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

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.