Redox Biology of Thioredoxin Systems in Health and Disease

The thioredoxin system, comprising thioredoxin (Trx), thioredoxin reductase (TrxR) and the electron donor NADPH, is a central regulator of cellular redox homeostasis. Trx reduces disulfide bonds in client proteins, modulating enzymatic activity, transcription factors and signal transduction pathways. TrxR restores oxidised Trx by catalysing NADPH‐dependent reduction of its active‐site disulfide, with a selenocysteine residue playing a pivotal role. Together with glutaredoxin and glutathione pathways, this network defends against reactive oxygen species (ROS), supports mitochondrial function and regulates processes such as cell proliferation, apoptosis and immune differentiation. Dysregulation of the thioredoxin system is implicated in cancer, chronic inflammation, autoimmune disorders and neurodegeneration. Therapeutic strategies targeting TrxR—with small molecules or repurposed drugs—offer promise for selective modulation of redox balance in disease, while Trx‐based biomarkers may aid patient stratification and treatment monitoring.

Research from Nature Portfolio

Recent studies have revealed a critical role for Trx in immune regulation. In one investigation, regulatory B cells (Breg) were shown to depend on mitochondrial electron transport and finely tuned ROS levels maintained by high expression of TXN, the gene encoding Trx. Inhibition of Trx led to mitochondrial depolarisation, elevated ROS and impaired Breg differentiation, whereas exogenous Trx restored mitochondrial polarity and regulatory function in cells from patients with systemic lupus erythematosus, highlighting therapeutic potential in autoimmunity.

Elucidation of redox‐sensing mechanisms has advanced through analysis of a model glutaredoxin (Grx) and a redox‐sensitive fluorescent protein. This work demonstrated that Grx catalyses disulfide reduction via a monothiol mechanism and forms a transient ternary complex with glutathione and the substrate. The fusion of Grx to the reporter accelerated reaction kinetics by several orders of magnitude, providing a mechanistic framework for intracellular redox measurement and challenging prior models of thiol‐disulfide exchange.

Redox Biology of Thioredoxin Systems in Health and Disease publication trend

The graph below shows the total number of articles in redox biology of thioredoxin systems in health and disease across all publications each year (not limited to Nature Index journals).

Technical terms

Thioredoxin (Trx): small oxidoreductase that reduces protein disulfide bonds to maintain redox balance and regulate signalling.

Thioredoxin reductase (TrxR): selenoenzyme that uses NADPH to regenerate reduced Trx from its oxidised form.

Reactive oxygen species (ROS): chemically reactive oxygen‐containing molecules that can damage cellular components or act as signalling mediators.

Selenocysteine (Sec): the 21st amino acid, containing selenium, critical for the catalytic activity of TrxR.

Glutaredoxin (Grx): thiol‐disulfide oxidoreductase that utilises glutathione to reduce protein disulfides and regulate S‐glutathionylation.

Regulatory B cell (Breg): subset of B lymphocytes that produces anti‐inflammatory cytokines and contributes to immune tolerance.

References

1. Thioredoxin is a metabolic rheostat controlling regulatory B cells. Nature Immunology (2024).
2. Deciphering the mechanism of glutaredoxin-catalyzed roGFP2 redox sensing reveals a ternary complex with glutathione for protein disulfide reduction. Nature Communications (2024).
3. Auranofin repurposing for lung and pancreatic cancer: low CA12 expression as a marker of sensitivity in patient-derived organoids, with potentiated efficacy by AKT inhibition. Journal of Experimental & Clinical Cancer Research (2024).
4. Thioredoxin and Glutaredoxin Systems. Journal of Biological Chemistry (1989).
5. Thioredoxin Reductase Is Irreversibly Modified by Curcumin A NOVEL MOLECULAR MECHANISM FOR ITS ANTICANCER ACTIVITY*. Journal of Biological Chemistry (2005).