OTUB1 regulation of ferroptosis and the protective role of ferrostatin-1 in lupus nephritis
Abstract Lupus nephritis (LN) is a prevalent and severe manifestation of systemic lupus erythematosus (SLE), leading to significant morbidity and mortality. OTUB1, a deubiquitinating enzyme, has emerged as a potential therapeutic target due to its role in cellular protection and regulation of ferrop...
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| Format: | Article |
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Nature Publishing Group
2024-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07185-5 |
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| author | Chen Liu Yu-hui Gan Wei-jing Yong Hong-de Xu Yong-chun Li Hui-miao Hu Zhan-zheng Zhao Yuan-yuan Qi |
| author_facet | Chen Liu Yu-hui Gan Wei-jing Yong Hong-de Xu Yong-chun Li Hui-miao Hu Zhan-zheng Zhao Yuan-yuan Qi |
| author_sort | Chen Liu |
| collection | DOAJ |
| description | Abstract Lupus nephritis (LN) is a prevalent and severe manifestation of systemic lupus erythematosus (SLE), leading to significant morbidity and mortality. OTUB1, a deubiquitinating enzyme, has emerged as a potential therapeutic target due to its role in cellular protection and regulation of ferroptosis, a form of cell death linked to LN. Our study revealed significantly reduced OTUB1 expression in the glomeruli of LN patients and podocytes, correlated with disease severity. CRISPR/Cas9-mediated OTUB1 knockout in podocytes resulted in pronounced injury, indicated by decreased levels of nephrin and podocin. Ferrostatin-1 treatment effectively mitigated this injury, restoring SLC7A11 expression and significantly reducing MDA levels, Fe2+ levels, BODIPY C11 expression, and normalized cysteine and glutathione expression. In the MRL/lpr mouse model, Ferrostatin-1 significantly improved renal function decreased proteinuria, and ameliorated renal histopathological changes, including reduced glomerular endothelial swelling, mesangial cell proliferation, and leukocyte infiltration. These results underscore the protective role of Ferrostatin-1 in modulating the pathogenesis of LN. OTUB1 plays a crucial protective role against podocyte injury in LN by regulating ferroptosis. Ferrostatin-1 effectively mitigates podocyte damage induced by OTUB1 deficiency, suggesting that targeting ferroptosis could be a promising therapeutic strategy for LN. |
| format | Article |
| id | doaj-art-431c0453dc124f08bdb16b41fcec7cd0 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death and Disease |
| spelling | doaj-art-431c0453dc124f08bdb16b41fcec7cd02024-11-10T12:44:59ZengNature Publishing GroupCell Death and Disease2041-48892024-11-01151111210.1038/s41419-024-07185-5OTUB1 regulation of ferroptosis and the protective role of ferrostatin-1 in lupus nephritisChen Liu0Yu-hui Gan1Wei-jing Yong2Hong-de Xu3Yong-chun Li4Hui-miao Hu5Zhan-zheng Zhao6Yuan-yuan Qi7Department of Nephrology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Nephrology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Nephrology, The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou UniversityDepartment of Nephrology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Nephrology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Nephrology, The First Affiliated Hospital of Zhengzhou UniversityAbstract Lupus nephritis (LN) is a prevalent and severe manifestation of systemic lupus erythematosus (SLE), leading to significant morbidity and mortality. OTUB1, a deubiquitinating enzyme, has emerged as a potential therapeutic target due to its role in cellular protection and regulation of ferroptosis, a form of cell death linked to LN. Our study revealed significantly reduced OTUB1 expression in the glomeruli of LN patients and podocytes, correlated with disease severity. CRISPR/Cas9-mediated OTUB1 knockout in podocytes resulted in pronounced injury, indicated by decreased levels of nephrin and podocin. Ferrostatin-1 treatment effectively mitigated this injury, restoring SLC7A11 expression and significantly reducing MDA levels, Fe2+ levels, BODIPY C11 expression, and normalized cysteine and glutathione expression. In the MRL/lpr mouse model, Ferrostatin-1 significantly improved renal function decreased proteinuria, and ameliorated renal histopathological changes, including reduced glomerular endothelial swelling, mesangial cell proliferation, and leukocyte infiltration. These results underscore the protective role of Ferrostatin-1 in modulating the pathogenesis of LN. OTUB1 plays a crucial protective role against podocyte injury in LN by regulating ferroptosis. Ferrostatin-1 effectively mitigates podocyte damage induced by OTUB1 deficiency, suggesting that targeting ferroptosis could be a promising therapeutic strategy for LN.https://doi.org/10.1038/s41419-024-07185-5 |
| spellingShingle | Chen Liu Yu-hui Gan Wei-jing Yong Hong-de Xu Yong-chun Li Hui-miao Hu Zhan-zheng Zhao Yuan-yuan Qi OTUB1 regulation of ferroptosis and the protective role of ferrostatin-1 in lupus nephritis Cell Death and Disease |
| title | OTUB1 regulation of ferroptosis and the protective role of ferrostatin-1 in lupus nephritis |
| title_full | OTUB1 regulation of ferroptosis and the protective role of ferrostatin-1 in lupus nephritis |
| title_fullStr | OTUB1 regulation of ferroptosis and the protective role of ferrostatin-1 in lupus nephritis |
| title_full_unstemmed | OTUB1 regulation of ferroptosis and the protective role of ferrostatin-1 in lupus nephritis |
| title_short | OTUB1 regulation of ferroptosis and the protective role of ferrostatin-1 in lupus nephritis |
| title_sort | otub1 regulation of ferroptosis and the protective role of ferrostatin 1 in lupus nephritis |
| url | https://doi.org/10.1038/s41419-024-07185-5 |
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