GPR56 function as a key repressor in hepatocyte pyroptosis and the pathogenesis of liver fibrosis
Abstract Background 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...
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| Language: | English |
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BMC
2025-06-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06619-8 |
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| author | Zhemin Shi Qi Liu Mengxia Zhang Xiaoxiao Du Yifan He Lina Zheng Wei Hong Tao Han Kun Zhang |
| author_facet | Zhemin Shi Qi Liu Mengxia Zhang Xiaoxiao Du Yifan He Lina Zheng Wei Hong Tao Han Kun Zhang |
| author_sort | Zhemin Shi |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusions Our study identify GPR56 as a suppressor of hepatocyte pyroptosis and liver fibrosis, underscoring its potential as a therapeutic and diagnostic target. |
| format | Article |
| id | doaj-art-ee7e90ccadc64928969a35a4379846fe |
| institution | OA Journals |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-ee7e90ccadc64928969a35a4379846fe2025-08-20T02:30:59ZengBMCJournal of Translational Medicine1479-58762025-06-0123111810.1186/s12967-025-06619-8GPR56 function as a key repressor in hepatocyte pyroptosis and the pathogenesis of liver fibrosisZhemin Shi0Qi Liu1Mengxia Zhang2Xiaoxiao Du3Yifan He4Lina Zheng5Wei Hong6Tao Han7Kun Zhang8Department of Histology and Developmental Biology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Histology and Developmental Biology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Histology and Developmental Biology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Histology and Developmental Biology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Histology and Developmental Biology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Histology and Developmental Biology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Histology and Developmental Biology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Hepatology and Gastroenterology, Tianjin Union Medical Center, Tianjin Medical University, Tianjin Union Medical Center Affiliated to Nankai UniversityDepartment of Histology and Developmental Biology, School of Basic Medical Sciences, Tianjin Medical UniversityAbstract Background 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. Methods 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. Results 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. Conclusions Our study identify GPR56 as a suppressor of hepatocyte pyroptosis and liver fibrosis, underscoring its potential as a therapeutic and diagnostic target.https://doi.org/10.1186/s12967-025-06619-8Liver fibrosisGPCRHepatocytesPyroptosisHepatic stellate cellsNF-κB |
| spellingShingle | Zhemin Shi Qi Liu Mengxia Zhang Xiaoxiao Du Yifan He Lina Zheng Wei Hong Tao Han Kun Zhang GPR56 function as a key repressor in hepatocyte pyroptosis and the pathogenesis of liver fibrosis Journal of Translational Medicine Liver fibrosis GPCR Hepatocytes Pyroptosis Hepatic stellate cells NF-κB |
| title | GPR56 function as a key repressor in hepatocyte pyroptosis and the pathogenesis of liver fibrosis |
| title_full | GPR56 function as a key repressor in hepatocyte pyroptosis and the pathogenesis of liver fibrosis |
| title_fullStr | GPR56 function as a key repressor in hepatocyte pyroptosis and the pathogenesis of liver fibrosis |
| title_full_unstemmed | GPR56 function as a key repressor in hepatocyte pyroptosis and the pathogenesis of liver fibrosis |
| title_short | GPR56 function as a key repressor in hepatocyte pyroptosis and the pathogenesis of liver fibrosis |
| title_sort | gpr56 function as a key repressor in hepatocyte pyroptosis and the pathogenesis of liver fibrosis |
| topic | Liver fibrosis GPCR Hepatocytes Pyroptosis Hepatic stellate cells NF-κB |
| url | https://doi.org/10.1186/s12967-025-06619-8 |
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