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Novel epigenetic biomarkers following ferroptosis and pyroptosis in a hypobaric hypoxia-induced renal injury model

  • 0School of Disaster and Emergency Medicine, Tianjin University, Tianjin, China; Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin, China; Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou, Zhejiang, China.
Archives of Biochemistry and Biophysics +

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October 9, 2025

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October 9, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Hypobaric hypoxia causes kidney damage through ferroptosis and pyroptosis. Mitochondrial DNA (mtDNA) methylation, specifically at mt-COX3 pos2 in cell-free DNA, serves as a novel biomarker for this renal injury.

Area Of Science

  • Renal Pathogenesis
  • Cell Death Mechanisms
  • Mitochondrial Epigenetics

Background

  • Hypobaric hypoxia poses a significant threat to oxygen-sensitive organs, particularly the kidneys.
  • Ferroptosis and pyroptosis are oxygen-dependent cell death pathways implicated in organ damage, but their roles in hypobaric hypoxia-induced kidney injury are not well understood.
  • The influence of mitochondrial DNA (mtDNA) methylation on kidney damage during hypobaric hypoxia requires further investigation.

Purpose Of The Study

  • To investigate the roles of ferroptosis and pyroptosis in hypobaric hypoxia-induced renal injury in a rat model.
  • To examine the methylation status of mitochondrial DNA (mtDNA) in renal tissue and circulation following hypobaric hypoxia exposure.
  • To identify potential biomarkers for hypobaric hypoxia-induced renal pathogenesis.

Main Methods

  • A rat model was established to simulate hypobaric hypoxia (6000-7000m for 6-72 hours).
  • Renal ferroptosis and pyroptosis were assessed using biochemical assays, gene expression analysis, and histological staining.
  • mtDNA methylation patterns (mt-COX1/2/3) were analyzed in kidney tissue, cytoplasmic DNA, and serum cell-free DNA (cf mtDNA) using pyrosequencing, with PCA employed for biomarker identification.

Main Results

  • Hypobaric hypoxia led to increased iron accumulation, lipid peroxidation, and tubular injury in the kidneys, indicative of ferroptosis.
  • Evidence of pyroptosis was observed through the activation of Caspase1 and GSDMD.
  • Mitochondrial damage and mtDNA leakage were confirmed by transmission electron microscopy, and mt-COX3 pos2 hypermethylation in serum cf mtDNA effectively distinguished hypoxia-exposed rats.

Conclusions

  • Ferroptosis and pyroptosis act synergistically to cause kidney injury under hypobaric hypoxia conditions.
  • Hypermethylation at the mt-COX3 pos2 site in serum cell-free mtDNA represents a novel and specific biomarker for hypobaric hypoxia-induced renal pathogenesis.
  • This study highlights the critical interplay between cell death pathways and epigenetic modifications in organ damage due to environmental stress.

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