against G-ECD.
• An N-acetylgalactosamine (GalNAc)-conjugated siRNA, a modern RNAi therapeutic format designed for liver delivery.

These interventions were able to both prevent and treat established MASH in the animal studies.

A new target for a growing disease

The findings position the GPNMB-RYK axis as a novel and promising therapeutic target for MASH. The disease is a leading cause of liver cirrhosis and cancer, and its global prevalence is rising alongside obesity and diabetes.

The identification of a specific pathogenic ligand-receptor pair and the demonstration of multiple viable blocking strategies provide a strong foundation for future drug development. The success of the GalNAc-siRNA approach is particularly notable, as this technology is already used in approved medicines.