Emerging Target Offers New Hope in Treating Fatty Liver Disease

A recent review highlights a promising therapeutic target for metabolic dysfunction–associated fatty liver disease (MAFLD) and its more severe form, metabolic dysfunction–associated steatohepatitis (MASH), offering new insight into the mechanisms driving liver inflammation, fibrosis, and metabolic dysfunction.¹

The findings, published in Liver International, come amid a heightened focus on finding new biological pathways that could improve treatment for the conditions. Despite a growing prevalence, treatment options remain limited, with most current approaches focused on lifestyle modification and a small number of emerging pharmacologic therapies.

The new research centers on the lysophosphatidylinositol (LPI)–G protein–coupled receptor 55 (GPR55) signaling pathway, which has gained increasing attention for its role in regulating metabolic processes and inflammation. LPI is a bioactive lipid molecule, while GPR55 is a receptor expressed in multiple tissues, including the liver. Together, they form a signaling axis that appears to influence key processes involved in the development and progression of fatty liver disease.

“Accumulating evidence suggests that the LPI/GPR55 axis modulates key hepatic pathological processes, including hepatic lipogenesis, chronic low-grade inflammation and fibrogenesis,” wrote the researchers, noting that in preclinical models, overactivation of this pathway has been associated with worsening liver injury, while inhibition appears to reduce inflammation and fibrosis.

One of the key mechanisms involves the pathway’s impact on hepatic lipid metabolism. Activation of GPR55 has been linked to increased fat synthesis and reduced fat breakdown, contributing to the buildup of triglycerides within hepatocytes. This accumulation creates a lipotoxic environment that promotes cellular stress and triggers inflammatory cascades, both central features of MASH progression.

In addition to metabolic effects, the LPI-GPR55 axis appears to play a role in immune system activation within the liver. The pathway influences the behavior of immune cells such as macrophages, which are involved in initiating and sustaining inflammation. Chronic activation of these immune responses can lead to persistent liver injury and promote the transition from simple steatosis to more advanced disease.

Scar tissue in the liver, or fibrosis, is another critical component of disease progression, and the LPI-GPR55 pathway may contribute here as well, noted the researchers. In their review, they describe how activation of GPR55 can stimulate hepatic stellate cells, the primary drivers of fibrosis. Once activated, these cells produce extracellular matrix proteins that accumulate over time, leading to structural damage and impaired liver function.

Importantly, the LPI-GPR55 axis does not operate in isolation. It interacts with other key metabolic and inflammatory pathways, including insulin signaling, oxidative stress responses, and cytokine networks. This interconnected role makes it an especially attractive target for therapeutic intervention, as modulating this pathway could have broad downstream effects on multiple aspects of disease biology.

Several experimental approaches are currently being explored to target this pathway.² These include small-molecule antagonists that block GPR55 activation, as well as strategies aimed at reducing LPI levels or altering its signaling effects. Early preclinical studies suggest that these approaches may improve liver histology, reduce inflammation, and slow fibrosis progression.

However, translating these findings into clinical practice will require further research, explained the researchers.¹ Most of the current evidence comes from laboratory and animal studies, and clinical trials will be necessary to determine whether targeting the LPI-GPR55 axis is safe and effective in humans. Additionally, MAFLD and MASH are multifactorial diseases, creating a likelihood that combination therapies targeting multiple pathways will be needed.

References:

1. Lian J, Larreu RR, Patil M, Falasca M. Targeting the LPI/GPRR55 axis in MAFLD and MASH: novel insights, therapeutic strategies and future directions. Liver Intern. Published online March 13, 2026. doi:10.1111/liv.70576

2. Ceni C, Benko MJ, Mohamed KA, et al. Novel potent selective agonists of the GPRR55 receptor based on the 3-benzylquinolin-2(1H)-one scaffold. Pharmaceuticals. 2022;15(7):768. doi:10.3390/ph15070768