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Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
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Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury

Li-Kai Chu1, Xu Cao1, Lin Wan1

  • 1Pediatric Institute of Soochow University, Children's Hospital of Soochow University, Soochow University, 215025, Suzhou, China.

Nature Communications
|December 18, 2023
PubMed

Insights

Ferroptosis, a cell death linked to kidney disease, is regulated by OTU deubiquitinase 5 (OTUD5) stabilizing glutathione peroxidase 4 (GPX4). Autophagy degrades OTUD5 during ischemia-reperfusion injury, causing GPX4 reduction and kidney damage.

Area of Science:

  • Nephrology
  • Cellular Biology
  • Biochemistry

Background:

  • Ferroptosis, an iron-dependent cell death, is implicated in kidney diseases and linked to reduced glutathione peroxidase 4 (GPX4).
  • The spatial distribution of GPX4-mediated ferroptosis and mechanisms of GPX4 reduction during ischemia-reperfusion (I/R) injury are poorly understood.

Purpose of the Study:

  • To investigate the spatial localization of renal GPX4 ferroptosis.
  • To identify molecular mechanisms regulating GPX4 levels during I/R injury.
  • To explore OTUD5 as a potential therapeutic target for I/R-induced kidney injury.

Main Methods:

  • Spatial transcriptomics to map GPX4 expression.
  • Protein-protein interaction studies to identify GPX4 regulators.
  • In vivo models of I/R injury with genetic manipulation and AAV-mediated gene delivery.

Main Results:

  • GPX4 is localized at the inner cortex-outer medulla boundary, a site of ferroptosis post-I/R.
  • OTU deubiquitinase 5 (OTUD5) stabilizes GPX4, conferring ferroptosis resistance.
  • I/R injury induces OTUD5 degradation via mTORC1-mediated autophagy, leading to GPX4 reduction and ferroptosis.
  • OTUD5 deficiency exacerbates, while OTUD5 delivery mitigates, I/R-induced kidney injury and ferroptosis.

Conclusions:

  • A novel autophagy-dependent ferroptosis pathway is identified, involving hypoxia/ischemia-induced OTUD5 degradation and subsequent GPX4 reduction.
  • OTUD5 represents a potential therapeutic target for mitigating ferroptosis and improving outcomes in I/R-related kidney diseases.

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