Ferroptosis Mechanisms in Ischemia-Reperfusion Injury

Ischaemia-reperfusion injury arises when blood flow returns to tissues after a period of oxygen deprivation, triggering an abrupt surge in reactive oxygen species and iron-catalysed lipid peroxidation. Ferroptosis, a regulated form of cell death distinguished by iron-dependent accumulation of lipid hydroperoxides and loss of antioxidant defences, has emerged as a central mediator of tissue damage in organs such as liver, heart, brain and intestine. Key regulators include the cystine/glutamate antiporter system Xc–, which supplies cystine for glutathione synthesis, and glutathione peroxidase 4 (GPX4), which detoxifies lipid peroxides. Upstream signals involve modulation of acyl-CoA synthetase long-chain family member 4 (ACSL4) to enrich membranes in polyunsaturated fatty acids, and transferrin receptor protein 1 (TFRC) to augment intracellular iron. Recent insights have revealed epitranscriptomic control of ferroptotic mediators, cross-talk with inflammatory pathways and context-dependent roles for mitochondrial metabolism. Therapeutic strategies aim to restore redox balance through ferroptosis inhibitors, iron chelators and agents that bolster GPX4 activity or disrupt pro-ferroptotic lipid synthesis, offering promise for improving outcomes in transplantation, stroke and other ischaemia-reperfusion settings.

Research from Nature Portfolio

A study of older livers undergoing ischaemia-reperfusion identified a decline in the RNA demethylase FTO as a driver of heightened ferroptosis. Reduced FTO activity led to stabilisation of mRNAs encoding the pro-ferroptotic enzymes ACSL4 and TFRC via m6A-dependent mechanisms, thereby increasing lipid peroxidation and iron uptake. Restoring FTO expression or enhancing its demethylase function with nicotinamide mononucleotide attenuated liver injury by repressing ACSL4 and TFRC, unveiling an epitranscriptomic pathway that may be harnessed to improve the viability of marginal donor organs.

Ferroptosis Mechanisms in Ischemia-Reperfusion Injury publication trend

The graph below shows the total number of articles in ferroptosis mechanisms in ischemia-reperfusion injury across all publications each year (not limited to Nature Index journals).

Technical terms

Ferroptosis: Regulated cell death driven by iron-dependent lipid peroxidation.

Reactive oxygen species (ROS): Chemically reactive molecules containing oxygen that can damage proteins, lipids and DNA.

Lipid peroxidation: Oxidative degradation of polyunsaturated fatty acids in cell membranes, leading to loss of integrity and cell death.

Glutathione peroxidase 4 (GPX4): Enzyme that reduces lipid hydroperoxides to non-toxic lipid alcohols, preventing ferroptosis.

System Xc–: Cystine/glutamate antiporter that imports cystine for glutathione synthesis and redox homeostasis.

Acyl-CoA synthetase long-chain family member 4 (ACSL4): Enzyme that esterifies polyunsaturated fatty acids, facilitating the formation of peroxidation-prone lipids.

Transferrin receptor protein 1 (TFRC): Cell surface receptor that mediates iron uptake, contributing to the labile iron pool that drives ferroptosis.

References

1. Targeting Ferroptosis: Pathological Mechanism and Treatment of Ischemia‐Reperfusion Injury. Oxidative Medicine and Cellular Longevity (2021).
2. FTO deficiency in older livers exacerbates ferroptosis during ischaemia/reperfusion injury by upregulating ACSL4 and TFRC. Nature Communications (2024).
3. Malic Enzyme 1 as a Novel Anti‐Ferroptotic Regulator in Hepatic Ischemia/Reperfusion Injury. Advanced Science (2023).
4. Anti-CHAC1 exosomes for nose-to-brain delivery of miR-760-3p in cerebral ischemia/reperfusion injury mice inhibiting neuron ferroptosis. Journal of Nanobiotechnology (2023).
5. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death & Differentiation (2019).