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Publications

Journal Article Epublish

PubMed: 39500879 DOI: 10.1038/s41419-024-07185-5

OTUB1 regulation of ferroptosis and the protective role of ferrostatin-1 in lupus nephritis.

Cell Death Dis 15(11):791

Authors: Chen Liu, Yu-Hui Gan, Wei-Jing Yong, Hong-de Xu, Yong-Chun Li, Hui-Miao Hu, Zhan-Zheng Zhao, Yuan-Yuan Qi

Affiliations

  • Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, P. R. China. Zhengzhou University, Zhengzhou, Henan, 450001, P. R. China. Laboratory of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, P. R. China.
  • Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, P. R. China. Zhengzhou University, Zhengzhou, Henan, 450001, P. R. China. School of Pharmaceutical Sciences, Zhengzhou University, 100 Ke xue Avenue, Zhengzhou, Henan, 450001, China.
  • Zhengzhou University, Zhengzhou, Henan, 450001, P. R. China. Ministry of Education of China, Institute of Drug Discovery and Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, China.
  • Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, P. R. China.
  • Zhengzhou University, Zhengzhou, Henan, 450001, P. R. China.
  • Laboratory of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, P. R. China.
  • Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, P. R. China. Zhengzhou University, Zhengzhou, Henan, 450001, P. R. China. Laboratory of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, P. R. China.

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, Fe 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.

MeSH

Cells, Podocytes, Ferroptosis, Lupus Nephritis, Therapeutics, Nephritis, Cell Death

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