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Caffeine improves hypoxia/reoxygenation induced neuronal cell injury through inhibiting cellular ferroptosis: an in vitro study

  • 0Cardiovascular Department, Tianyou Hospital affiliated to Wuhan University of Science and Technology, Wuhan, Hubei, P.R. China.
Neurological Research +

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February 25, 2025

|

February 25, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Caffeine protects neurons from hypoxia/reoxygenation injury by inhibiting ferroptosis, a cell death pathway. It targets ACSL4, a key protein, reducing oxidative stress and inflammation for neuroprotection.

Area Of Science

  • Neuroscience
  • Cell Biology
  • Pharmacology

Background

  • Ferroptosis, a cell death pathway driven by lipid peroxidation and iron, contributes to neuronal injury after hypoxia/reoxygenation (H/R).
  • Caffeine exhibits neuroprotective effects, but its mechanism in ferroptosis is not fully understood.
  • Acyl-CoA synthetase 4 (ACSL4) is a critical protein in ferroptosis regulation.

Purpose Of The Study

  • To investigate caffeine's neuroprotective effects against H/R-induced ferroptosis.
  • To elucidate caffeine's role in regulating ACSL4 expression and activity.
  • To explore ACSL4 as a potential therapeutic target for caffeine-mediated neuroprotection.

Main Methods

  • Molecular docking assessed caffeine's interaction with ferroptosis proteins ACSL4 and GPX4.
  • An in vitro H/R model using HT-22 cells was established and treated with caffeine.
  • ACSL4 was manipulated (silenced/overexpressed) to determine its role in caffeine's effects on cell viability, ferroptosis markers, and mitochondrial function.

Main Results

  • Caffeine showed favorable binding affinities with ACSL4 and GPX4.
  • Caffeine dose-dependently improved cell viability, reduced inflammatory cytokines (TNF-α, IL-1β, IL-6), and inhibited ferroptosis.
  • ACSL4 manipulation confirmed its critical role: overexpression reversed caffeine's benefits, while silencing enhanced them, impacting lipid peroxidation, iron levels, ROS, MDA, GSH, and mitochondrial membrane potential.

Conclusions

  • Caffeine confers neuroprotection against H/R injury by modulating ACSL4-mediated ferroptosis.
  • Caffeine reduces oxidative stress and inflammation, highlighting ACSL4 as a therapeutic target.
  • This study provides mechanistic insights into caffeine's neuroprotective potential via ferroptosis regulation.

Keywords:

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