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已发表论文
CYBB介导的铁死亡驱动狼疮性肾炎足细胞损伤并可作为治疗靶点
Authors Wang B, Jiang H, Wu D , Liu M, Chen H, Zhao S, Yan Y, Li S, Fang X, Wu R
Received 23 October 2025
Accepted for publication 24 December 2025
Published 22 January 2026 Volume 2026:19 575320
DOI https://doi.org/10.2147/JIR.S575320
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Wenjian Li
Bihua Wang,* Houhui Jiang,* Dengfeng Wu, Mengxia Liu, Haili Chen, Sheng Zhao, Yuxin Yan, Sanyun Li, Xia Fang, Rui Wu
Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Rui Wu, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Donghu District, Nanchang, Jiangxi, 330006, People’s Republic of China, Email ndyfy00400@ncu.edu.cn
Objective: Lupus nephritis (LN) is a major cause of kidney failure in systemic lupus erythematosus, with podocyte injury being a key determinant of proteinuria and poor renal outcome. Ferroptosis, an iron-dependent form of regulated cell death, has been implicated in kidney diseases, but its role in LN remains unclear.
Methods: We integrated in vivo experiments using MRL/lpr mice, in vitro assays with immortalized podocytes (MPC5), and transcriptomic analysis of human glomerular datasets (GSE32591). Ferroptosis involvement was evaluated by ferrostatin-1 (Fer-1) treatment, measurement of ferroptosis markers, and assessment of podocyte proteins. Bioinformatic analyses (differential expression, WGCNA, LASSO regression, and FerrDb integration) identified candidate ferroptosis regulators, followed by functional validation of CYBB via siRNA knockdown and overexpression.
Results: Progressive nephritis in MRL/lpr mice showed iron overload, lipid peroxidation, glutathione depletion, and GPX4 downregulation, leading to podocyte loss and proteinuria. Fer-1 treatment markedly ameliorated renal pathology and preserved podocyte integrity. Human LN datasets identified CYBB as a ferroptosis-related hub gene upregulated in disease. CYBB expression correlated with renal dysfunction and oxidative injury, while in vitro assays confirmed that CYBB overexpression enhanced ROS generation and ferroptotic podocyte damage, whereas CYBB knockdown or Fer-1 reversed these effects.
Conclusion: These findings identify CYBB-mediated ferroptosis as a key driver of podocyte injury in LN. By promoting ROS generation and lipid peroxidation, CYBB serves as a mechanistic link between oxidative stress and ferroptotic cell death. Both pharmacological and genetic inhibition of CYBB mitigated ferroptosis, preserved podocyte integrity, and improved renal function, highlighting CYBB as a promising therapeutic target in lupus nephritis.
Keywords: lupus nephritis, podocyte injury, ferroptosis, CYBB
Department of Rheumatology and Immunology, The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Rui Wu, The First Affiliated Hospital of Nanchang University, No. 17, Yongwaizheng Street, Donghu District, Nanchang, Jiangxi, 330006, People’s Republic of China, Email ndyfy00400@ncu.edu.cn
Objective: Lupus nephritis (LN) is a major cause of kidney failure in systemic lupus erythematosus, with podocyte injury being a key determinant of proteinuria and poor renal outcome. Ferroptosis, an iron-dependent form of regulated cell death, has been implicated in kidney diseases, but its role in LN remains unclear.
Methods: We integrated in vivo experiments using MRL/lpr mice, in vitro assays with immortalized podocytes (MPC5), and transcriptomic analysis of human glomerular datasets (GSE32591). Ferroptosis involvement was evaluated by ferrostatin-1 (Fer-1) treatment, measurement of ferroptosis markers, and assessment of podocyte proteins. Bioinformatic analyses (differential expression, WGCNA, LASSO regression, and FerrDb integration) identified candidate ferroptosis regulators, followed by functional validation of CYBB via siRNA knockdown and overexpression.
Results: Progressive nephritis in MRL/lpr mice showed iron overload, lipid peroxidation, glutathione depletion, and GPX4 downregulation, leading to podocyte loss and proteinuria. Fer-1 treatment markedly ameliorated renal pathology and preserved podocyte integrity. Human LN datasets identified CYBB as a ferroptosis-related hub gene upregulated in disease. CYBB expression correlated with renal dysfunction and oxidative injury, while in vitro assays confirmed that CYBB overexpression enhanced ROS generation and ferroptotic podocyte damage, whereas CYBB knockdown or Fer-1 reversed these effects.
Conclusion: These findings identify CYBB-mediated ferroptosis as a key driver of podocyte injury in LN. By promoting ROS generation and lipid peroxidation, CYBB serves as a mechanistic link between oxidative stress and ferroptotic cell death. Both pharmacological and genetic inhibition of CYBB mitigated ferroptosis, preserved podocyte integrity, and improved renal function, highlighting CYBB as a promising therapeutic target in lupus nephritis.
Keywords: lupus nephritis, podocyte injury, ferroptosis, CYBB