Background <p>Given the rising prevalence of liver fibrosis, there is an urgent need to improve the effective diagnostic methods and treatment of liver fibrosis. Although GPCRs are involved in various physiological and pathological processes, however, the hepatic functions of GPR56 have rarely been explored. This study aims to investigate the role and underlying mechanisms of GPR56 in liver fibrosis.</p> Methods <p>The expression of GPR56 in carbon tetrachloride (CCl₄) and bile duct ligation (BDL) induced mouse liver fibrosis, as well as human fibrotic liver tissues, was assessed by western blot, qRT-PCR and immunohistochemistry. Then, WGCNA combined with GO enrichment analysis were employed to predict the functions of GPR56. Additionally, Gain- and loss-of-function models (in vitro and in vivo) were established to explore GPR56’s function and the signaling pathways involved in liver fibrosis and hepatocyte pyroptosis.</p> Results <p>GPR56 was upregulated in both human and mouse fibrotic liver tissues, as well as hepatocytes from CCl₄-induced liver fibrosis mice. ROC analysis showed high diagnostic accuracy for cirrhosis (AUC = 0.895, 95% CI: 0.783–1.000). Moreover, WGCNA and GO enrichment analysis speculated that GPR56 was involved in the inflammatory response and extracellular matrix (ECM) synthesis. In vivo assays revealed that hepatocyte-specific overexpression of GPR56 attenuated, while knockdown of GPR56 exacerbated NLRP3 inflammasome-mediated pyroptosis and liver fibrosis. In vitro experiments confirmed that GPR56 inhibited hepatocyte pyroptosis, leading to the inactivation of hepatic stellate cells (HSC). Mechanistic experiments further revealed that GPR56 attenuated hepatocyte pyroptosis via inhibiting the activation of NF-κB pathway.</p> Conclusions <p>Our study identify GPR56 as a suppressor of hepatocyte pyroptosis and liver fibrosis, underscoring its potential as a therapeutic and diagnostic target.</p>