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Abstract: SA-PO157

OTUD5 Mediates GPX4 Stability and Ferroptosis in Renal Tubular Cells During Ischemia-Reperfusion Injury

Session Information

  • AKI: Mechanisms - III
    November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Liu, Jun, University of California Davis, Davis, California, United States
  • Hsu, Ssu-Wei, University of California Davis, Davis, California, United States
  • Guo, Fujia, University of California Los Angeles, Los Angeles, California, United States
  • Oshiro, Lindsay, University of California Davis, Davis, California, United States
  • Yan, Xiang-Ming, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
  • Chen, Ching-Hsien, University of California Davis, Davis, California, United States

Acute kidney injury (AKI) is a severe kidney disease often linked with renal tubular cell ferroptosis, an iron-dependent, non-apoptotic cell death characterized by lipid peroxide accumulation. This can be triggered by ischemia-reperfusion (I/R) and typically results from decreased glutathione peroxidase 4 (GPX4) expression. However, the specific molecular events underlying GPX4 reduction following I/R remain poorly understood.


Our research involved identifying and characterizing the role of GPX4-interacting proteins in renal tubular cells. We also studied the susceptibility of renal regions to I/R injury using spatial transcriptomics. Both in vitro assays and in vivo experiments using mice with conditionally deleted Otud5 were employed to evaluate the function of OTU deubiquitinase 5 (OTUD5) in ferroptosis and AKI.


OTUD5 was found to interact with and stabilize GPX4, conferring resistance to ferroptosis in renal tubular cells. During I/R, the inability of OTUD5 to deubiquitinate, triggered by mTORC1-mediated macroautophagy, led to GPX4 degradation and ferroptosis. Spatial transcriptomics revealed hyperactivity of cell ferroptosis and autophagy in the region between the kidney's inner cortex and medulla outstrip, susceptible to I/R injury. Functionally, OTUD5 deletion resulted in heightened renal tubular cell ferroptosis in vitro, and mice with tubular epithelial cell-specific Otud5 deletion demonstrated exacerbated AKI in response to I/R. Conversely, adeno-associated virus-mediated Otud5 delivery reduced ferroptosis and promoted renal function recovery.


Our findings unveil a novel autophagy-dependent ferroptosis module: I/R-induced OTUD5 macroautophagy leads to GPX4 degradation and tubular cell ferroptosis. Targeting this pathway may offer a potential therapeutic strategy for I/R-related kidney diseases.


  • Other U.S. Government Support