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SPATA2/CYLD Pathway-Dependent Deubiquitylation of p53 Promotes Ferroptosis in Rat Heart After Ischaemia/Reperfusion Through Suppression of SLC7A11

  • 0Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China; Department of Pharmacy, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Heart, Lung & Circulation +

|

May 19, 2025

|

May 19, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

The SPATA2/CYLD pathway promotes heart cell death (ferroptosis) after ischemia/reperfusion injury by de-ubiquitylating p53, which suppresses SLC7A11 and glutathione peroxidase 4 (GPX4). This pathway exacerbates myocardial I/R injury.

Area Of Science

  • Cardiovascular Biology
  • Cell Death Mechanisms
  • Molecular Pathology

Background

  • Ferroptosis, an iron-dependent cell death, significantly contributes to myocardial ischemia/reperfusion (I/R) injury.
  • Glutathione peroxidase 4 (GPX4) downregulation accelerates ferroptosis, but the precise mechanisms remain unclear.
  • Solute carrier family 7A member 11 (SLC7A11) is crucial for GPX4 levels and its transcription is negatively regulated by p53.

Purpose Of The Study

  • To investigate the role of the spermatogenesis-associated protein 2 (SPATA2)/cylindromatosis (CYLD) pathway in promoting myocardial ferroptosis following I/R.
  • To determine if this pathway acts via p53-dependent inhibition of SLC7A11.

Main Methods

  • Established rat myocardial I/R injury model (1h ischemia, 3h reperfusion).
  • Utilized H9c2 cell model (8h hypoxia, 12h re-oxygenation) to mimic I/R injury in vitro.
  • Assessed protein levels, ubiquitination, and interactions, including SPATA2 knockdown and lurasidone treatment.

Main Results

  • SPATA2 and CYLD levels increased in I/R hearts and H/R cells, correlating with elevated p53.
  • SPATA2 knockdown reversed p53 ubiquitination and levels, increasing SLC7A11 and GPX4, thereby reducing ferroptosis.
  • Lurasidone, an SPATA2 inhibitor, replicated these protective effects in I/R rat hearts.

Conclusions

  • The SPATA2/CYLD pathway promotes ferroptosis in myocardial I/R injury.
  • This occurs through de-ubiquitylation of p53, leading to suppressed SLC7A11 expression.
  • Targeting the SPATA2/CYLD pathway may offer a therapeutic strategy for I/R injury.

Keywords:

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