Redox Regulation in Cellular Stress Responses

Cellular stress responses are orchestrated through a balance of oxidation and reduction reactions that regulate signalling pathways, gene expression and protein function. Reactive oxygen species such as hydrogen peroxide serve both as damaging agents at high levels and as second messengers at sub-lethal concentrations. Redox‐sensitive proteins, particularly those bearing reactive cysteine residues, undergo reversible modifications that adjust their activity, localisation and interactions. Central to this process are peroxiredoxins, thioredoxins and glutathione systems, which together maintain redox homeostasis while permitting transient localised oxidation. Under acute or chronic stress, the redox network coordinates antioxidant defence, repair of macromolecular damage and activation of transcription factors that drive cell‐cycle arrest, senescence or programmed cell death. Dysregulation of this system has widespread implications for ageing, neurodegeneration, inflammation and cancer. Recent advances have elucidated how dynamic oxidation of individual protein residues can switch enzymatic function to chaperone activity, reshape signalling complexes and modulate global stress programmes, thus highlighting redox regulation as a versatile mechanism of cellular adaptation with growing potential for therapeutic intervention.

Research from Nature Portfolio

Recent studies have revealed that hydrogen peroxide elicits a dose- and time-dependent sequence of transcription factor activation, in which low peroxide levels stimulate NRF2, p53 and JUN, whereas higher levels suppress these and instead activate FOXO1, NF-κB and NFAT1. Live‐cell imaging showed that the pattern of factor engagement differs when peroxide is delivered as an acute bolus versus continuous generation, reflecting distinct stress modalities. Crucially, 2-Cys peroxiredoxins were identified as central modulators of this coordination: their oxidation state controls which transcriptional programmes become engaged, thereby determining whether cells prioritise repair and survival or initiate apoptotic pathways.

Redox Regulation in Cellular Stress Responses publication trend

The graph below shows the total number of articles in redox regulation in cellular stress responses across all publications each year (not limited to Nature Index journals).

Technical terms

Reactive oxygen species (ROS): Oxygen‐derived molecules such as superoxide and hydrogen peroxide that can oxidise biomolecules or act as signalling messengers.

Redox regulation: The reversible control of protein structure and activity through oxidation–reduction of susceptible amino acids, especially cysteines.

Peroxiredoxin (Prdx): A family of thiol peroxidases that reduce hydroperoxides and function as local redox sensors and chaperones.

Sulfenylation: The formation of a cysteine sulfenic acid (–SOH) intermediate, a reversible post-translational modification in redox signalling.

Disulfide bond: A covalent linkage between two cysteine thiols that influences protein folding, stability and intermolecular interactions.

References

1. Temporal coordination of the transcription factor response to H2O2 stress. Nature Communications (2024).
2. Disulfide-Bond-Induced Structural Frustration and Dynamic Disorder in a Peroxiredoxin from MAS NMR. Journal of the American Chemical Society (2023).
3. A peroxiredoxin-P38 MAPK scaffold increases MAPK activity by MAP3K-independent mechanisms. Molecular Cell (2023).