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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.<\/jats:p>","DOI":"10.3390\/ijms26136308","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T06:56:54Z","timestamp":1751353014000},"page":"6308","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Therapeutic Effect of GPR81 in Autoimmune Hepatitis and Hepatocellular Carcinoma via Regulating the Immune Response"],"prefix":"10.3390","volume":"26","author":[{"given":"Yongmei","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Human Histology and Embryology, Center for Tissues Stem Cell and Translational Medicine Research, Key Laboratory of Regenerative Medicine in Guizhou Province, Guizhou Medical University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqian","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Human Histology and Embryology, Center for Tissues Stem Cell and Translational Medicine Research, Key Laboratory of Regenerative Medicine in Guizhou Province, Guizhou Medical University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuxian","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Human Histology and Embryology, Center for Tissues Stem Cell and Translational Medicine Research, Key Laboratory of Regenerative Medicine in Guizhou Province, Guizhou Medical University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"He","sequence":"additional","affiliation":[{"name":"Department of Human Histology and Embryology, Center for Tissues Stem Cell and Translational Medicine Research, Key Laboratory of Regenerative Medicine in Guizhou Province, Guizhou Medical University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Human Histology and Embryology, Center for Tissues Stem Cell and Translational Medicine Research, Key Laboratory of Regenerative Medicine in Guizhou Province, Guizhou Medical University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Human Histology and Embryology, Center for Tissues Stem Cell and Translational Medicine Research, Key Laboratory of Regenerative Medicine in Guizhou Province, Guizhou Medical University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3957-2666","authenticated-orcid":false,"given":"Youbo","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Human Histology and Embryology, Center for Tissues Stem Cell and Translational Medicine Research, Key Laboratory of Regenerative Medicine in Guizhou Province, Guizhou Medical University, Guiyang 550025, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/s41575-022-00643-5","article-title":"Benign liver tumours: Understanding molecular physiology to adapt clinical management","volume":"19","author":"Nault","year":"2022","journal-title":"Nat. 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