Inhibition of RAC1 activator DOCK2 ameliorates cholestatic liver injury via regulating macrophage polarisation and hepatic stellate cell activation
Abstract Background The Rho GTPase Rac family small GTPase 1 (RAC1) is considered a promising fibrotic therapeutic target, but the role of its activator, dedicator of cytokinesis 2 (DOCK2), in liver fibrosis is largely unknown. This study aimed to investigate the expression and role of DOCK2 in chol...
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BMC
2025-02-01
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| Series: | Biology Direct |
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| Online Access: | https://doi.org/10.1186/s13062-025-00612-3 |
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| author | Jianli Qiu Yitong Qu Yinli Li Cancan Li Junling Wang Lu Meng Xiaojin Jing Jiangping Fu Yan Xu Yuna Chai |
| author_facet | Jianli Qiu Yitong Qu Yinli Li Cancan Li Junling Wang Lu Meng Xiaojin Jing Jiangping Fu Yan Xu Yuna Chai |
| author_sort | Jianli Qiu |
| collection | DOAJ |
| description | Abstract Background The Rho GTPase Rac family small GTPase 1 (RAC1) is considered a promising fibrotic therapeutic target, but the role of its activator, dedicator of cytokinesis 2 (DOCK2), in liver fibrosis is largely unknown. This study aimed to investigate the expression and role of DOCK2 in cholestasis-induced liver fibrosis and to further explore the potential mechanisms. Results Cholestasis was induced in male C57BL/6 mice by bile duct ligation (BDL). DOCK2 knockdown was achieved by tail vein injection of adenovirus containing DOCK2-targeting shRNA. The effect of DOCK2 knockdown on cholestatic liver injury was evaluated at different time points after BDL. Hepatic DOCK2 expression gradually increased after BDL. Knockdown of DOCK2 reduced the necrotic area in BDL liver and downregulated serum levels of liver injury indicators. At 3d post-BDL (acute phase), DOCK2 knockdown alleviated M1 macrophage inflammation in the liver, as evidenced by reduced infiltrating iNOS + macrophages and inflammatory cytokines and mitigated NLRP3 inflammasome activation. At 14d post-BDL (chronic phase), DOCK2 knockdown suppressed hepatic stellate cell (HSC) activation and liver fibrosis as indicated by decreased α-SMA + HSCs and extracellular matrix deposition. In vitro experiments further demonstrated that DOCK2 knockdown suppressed M1 macrophage polarisation and HSC to myofibroblast transition, accompanied by inhibition of RAC1 activation. Conclusions In summary, this study demonstrates for the first time that the RAC1 activator DOCK2 regulates M1 macrophage polarisation and hepatic stellate cell activation to promote cholestasis-induced liver inflammation and fibrosis, suggesting that DOCK2 may be a potential therapeutic target in cholestatic liver injury. |
| format | Article |
| id | doaj-art-01c2ae99d7f64abc9993226eaf9fe520 |
| institution | Kabale University |
| issn | 1745-6150 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Biology Direct |
| spelling | doaj-art-01c2ae99d7f64abc9993226eaf9fe5202025-02-09T12:16:41ZengBMCBiology Direct1745-61502025-02-0120111610.1186/s13062-025-00612-3Inhibition of RAC1 activator DOCK2 ameliorates cholestatic liver injury via regulating macrophage polarisation and hepatic stellate cell activationJianli Qiu0Yitong Qu1Yinli Li2Cancan Li3Junling Wang4Lu Meng5Xiaojin Jing6Jiangping Fu7Yan Xu8Yuna Chai9Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese MedicineDepartment of Pediatrics, The First Affiliated Hospital of Henan University of Chinese MedicineDepartment of Pediatrics, The First Affiliated Hospital of Henan University of Chinese MedicineDepartment of Pediatrics, The First Affiliated Hospital of Henan University of Chinese MedicineDepartment of Pediatrics, The First Affiliated Hospital of Henan University of Chinese MedicineDepartment of Pediatrics, The First Affiliated Hospital of Henan University of Chinese MedicineDepartment of Pediatrics, The First Affiliated Hospital of Henan University of Chinese MedicineDepartment of Pediatrics, The First Affiliated Hospital of Henan University of Chinese MedicineDepartment of Pediatrics, The First Affiliated Hospital of Henan University of Chinese MedicineDepartment of Pharmacy, The First Affiliated Hospital of Zhengzhou UniversityAbstract Background The Rho GTPase Rac family small GTPase 1 (RAC1) is considered a promising fibrotic therapeutic target, but the role of its activator, dedicator of cytokinesis 2 (DOCK2), in liver fibrosis is largely unknown. This study aimed to investigate the expression and role of DOCK2 in cholestasis-induced liver fibrosis and to further explore the potential mechanisms. Results Cholestasis was induced in male C57BL/6 mice by bile duct ligation (BDL). DOCK2 knockdown was achieved by tail vein injection of adenovirus containing DOCK2-targeting shRNA. The effect of DOCK2 knockdown on cholestatic liver injury was evaluated at different time points after BDL. Hepatic DOCK2 expression gradually increased after BDL. Knockdown of DOCK2 reduced the necrotic area in BDL liver and downregulated serum levels of liver injury indicators. At 3d post-BDL (acute phase), DOCK2 knockdown alleviated M1 macrophage inflammation in the liver, as evidenced by reduced infiltrating iNOS + macrophages and inflammatory cytokines and mitigated NLRP3 inflammasome activation. At 14d post-BDL (chronic phase), DOCK2 knockdown suppressed hepatic stellate cell (HSC) activation and liver fibrosis as indicated by decreased α-SMA + HSCs and extracellular matrix deposition. In vitro experiments further demonstrated that DOCK2 knockdown suppressed M1 macrophage polarisation and HSC to myofibroblast transition, accompanied by inhibition of RAC1 activation. Conclusions In summary, this study demonstrates for the first time that the RAC1 activator DOCK2 regulates M1 macrophage polarisation and hepatic stellate cell activation to promote cholestasis-induced liver inflammation and fibrosis, suggesting that DOCK2 may be a potential therapeutic target in cholestatic liver injury.https://doi.org/10.1186/s13062-025-00612-3DOCK2RAC1CholestasisLiver fibrosisHepatic stellate cellMacrophage polarisation |
| spellingShingle | Jianli Qiu Yitong Qu Yinli Li Cancan Li Junling Wang Lu Meng Xiaojin Jing Jiangping Fu Yan Xu Yuna Chai Inhibition of RAC1 activator DOCK2 ameliorates cholestatic liver injury via regulating macrophage polarisation and hepatic stellate cell activation Biology Direct DOCK2 RAC1 Cholestasis Liver fibrosis Hepatic stellate cell Macrophage polarisation |
| title | Inhibition of RAC1 activator DOCK2 ameliorates cholestatic liver injury via regulating macrophage polarisation and hepatic stellate cell activation |
| title_full | Inhibition of RAC1 activator DOCK2 ameliorates cholestatic liver injury via regulating macrophage polarisation and hepatic stellate cell activation |
| title_fullStr | Inhibition of RAC1 activator DOCK2 ameliorates cholestatic liver injury via regulating macrophage polarisation and hepatic stellate cell activation |
| title_full_unstemmed | Inhibition of RAC1 activator DOCK2 ameliorates cholestatic liver injury via regulating macrophage polarisation and hepatic stellate cell activation |
| title_short | Inhibition of RAC1 activator DOCK2 ameliorates cholestatic liver injury via regulating macrophage polarisation and hepatic stellate cell activation |
| title_sort | inhibition of rac1 activator dock2 ameliorates cholestatic liver injury via regulating macrophage polarisation and hepatic stellate cell activation |
| topic | DOCK2 RAC1 Cholestasis Liver fibrosis Hepatic stellate cell Macrophage polarisation |
| url | https://doi.org/10.1186/s13062-025-00612-3 |
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