Taxifolin attenuates liver fibrosis by regulating the phosphorylation of NDRG1 at Thr328 via hepatocyte-stellate cell cross talk
Taxifolin (TAX) is a natural compound known for its liver protection effect, but the mechanism remains unknown. Phosphorylated proteomics analyses discovered that the phosphorylation level of NDRG1 at T328 was a key event of TAX-improved liver fibrosis. We established models with NDRG1 knockout (KO)...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-04-01
|
| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383525000905 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850143661922189312 |
|---|---|
| author | Chuan Ding Zeping Wang Kao Shi Sunan Li Xinyue Dou Yan Ning Gang Cheng Qiao Yang Xianan Sang Mengyun Peng Qiang Lyu Lu Wang Xin Han Gang Cao |
| author_facet | Chuan Ding Zeping Wang Kao Shi Sunan Li Xinyue Dou Yan Ning Gang Cheng Qiao Yang Xianan Sang Mengyun Peng Qiang Lyu Lu Wang Xin Han Gang Cao |
| author_sort | Chuan Ding |
| collection | DOAJ |
| description | Taxifolin (TAX) is a natural compound known for its liver protection effect, but the mechanism remains unknown. Phosphorylated proteomics analyses discovered that the phosphorylation level of NDRG1 at T328 was a key event of TAX-improved liver fibrosis. We established models with NDRG1 knockout (KO) in vivo and in vitro, demonstrating that NDRG1 KO attenuated the development of hepatocyte injury, and combining NDRG1 KO and TAX administration did not result in a reduction in protection against liver injury. Cellular thermal shift assay and surface plasma resonance analysis showed that TAX directly binds to NDRG1 rather than its upstream kinase, subsequently demonstrating that TAX regulated phosphorylation of NDRG1 at T328 through binding to its C289 site. NDRG1 T328A (phosphorylated mutation) and T328E (mimic phosphorylation) in vivo and in vitro confirmed that pNDRG1T328 exacerbates hepatocyte injury along with DNA damage, inflammatory response, and apoptosis, thereby contributing to hepatic stellate cells (HSCs) activation. In contrast, TAX can inhibit the above pathological abnormalities and block hepatocyte injury-triggered HSCs activation and fibrosis. Overall, TAX is a potent liver protection drug primarily targeting NDRG1 and inhibiting pNDRG1T328 in hepatocytes. |
| format | Article |
| id | doaj-art-cd2df7782d264bd0b6ae7dbf5974634f |
| institution | OA Journals |
| issn | 2211-3835 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj-art-cd2df7782d264bd0b6ae7dbf5974634f2025-08-20T02:28:37ZengElsevierActa Pharmaceutica Sinica B2211-38352025-04-011542059207610.1016/j.apsb.2025.02.017Taxifolin attenuates liver fibrosis by regulating the phosphorylation of NDRG1 at Thr328 via hepatocyte-stellate cell cross talkChuan Ding0Zeping Wang1Kao Shi2Sunan Li3Xinyue Dou4Yan Ning5Gang Cheng6Qiao Yang7Xianan Sang8Mengyun Peng9Qiang Lyu10Lu Wang11Xin Han12Gang Cao13The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310000, China; School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, ChinaSchool of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, ChinaSchool of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, ChinaSchool of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, ChinaSchool of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, ChinaSchool of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, ChinaSchool of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, ChinaSchool of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, ChinaSchool of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, ChinaSchool of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, ChinaSchool of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, ChinaSchool of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, ChinaThe First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310000, China; School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, China; Corresponding authors.The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310000, China; School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou 310053, China; Corresponding authors.Taxifolin (TAX) is a natural compound known for its liver protection effect, but the mechanism remains unknown. Phosphorylated proteomics analyses discovered that the phosphorylation level of NDRG1 at T328 was a key event of TAX-improved liver fibrosis. We established models with NDRG1 knockout (KO) in vivo and in vitro, demonstrating that NDRG1 KO attenuated the development of hepatocyte injury, and combining NDRG1 KO and TAX administration did not result in a reduction in protection against liver injury. Cellular thermal shift assay and surface plasma resonance analysis showed that TAX directly binds to NDRG1 rather than its upstream kinase, subsequently demonstrating that TAX regulated phosphorylation of NDRG1 at T328 through binding to its C289 site. NDRG1 T328A (phosphorylated mutation) and T328E (mimic phosphorylation) in vivo and in vitro confirmed that pNDRG1T328 exacerbates hepatocyte injury along with DNA damage, inflammatory response, and apoptosis, thereby contributing to hepatic stellate cells (HSCs) activation. In contrast, TAX can inhibit the above pathological abnormalities and block hepatocyte injury-triggered HSCs activation and fibrosis. Overall, TAX is a potent liver protection drug primarily targeting NDRG1 and inhibiting pNDRG1T328 in hepatocytes.http://www.sciencedirect.com/science/article/pii/S2211383525000905TaxifolinLiver fibrosispNDRG1T328HepatocyteLiver injuryHSCs |
| spellingShingle | Chuan Ding Zeping Wang Kao Shi Sunan Li Xinyue Dou Yan Ning Gang Cheng Qiao Yang Xianan Sang Mengyun Peng Qiang Lyu Lu Wang Xin Han Gang Cao Taxifolin attenuates liver fibrosis by regulating the phosphorylation of NDRG1 at Thr328 via hepatocyte-stellate cell cross talk Acta Pharmaceutica Sinica B Taxifolin Liver fibrosis pNDRG1T328 Hepatocyte Liver injury HSCs |
| title | Taxifolin attenuates liver fibrosis by regulating the phosphorylation of NDRG1 at Thr328 via hepatocyte-stellate cell cross talk |
| title_full | Taxifolin attenuates liver fibrosis by regulating the phosphorylation of NDRG1 at Thr328 via hepatocyte-stellate cell cross talk |
| title_fullStr | Taxifolin attenuates liver fibrosis by regulating the phosphorylation of NDRG1 at Thr328 via hepatocyte-stellate cell cross talk |
| title_full_unstemmed | Taxifolin attenuates liver fibrosis by regulating the phosphorylation of NDRG1 at Thr328 via hepatocyte-stellate cell cross talk |
| title_short | Taxifolin attenuates liver fibrosis by regulating the phosphorylation of NDRG1 at Thr328 via hepatocyte-stellate cell cross talk |
| title_sort | taxifolin attenuates liver fibrosis by regulating the phosphorylation of ndrg1 at thr328 via hepatocyte stellate cell cross talk |
| topic | Taxifolin Liver fibrosis pNDRG1T328 Hepatocyte Liver injury HSCs |
| url | http://www.sciencedirect.com/science/article/pii/S2211383525000905 |
| work_keys_str_mv | AT chuanding taxifolinattenuatesliverfibrosisbyregulatingthephosphorylationofndrg1atthr328viahepatocytestellatecellcrosstalk AT zepingwang taxifolinattenuatesliverfibrosisbyregulatingthephosphorylationofndrg1atthr328viahepatocytestellatecellcrosstalk AT kaoshi taxifolinattenuatesliverfibrosisbyregulatingthephosphorylationofndrg1atthr328viahepatocytestellatecellcrosstalk AT sunanli taxifolinattenuatesliverfibrosisbyregulatingthephosphorylationofndrg1atthr328viahepatocytestellatecellcrosstalk AT xinyuedou taxifolinattenuatesliverfibrosisbyregulatingthephosphorylationofndrg1atthr328viahepatocytestellatecellcrosstalk AT yanning taxifolinattenuatesliverfibrosisbyregulatingthephosphorylationofndrg1atthr328viahepatocytestellatecellcrosstalk AT gangcheng taxifolinattenuatesliverfibrosisbyregulatingthephosphorylationofndrg1atthr328viahepatocytestellatecellcrosstalk AT qiaoyang taxifolinattenuatesliverfibrosisbyregulatingthephosphorylationofndrg1atthr328viahepatocytestellatecellcrosstalk AT xianansang taxifolinattenuatesliverfibrosisbyregulatingthephosphorylationofndrg1atthr328viahepatocytestellatecellcrosstalk AT mengyunpeng taxifolinattenuatesliverfibrosisbyregulatingthephosphorylationofndrg1atthr328viahepatocytestellatecellcrosstalk AT qianglyu taxifolinattenuatesliverfibrosisbyregulatingthephosphorylationofndrg1atthr328viahepatocytestellatecellcrosstalk AT luwang taxifolinattenuatesliverfibrosisbyregulatingthephosphorylationofndrg1atthr328viahepatocytestellatecellcrosstalk AT xinhan taxifolinattenuatesliverfibrosisbyregulatingthephosphorylationofndrg1atthr328viahepatocytestellatecellcrosstalk AT gangcao taxifolinattenuatesliverfibrosisbyregulatingthephosphorylationofndrg1atthr328viahepatocytestellatecellcrosstalk |