# The Therapeutic Effect of GPR81 in Autoimmune Hepatitis and Hepatocellular Carcinoma via Regulating the Immune Response

## TL;DR

This study explores how GPR81 affects autoimmune hepatitis and liver cancer by regulating immune responses, suggesting it could be a new treatment target.

## Contribution

The study reveals GPR81's dual role in inflammation and cancer, proposing it as a potential therapeutic target for both conditions.

## Key findings

- 3,5-DHBA reduced T cell activity and inflammation while increasing MDSCs, inhibiting AIH.
- GPR81 inhibition suppressed HCC cell growth and tumor size, and increased immune cell activity.
- GPR81 modulation may bridge inflammation and cancer, offering a novel treatment strategy.

## Abstract

Autoimmune hepatitis (AIH) is linked to an increased risk of hepatocellular carcinoma (HCC). However, the precise connection between the two remains unclear. GPR81, a G-protein-coupled receptor located on the membranes of various cell types, plays a role in numerous physiological processes. We established an AIH animal model and activated GPR81 using the agonist 3,5-dihydroxybenzoic acid (3,5-DHBA). Additionally, the effect of GPR81 inhibition on tumor and immune cell dynamics was examined using the HepG2, Hep3B, and Hepa1-6 cell lines with the antagonist 3-hydroxybutyric acid (3-OBA). Our results demonstrated that 3,5-DHBA treatment reduced T cell and pro-inflammatory cytokine secretion, while MDSC secretion increased, inhibiting Concanavalin A (Con A)-induced AIH. The inhibition of GPR81 by 3-OBA suppressed HCC cell proliferation and invasion, reduced tumor volume and weight, and downregulated PD-L1 expression. Furthermore, CTL and DC activity in the spleen and tumors increased, while MDSC activity decreased. This study confirms that GPR81 plays an important role in both inflammation and tumorigenesis, suggesting that GPR81 may serve as a bridge in the transformation of inflammation into cancer. Modulating GPR81 activity may provide a novel therapeutic strategy for hepatitis and cancer.