Quercetagetin alleviates liver fibrosis in non-alcoholic fatty liver disease by promoting ferroptosis of hepatic stellate cells through GPX4 ubiquitination
Abstract Background Lang Qing A Ta (Huagan Tongluo Fang, HGTLF) is a Tibetan medicine with significant anti-liver fibrosis effects and good efficacy in the treatment of liver diseases, including non-alcoholic fatty liver disease (NAFLD). Quercetagetin (QG) has been identified as an active ingredient...
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BMC
2025-06-01
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| Series: | Chinese Medicine |
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| Online Access: | https://doi.org/10.1186/s13020-025-01109-x |
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| author | Yuping Qiu Shupei Li Mingzuo Jiang Ang Huang Ya Yang Xi Chen Hui Li Zhizhou Yang Juan Wei Ji Xuan |
| author_facet | Yuping Qiu Shupei Li Mingzuo Jiang Ang Huang Ya Yang Xi Chen Hui Li Zhizhou Yang Juan Wei Ji Xuan |
| author_sort | Yuping Qiu |
| collection | DOAJ |
| description | Abstract Background Lang Qing A Ta (Huagan Tongluo Fang, HGTLF) is a Tibetan medicine with significant anti-liver fibrosis effects and good efficacy in the treatment of liver diseases, including non-alcoholic fatty liver disease (NAFLD). Quercetagetin (QG) has been identified as an active ingredient of HGTLF that is absorbed into the blood. This study aims to investigate the role of QG in the anti-liver fibrosis effect of HGTLF in NAFLD. Methods CCl4 injection-induced liver fibrosis and high-fat, high-cholesterol diet-induced non-alcoholic steatohepatitis (NASH) mouse models were established. Transforming growth factor-β1 (TGF-β1)-induced hepatic stellate cells (HSCs) were used as in vitro models. The effect of QG on the stability and degradation pathway of glu-tathione peroxidase 4 (GPX4) protein was investigated. Results QG improved liver function and hyperlipidemia in CCl4-injected mice and NASH mice, and alleviated hepatic lipid deposition and hepatic fibrosis. TGF-β1 treatment promoted the expression of α-smooth muscle actin and fibrosis-related genes, while QG reversed this phenomenon and inhibited HSC activation. QG increased the intracellular labile iron pool and lipid reactive oxygen species in HSCs. Treatment with the ferroptosis inhibitor ferrostatin-1 reversed the inhibitory effect of QG on TGF-β1-induced HSC activation. QG reduced GPX4 protein stability and regulated GPX4 K167 ubiquitination via the membrane-associated ring-CH-type finger 8 (MARCHF8)-mediated ubiquitin–proteasome pathway. Interference with MARCHF8 attenuated the effect of QG and promoted HSC activation induced by TGF-β1. Conclusion QG, the active ingredient of HGTLF, can induce ferroptosis of HSCs by targeting the degradation of GPX4 through ubiquitination and inhibit HSC activation, thereby alleviating liver fibrosis in NAFLD. |
| format | Article |
| id | doaj-art-2b2ac95fca3744aa8cda385c3f01d628 |
| institution | OA Journals |
| issn | 1749-8546 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
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| series | Chinese Medicine |
| spelling | doaj-art-2b2ac95fca3744aa8cda385c3f01d6282025-08-20T02:10:34ZengBMCChinese Medicine1749-85462025-06-0120111810.1186/s13020-025-01109-xQuercetagetin alleviates liver fibrosis in non-alcoholic fatty liver disease by promoting ferroptosis of hepatic stellate cells through GPX4 ubiquitinationYuping Qiu0Shupei Li1Mingzuo Jiang2Ang Huang3Ya Yang4Xi Chen5Hui Li6Zhizhou Yang7Juan Wei8Ji Xuan9Department of Gastroenterology, School of Medicine, Jinling Hospital, Nanjing UniversityJinling Clinical Medical College, Nanjing University of Chinese MedicineDepartment of Gastroenterology, School of Medicine, Jinling Hospital, Nanjing UniversityDepartment of Gastroenterology and Hepatology, The First Medical Center of PLA General HospitalDepartment of Gastroenterology, School of Medicine, Jinling Hospital, Nanjing UniversityDepartment of Gastroenterology, School of Medicine, Jinling Hospital, Nanjing UniversityDepartment of Gastroenterology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese MedicineDepartment of Outpatient and Emergency, Qinhuai Medical District, Affiliated Hospital of Medical School, Jinling Hospital, Nanjing UniversityDepartment of Gastroenterology, School of Medicine, Jinling Hospital, Nanjing UniversityDepartment of Gastroenterology, School of Medicine, Jinling Hospital, Nanjing UniversityAbstract Background Lang Qing A Ta (Huagan Tongluo Fang, HGTLF) is a Tibetan medicine with significant anti-liver fibrosis effects and good efficacy in the treatment of liver diseases, including non-alcoholic fatty liver disease (NAFLD). Quercetagetin (QG) has been identified as an active ingredient of HGTLF that is absorbed into the blood. This study aims to investigate the role of QG in the anti-liver fibrosis effect of HGTLF in NAFLD. Methods CCl4 injection-induced liver fibrosis and high-fat, high-cholesterol diet-induced non-alcoholic steatohepatitis (NASH) mouse models were established. Transforming growth factor-β1 (TGF-β1)-induced hepatic stellate cells (HSCs) were used as in vitro models. The effect of QG on the stability and degradation pathway of glu-tathione peroxidase 4 (GPX4) protein was investigated. Results QG improved liver function and hyperlipidemia in CCl4-injected mice and NASH mice, and alleviated hepatic lipid deposition and hepatic fibrosis. TGF-β1 treatment promoted the expression of α-smooth muscle actin and fibrosis-related genes, while QG reversed this phenomenon and inhibited HSC activation. QG increased the intracellular labile iron pool and lipid reactive oxygen species in HSCs. Treatment with the ferroptosis inhibitor ferrostatin-1 reversed the inhibitory effect of QG on TGF-β1-induced HSC activation. QG reduced GPX4 protein stability and regulated GPX4 K167 ubiquitination via the membrane-associated ring-CH-type finger 8 (MARCHF8)-mediated ubiquitin–proteasome pathway. Interference with MARCHF8 attenuated the effect of QG and promoted HSC activation induced by TGF-β1. Conclusion QG, the active ingredient of HGTLF, can induce ferroptosis of HSCs by targeting the degradation of GPX4 through ubiquitination and inhibit HSC activation, thereby alleviating liver fibrosis in NAFLD.https://doi.org/10.1186/s13020-025-01109-xNon-alcoholic fatty liver diseaseHepatic stellate cellsQuercetagetinFerroptosisGPX4 ubiquitination |
| spellingShingle | Yuping Qiu Shupei Li Mingzuo Jiang Ang Huang Ya Yang Xi Chen Hui Li Zhizhou Yang Juan Wei Ji Xuan Quercetagetin alleviates liver fibrosis in non-alcoholic fatty liver disease by promoting ferroptosis of hepatic stellate cells through GPX4 ubiquitination Chinese Medicine Non-alcoholic fatty liver disease Hepatic stellate cells Quercetagetin Ferroptosis GPX4 ubiquitination |
| title | Quercetagetin alleviates liver fibrosis in non-alcoholic fatty liver disease by promoting ferroptosis of hepatic stellate cells through GPX4 ubiquitination |
| title_full | Quercetagetin alleviates liver fibrosis in non-alcoholic fatty liver disease by promoting ferroptosis of hepatic stellate cells through GPX4 ubiquitination |
| title_fullStr | Quercetagetin alleviates liver fibrosis in non-alcoholic fatty liver disease by promoting ferroptosis of hepatic stellate cells through GPX4 ubiquitination |
| title_full_unstemmed | Quercetagetin alleviates liver fibrosis in non-alcoholic fatty liver disease by promoting ferroptosis of hepatic stellate cells through GPX4 ubiquitination |
| title_short | Quercetagetin alleviates liver fibrosis in non-alcoholic fatty liver disease by promoting ferroptosis of hepatic stellate cells through GPX4 ubiquitination |
| title_sort | quercetagetin alleviates liver fibrosis in non alcoholic fatty liver disease by promoting ferroptosis of hepatic stellate cells through gpx4 ubiquitination |
| topic | Non-alcoholic fatty liver disease Hepatic stellate cells Quercetagetin Ferroptosis GPX4 ubiquitination |
| url | https://doi.org/10.1186/s13020-025-01109-x |
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