ABSTRACT

Metabolic dysfunction-associated fatty liver disease (MAFLD), recently redefined from non-alcoholic fatty liver disease (NAFLD), highlights the central role of metabolic dysfunction in its pathophysiology. The L-α-lysophosphatidylinositol/G protein-coupled receptor 55 (LPI/GPR55) axis, an element of the endocannabinoidome, has emerged as a key driver behind liver disease progression, leading to the progression of metabolic dysfunction associated steatohepatitis (MASH). Implicated in hepatic lipid accumulation, inflammation and fibrosis, this axis has detrimental effects in hepatocytes, Kupffer cells and hepatic stellate cells. Furthermore, recent evidence suggests that this axis induces de novo lipogenesis, promoting pro-inflammatory cytokine production, leading to fibrosis and the transition toward a steatotic liver. The enzyme membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) modulates this axis by acylation of LPI, exacerbating hepatic steatosis and insulin resistance. Until recently, no pharmacologic treatments were approved for MAFLD. However, resmetirom received FDA approval in March 2024 for the treatment of MASH, and semaglutide (Wegovy) was granted accelerated FDA approval in August 2025 for MASH with moderate-to-advanced fibrosis. Additional agents such as tirzepatide and retatrutide remain in late-stage clinical development. We propose that targeting the endocannabinoidome, specifically the LPI/GPR55 axis, represents a promising therapeutic strategy for liver disease. Previous attempts to target GPR55 therapeutically have involved small-molecule agonists and phytocannabinoids with antagonistic activity. However, progress remains limited due to the context-specific roles of GPR55 across different tissues and signalling pathways. As such, future strategies involving the LPI/GPR55 axis must focus on hepatic-specific GPR55 modulation using selective ligands and advanced delivery systems, mitigating off-target effects. This review elucidates the mechanistic role of the LPI/GPR55 axis, combining the role of MBOAT7 in the pathophysiology of metabolic-associated liver disease.

Lian, J., R. R. Lareu, M. Patil, and M. Falasca. 2026. Targeting the LPI/GPR55 Axis in MAFLD and MASH: Novel Insights, Therapeutic Strategies and Future Directions.Liver International 46 (4)

ABSTRACT

This mouse study investigates the efficacy of ellagic acid (EA), a potent antioxidant in fruits and nuts, and inulin, a prebiotic known for gut microbiota benefits, in nonalcoholic steatohepatitis (NASH). A Western-style diet (WD) was used to induce NASH in C57BL/6J male mice for 16 weeks. Mice then received EA (100 mg/kg/day, oral gavage, 5 days/week) and/or 5% inulin (w/w in diet) for 12 weeks while continuing WD. Inulin increased energy intake and trended toward higher body weight and fasting glucose. EA reduced liver weights and restored the liver-to-body weight ratio. EA and inulin combined significantly reduced steatosis and hepatocyte ballooning, while EA alone reduced liver inflammation and improved biomarkers. In contrast, inulin alone worsened several liver parameters and increased LDL serum levels. EA, alone or combined with inulin, significantly reduced LDL. EA-treated groups showed elevated urinary 3'-methylellagic acid. Importantly, the combination of EA and inulin significantly increased urolithin A, C, and D, indicating enhanced EA metabolism and postbiotic production. While inulin alone exacerbated NASH features, EA significantly improved liver health. The combination of EA and inulin offset the adverse effects of inulin but did not further enhance the therapeutic efficacy of EA.

Senavirathna, T., A. Shafaei, R. R. Lareu, and L. Balmer. 2026. Ellagic Acid Reduces Inulin's Adverse Effects: A Combined Approach to Enhance Therapeutic Potential in Nonalcoholic Steatohepatitis.Molecular Nutrition and Food Research 70 (7)