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Background <p>HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase Family Member 6 (HERC6) is an IFN-stimulated gene (ISG) encoding an E3 ubiquitin ligase that plays significant roles in antiviral innate immunity. However, current research on HERC6 has primarily focused on the liver and immune cells. Its expression, regulation, and function in the kidney, particularly in podocytes remain largely unexplored. The aim of this study is to investigate the pathogenic role and mechanism of the E3 ubiquitin ligase HERC6 in podocyte injury of lupus nephritis (LN).</p> Methods <p>Key genes were identified through bioinformatic screening of LN patient datasets. HERC6 expression was validated in renal tissues from LN patients and two lupus murine models, and the correlation between its urinary HERC6 levels and the clinical parameters of patients was analyzed. In vivo, the therapeutic efficacy of renal HERC6 knockdown was evaluated in MRL/<i>lpr</i> mice using AAV9-mediated delivery of HERC6-specific shRNA.In vitro, podocytes were stimulated with IFN-α to investigate gene induction. Following HERC6 knockdown, cellular phenotypes, inflammatory cytokine secretion, apoptosis, cell cycle, and mitotic spindle morphology were analyzed using qPCR, western blot, flow cytometry, ELISA, and immunofluorescence.</p> Results <p>Bioinformatic analysis identified HERC6 as a key differentially expressed gene in LN. Its significant upregulation was validated in renal tissues especially in glomerulus from LN patients and two murine lupus models. Moreover, clinical specimen analysis verified significantly elevated urinary HERC6 levels in LN patients, which correlated tightly with disease activity indicators, including proteinuria and hypocomplementemia. Renal-targeted HERC6 knockdown significantly attenuated lupus nephritis progression in MRL/<i>lpr</i> mice, alleviated both LN progression and podocyte injury. Mechanistically, type I interferon (IFN-α) directly induced HERC6 expression in podocytes. Functional experiments demonstrated that HERC6 knockdown markedly alleviated IFN-α-induced podocyte injury, characterized by restoring expression of podocyte markers, reducing secretion of inflammatory cytokines and decreasing apoptosis. Further investigation revealed that HERC6 deficiency reversed IFN-α-induced mitotic spindle abnormalities and G2/M phase arrest.</p> Conclusion <p>This study unveiled a novel pathway wherein HERC6 induced podocyte injury through disruption of mitotic homeostasis, revealed its potential as a therapeutic target in LN.</p> Graphical Abstract <p></p>

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Interferon α-induced HERC6 provokes podocyte dysfunction via mitotic catastrophe in lupus nephritis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月22日

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  • Xiaoquan Wei,
  • Shuhui Wang,
  • Wenkun Peng,
  • Yang Hang,
  • Qianyue Yang,
  • Shuning Sun,
  • Defang Meng,
  • Min Nie,
  • Genhong Yao,
  • Lingyun Sun

摘要

Background

HECT and RLD Domain Containing E3 Ubiquitin Protein Ligase Family Member 6 (HERC6) is an IFN-stimulated gene (ISG) encoding an E3 ubiquitin ligase that plays significant roles in antiviral innate immunity. However, current research on HERC6 has primarily focused on the liver and immune cells. Its expression, regulation, and function in the kidney, particularly in podocytes remain largely unexplored. The aim of this study is to investigate the pathogenic role and mechanism of the E3 ubiquitin ligase HERC6 in podocyte injury of lupus nephritis (LN).

Methods

Key genes were identified through bioinformatic screening of LN patient datasets. HERC6 expression was validated in renal tissues from LN patients and two lupus murine models, and the correlation between its urinary HERC6 levels and the clinical parameters of patients was analyzed. In vivo, the therapeutic efficacy of renal HERC6 knockdown was evaluated in MRL/lpr mice using AAV9-mediated delivery of HERC6-specific shRNA.In vitro, podocytes were stimulated with IFN-α to investigate gene induction. Following HERC6 knockdown, cellular phenotypes, inflammatory cytokine secretion, apoptosis, cell cycle, and mitotic spindle morphology were analyzed using qPCR, western blot, flow cytometry, ELISA, and immunofluorescence.

Results

Bioinformatic analysis identified HERC6 as a key differentially expressed gene in LN. Its significant upregulation was validated in renal tissues especially in glomerulus from LN patients and two murine lupus models. Moreover, clinical specimen analysis verified significantly elevated urinary HERC6 levels in LN patients, which correlated tightly with disease activity indicators, including proteinuria and hypocomplementemia. Renal-targeted HERC6 knockdown significantly attenuated lupus nephritis progression in MRL/lpr mice, alleviated both LN progression and podocyte injury. Mechanistically, type I interferon (IFN-α) directly induced HERC6 expression in podocytes. Functional experiments demonstrated that HERC6 knockdown markedly alleviated IFN-α-induced podocyte injury, characterized by restoring expression of podocyte markers, reducing secretion of inflammatory cytokines and decreasing apoptosis. Further investigation revealed that HERC6 deficiency reversed IFN-α-induced mitotic spindle abnormalities and G2/M phase arrest.

Conclusion

This study unveiled a novel pathway wherein HERC6 induced podocyte injury through disruption of mitotic homeostasis, revealed its potential as a therapeutic target in LN.

Graphical Abstract