Oxidative Stress and Lipid Peroxidation Mechanisms

Oxidative stress arises when the generation of reactive oxygen species (ROS) outstrips the capacity of cellular antioxidant systems, leading to damage of biomolecules. Lipid peroxidation is a key consequence of oxidative imbalance, in which ROS attack polyunsaturated fatty acids in membrane phospholipids, initiating a chain reaction that yields lipid hydroperoxides. These unstable intermediates fragment to produce electrophilic aldehydes such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE). Beyond their cytotoxic potential, these aldehydes function as secondary messengers in redox signalling, modulating pathways that govern cell survival, inflammation and death. The formation of covalent adducts with proteins and nucleic acids by Michael addition underpins much of their biological impact, altering enzyme activity and transcriptional responses. Recent work has illuminated the dual nature of lipid peroxidation products: at low concentrations they enact adaptive signalling through sensors such as NRF2 and KEAP1, whereas at higher levels they provoke irreversible damage, including mitochondrial dysfunction, endoplasmic reticulum stress and the execution of ferroptotic cell death. A deeper understanding of the enzymes responsible for aldehyde detoxification, including glutathione-dependent conjugation and aldo-keto reductases, is critical for designing interventions that can restore redox homeostasis and prevent progression of oxidative stress–related diseases.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Oxidative Stress and Lipid Peroxidation Mechanisms publication trend

The graph below shows the total number of articles in oxidative stress and lipid peroxidation mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Reactive oxygen species (ROS): Chemically reactive molecules derived from oxygen, including free radicals and peroxides.

Lipid peroxidation: A chain-reaction process in which ROS attack membrane polyunsaturated fatty acids, generating lipid hydroperoxides and secondary aldehydes.

4-Hydroxy-2-nonenal (4-HNE): A highly reactive α,β-unsaturated aldehyde formed during lipid peroxidation, acting as both cytotoxin and second messenger.

Malondialdehyde (MDA): A reactive dialdehyde by-product of lipid peroxidation that forms crosslinks with proteins and nucleic acids.

Michael addition: A nucleophilic addition reaction through which electrophilic aldehydes covalently modify nucleophilic amino acid side chains.

Ferroptosis: A form of regulated cell death driven by iron-dependent lipid peroxidation and depletion of glutathione.

References

1. Oxidative stress and lipotoxicity. Journal of Lipid Research (2016).
2. Lipid Peroxidation-Derived Aldehydes, 4-Hydroxynonenal and Malondialdehyde in Aging-Related Disorders. Antioxidants (2018).
3. Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4‐Hydroxy‐2‐Nonenal. Oxidative Medicine and Cellular Longevity (2014).
4. 4-Hydroxy-nonenal—A Bioactive Lipid Peroxidation Product †. Biomolecules (2015).
5. Quantitative Chemoproteomics for Site-Specific Analysis of Protein Alkylation by 4‑Hydroxy-2-Nonenal in Cells. Analytical Chemistry (2015).
6. The Reactive Oxygen Species- and Michael Acceptor-inducible Human Aldo-Keto Reductase AKR1C1 Reduces the α,β-Unsaturated Aldehyde 4-Hydroxy-2-nonenal to 1,4-Dihydroxy-2-nonene*. Journal of Biological Chemistry (2000).