Targeting the LPI/GPR55 Axis in MAFLD and MASH: Novel Insights, Therapeutic Strategies and Future Directions

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.