The research progress of ferroptosis in acute lung injury

TL;DR

This review explores how ferroptosis, a type of cell death, contributes to acute lung injury and potential treatments to stop it.

Contribution

The paper reviews subtype-specific ferroptosis mechanisms in ALI and evaluates emerging therapeutic strategies.

Findings

Ferroptosis is driven by iron overload and lipid peroxidation in ALI.

GPX4 inactivation and ACSL4 upregulation are core mechanisms.

Targeting Nrf2 or using inhibitors like Lip-1 alleviates ferroptosis.

Abstract

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is increasingly recognized as a pivotal mechanism in the pathogenesis of acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS). Its core molecular machinery, including glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4), and the cystine/glutamate antiporter system Xc-, becomes dysregulated across various ALI subtypes, such as sepsis, ischemia-reperfusion, and COVID-19.This review delineates how ferroptosis contributes to ALI through iron overload, uncontrolled lipid peroxidation, and failure of antioxidant defenses, ultimately leading to pulmonary endothelial and epithelial cell death. We further summarize subtype-specific mechanisms and evaluate emerging therapeutic strategies, including ferroptosis inhibitors (e.g., liproxstatin-1), Nrf2 activators, and iron chelators, highlighting their potential for targeted intervention in ALI/ARDS.

•Ferroptosis is driven by iron overload and lipid peroxidation in ALI.•GPX4 inactivation and ACSL4 upregulation are core mechanisms.•Targeting Nrf2 or using inhibitors (e.g., Lip-1) alleviates ferroptosis.•It is a key pathway in sepsis, IRI, and COVID-19 related ALI.

Ferroptosis is driven by iron overload and lipid peroxidation in ALI.

GPX4 inactivation and ACSL4 upregulation are core mechanisms.

Targeting Nrf2 or using inhibitors (e.g., Lip-1) alleviates ferroptosis.

It is a key pathway in sepsis, IRI, and COVID-19 related ALI.

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