The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells
Ferroptosis is a recently discovered form of programmed cell death, but its regulatory mechanisms are not fully understood. In the current study, we reported that the BRD7-P53-SLC25A28 axis played a crucial role in regulating ferroptosis in hepatic stellate cells (HSCs). Upon exposure to ferroptosis...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-09-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231720308247 |
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| author | Zili Zhang Mei Guo Min Shen Desong Kong Feng Zhang Jiangjuan Shao Shanzhong Tan Shijun Wang Anping Chen Peng Cao Shizhong Zheng |
| author_facet | Zili Zhang Mei Guo Min Shen Desong Kong Feng Zhang Jiangjuan Shao Shanzhong Tan Shijun Wang Anping Chen Peng Cao Shizhong Zheng |
| author_sort | Zili Zhang |
| collection | DOAJ |
| description | Ferroptosis is a recently discovered form of programmed cell death, but its regulatory mechanisms are not fully understood. In the current study, we reported that the BRD7-P53-SLC25A28 axis played a crucial role in regulating ferroptosis in hepatic stellate cells (HSCs). Upon exposure to ferroptosis inducers, bromodomain-containing protein 7 (BRD7) protein expression was remarkably increased through the inhibition of the ubiquitin-proteasome pathway. CRISPR/Cas9-mediated BRD7 knockout conferred resistance to HSC ferroptosis, whereas specific BRD7 plasmid-mediated BRD7 overexpression facilitated HSC ferroptosis. Interestingly, the elevated BRD7 expression exhibited to promote p53 mitochondrial translocation via direct binding with p53 N-terminal transactivation domain (TAD), which may be the underlying mechanisms for BRD7-enhanced HSC ferroptosis. Site-directed mutations of serine 392 completely blocked the binding of BRD7 to p53, and, in turn, prevented p53 mitochondrial translocation and HSC ferroptosis. Importantly, mitochondrial p53 interacted with solute carrier family 25 member 28 (SLC25A28) to form complex and enhanced the activity of SLC25A28, which could lead to the abnormal accumulation of redox-active iron and hyperfunction of electron transfer chain (ETC). SLC25A28 knockdown impaired BRD7-or p53-mediated ferroptotic events. In mice, erastin treatment ameliorated pathological damage of liver fibrosis through inducing HSC ferroptosis. HSC-specific blockade of BRD7-P53-SLC25A28 axis could abrogate erastin-induced HSC ferroptosis. Of note, we analyzed the effect of sorafenib on HSC ferroptosis in advanced fibrotic patients with hepatocellular carcinoma receiving sorafenib monotherapy. Attractively, BRD7 upregulation, p53 mitochondrial translocation, combination of SLC25A28 and p53, and ferroptosis induction occurred in primary human HSCs. Overall, these findings reveal novel signal transduction and regulatory mechanism of ferroptosis, and also suggest BRD7-P53-SLC25A28 axis as potential targets for liver fibrosis. |
| first_indexed | 2024-12-21T03:24:25Z |
| format | Article |
| id | doaj.art-c543470a43364137a063f001b1685efe |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-21T03:24:25Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-c543470a43364137a063f001b1685efe2022-12-21T19:17:39ZengElsevierRedox Biology2213-23172020-09-0136101619The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cellsZili Zhang0Mei Guo1Min Shen2Desong Kong3Feng Zhang4Jiangjuan Shao5Shanzhong Tan6Shijun Wang7Anping Chen8Peng Cao9Shizhong Zheng10Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, ChinaDepartment of Pathogenic Biology and Immunology, Medical School, Southeast University, Nanjing, 210009, ChinaDepartment of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, ChinaDepartment of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, ChinaDepartment of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, ChinaDepartment of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, ChinaNanjing Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210003, ChinaCollege of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250035, ChinaDepartment of Pathology, School of Medicine, Saint Louis University, St Louis, MO63104, USADepartment of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China; Corresponding author. Nanjing University of Chinese Medicine, China.Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China; Corresponding author. Nanjing University of Chinese Medicine, China.Ferroptosis is a recently discovered form of programmed cell death, but its regulatory mechanisms are not fully understood. In the current study, we reported that the BRD7-P53-SLC25A28 axis played a crucial role in regulating ferroptosis in hepatic stellate cells (HSCs). Upon exposure to ferroptosis inducers, bromodomain-containing protein 7 (BRD7) protein expression was remarkably increased through the inhibition of the ubiquitin-proteasome pathway. CRISPR/Cas9-mediated BRD7 knockout conferred resistance to HSC ferroptosis, whereas specific BRD7 plasmid-mediated BRD7 overexpression facilitated HSC ferroptosis. Interestingly, the elevated BRD7 expression exhibited to promote p53 mitochondrial translocation via direct binding with p53 N-terminal transactivation domain (TAD), which may be the underlying mechanisms for BRD7-enhanced HSC ferroptosis. Site-directed mutations of serine 392 completely blocked the binding of BRD7 to p53, and, in turn, prevented p53 mitochondrial translocation and HSC ferroptosis. Importantly, mitochondrial p53 interacted with solute carrier family 25 member 28 (SLC25A28) to form complex and enhanced the activity of SLC25A28, which could lead to the abnormal accumulation of redox-active iron and hyperfunction of electron transfer chain (ETC). SLC25A28 knockdown impaired BRD7-or p53-mediated ferroptotic events. In mice, erastin treatment ameliorated pathological damage of liver fibrosis through inducing HSC ferroptosis. HSC-specific blockade of BRD7-P53-SLC25A28 axis could abrogate erastin-induced HSC ferroptosis. Of note, we analyzed the effect of sorafenib on HSC ferroptosis in advanced fibrotic patients with hepatocellular carcinoma receiving sorafenib monotherapy. Attractively, BRD7 upregulation, p53 mitochondrial translocation, combination of SLC25A28 and p53, and ferroptosis induction occurred in primary human HSCs. Overall, these findings reveal novel signal transduction and regulatory mechanism of ferroptosis, and also suggest BRD7-P53-SLC25A28 axis as potential targets for liver fibrosis.http://www.sciencedirect.com/science/article/pii/S2213231720308247Hepatic stellate cellBRD7P53SLC25A28Ferroptosis |
| spellingShingle | Zili Zhang Mei Guo Min Shen Desong Kong Feng Zhang Jiangjuan Shao Shanzhong Tan Shijun Wang Anping Chen Peng Cao Shizhong Zheng The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells Redox Biology Hepatic stellate cell BRD7 P53 SLC25A28 Ferroptosis |
| title | The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells |
| title_full | The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells |
| title_fullStr | The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells |
| title_full_unstemmed | The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells |
| title_short | The BRD7-P53-SLC25A28 axis regulates ferroptosis in hepatic stellate cells |
| title_sort | brd7 p53 slc25a28 axis regulates ferroptosis in hepatic stellate cells |
| topic | Hepatic stellate cell BRD7 P53 SLC25A28 Ferroptosis |
| url | http://www.sciencedirect.com/science/article/pii/S2213231720308247 |
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