Targeting GPR68 Alleviates Inflammation and Lipid Accumulation in Metabolic Dysfunction-Associated Steatohepatitis

TL;DR

Blocking GPR68, a receptor that senses acidic changes, reduces liver inflammation and fat buildup in a mouse model of metabolic dysfunction-associated steatohepatitis (MASH), suggesting a new treatment approach.

Contribution

This study identifies GPR68 as a key driver of MASH pathology and demonstrates that inhibiting it can alleviate disease symptoms in mice.

Findings

GPR68 expression is increased in the liver during MASH progression in mice.

Inhibiting GPR68 reduces liver inflammation, lipid accumulation, and pro-inflammatory cytokine release in a mouse model of MASH.

GPR68 inhibition dampens acidification-associated inflammatory signaling in the liver.

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a common chronic liver disease for which effective drug treatments are still lacking. In this study, we show that GPR68, a receptor that senses acidic changes in tissues, is abnormally increased in the liver during MASH progression. Blocking GPR68 activity reduced liver inflammation and fat accumulation in a diet-induced mouse model of MASH. These findings suggest that targeting acid-sensing pathways, such as GPR68, may offer a new therapeutic approach for MASH.

Metabolic dysfunction-associated steatohepatitis (MASH) is a prevalent chronic liver disease characterized by hepatocellular injury, inflammation, and lipid accumulation, for which effective pharmacotherapies remain limited. Tissue acidification has emerged as a critical inflammatory cue in metabolic diseases; however, whether proton-sensing signaling contributes to MASH pathogenesis is largely unknown. Here, we identify the proton-sensing G protein-coupled receptor GPR68 (OGR1) as a key inflammatory and metabolic regulator in diet-induced MASH. In a high-fat diet-induced mouse model, hepatic GPR68 expression was markedly upregulated during MASH progression. Inhibiting GPR68 with ogremorphin significantly ameliorated MASH pathology, as evidenced by reduced hepatic inflammation and lipid accumulation, improved histological features, and attenuated expression and release of pro-inflammatory cytokines, including IL-6 and TNF-α. Mechanistically, GPR68 inhibition dampened acidification-associated inflammatory signaling in the liver. Together, these findings establish GPR68 as a tractable proton-sensing inflammatory node that links tissue acidification to metabolic liver injury and highlight GPR68 as a promising therapeutic strategy for MASH.

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