Integrated screening identifies GPR31 as a key driver and druggable target for metabolic dysfunction-associated...

Area of Science:

• Hepatology
• Molecular Biology
• Pharmacology

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) is a prevalent liver disease with limited treatment options.
• Identifying novel pathogenic genes and therapeutic targets is crucial for MASH management.

Purpose of the Study:

• To conduct an integrated screening to identify genes and targets for MASH.
• To investigate the role of GPR31 in MASH pathogenesis.
• To develop and evaluate a GPR31-targeting therapeutic strategy for MASH.

Main Methods:

• Multilayered screening for MASH pathogenic genes and druggable targets.
• Investigated GPR31's mechanism involving Gαi3, glycosylation, and PKCδ-MAPK signaling.
• Utilized hepatocyte-specific GPR31 knockout and transgenic mouse models.
• Developed and tested the small-molecule inhibitor G4451 in rodent and nonhuman primate MASH models.

Main Results:

• GPR31 was identified as a previously uncharacterized critical contributor to MASH.
• GPR31 promotes MASH via Gαi3-dependent activation of PKCδ-MAPK signaling.
• Hepatocyte-specific GPR31 deficiency ameliorated MASH, while its overexpression aggravated the condition.
• G4451 specifically inhibited the GPR31-Gαi3 interaction and blocked MASH progression in preclinical models.

Conclusions:

• GPR31 is a key therapeutic target for MASH.
• Targeting the GPR31-Gαi3 interaction with G4451 shows significant therapeutic potential for MASH.
• Interference with GPR31 offers a promising strategy for MASH treatment.