Metalloreductase Proteins in Cancer Diagnosis and Therapy

Metalloreductase proteins, notably members of the STEAP (six-transmembrane epithelial antigen of the prostate) family, catalyse the reduction of ferric and cupric ions, thereby regulating metal uptake and redox biology within cells. These activities underpin fundamental processes such as cellular proliferation, survival and regulated cell death. In many tumour types, overexpression of STEAP proteins drives aggressive phenotypes by altering iron homeostasis, supporting growth signalling and suppressing oxidative damage. Conversely, targeted inhibition of metalloreductase activity can promote ferroptotic cell death in malignancies that exhibit iron addiction. Beyond direct modulation of tumour cell fate, STEAP proteins serve as accessible cell-surface biomarkers amenable to diagnostic imaging and biosensor technologies. Together, structural insights into the transmembrane electron-transfer machinery and mechanistic studies of ferroptosis link metalloreductases to both precision diagnostics and novel therapeutic strategies, with potential applications across prostate, ovarian, hepatic and other solid cancers.

Research from Nature Portfolio

High-resolution cryo-electron microscopy structures of human STEAP4 have revealed its domain architecture and electron-transfer pathway, showing how NADPH and flavin-adenine dinucleotide co-localise to drive Fe3+ reduction at a conserved heme centre. These structural models provide a blueprint for rational design of small-molecule inhibitors that block iron reduction and limit tumour growth. Functional analyses in prostate cancer models have demonstrated that genetic knockdown of STEAP2 markedly decreases cell proliferation, migration and invasive capacity, concomitant with downregulation of matrix-remodelling proteases. These findings position STEAP2 as both a prognostic marker of aggressive disease and a candidate therapeutic target for intervention strategies aimed at impairing metalloreductase-driven invasion.

Metalloreductase Proteins in Cancer Diagnosis and Therapy publication trend

The graph below shows the total number of articles in metalloreductase proteins in cancer diagnosis and therapy across all publications each year (not limited to Nature Index journals).

Technical terms

Metalloreductase: Enzyme that catalyses the reduction of metal ions, facilitating cellular metal uptake and redox balance.

Ferroptosis: Iron-dependent form of regulated cell death driven by lipid peroxide accumulation.

Biomarker: Measurable molecule indicative of a physiological or pathological state, used in diagnosis or prognosis.

Cryo-electron microscopy (cryo-EM): Imaging technique that determines high-resolution structures of macromolecules in native-like frozen state.

Transmembrane domain: Protein region spanning the lipid bilayer, often mediating transport or signal transduction.

NADPH: Nicotinamide adenine dinucleotide phosphate, a cofactor that donates electrons in reductive biosynthetic and detoxification reactions.

References

1. STEAP1 Knockdown Decreases the Sensitivity of Prostate Cancer Cells to Paclitaxel, Docetaxel and Cabazitaxel. International Journal of Molecular Sciences (2023).
2. STEAP3 Affects Ovarian Cancer Progression by Regulating Ferroptosis through the p53/SLC7A11 Pathway. Mediators of Inflammation (2024).
3. Development of a novel electrochemical biosensor based on plastic antibodies for detection of STEAP1 biomarker in cancer. Bioelectrochemistry (2023).
4. Cryo-EM structures of human STEAP4 reveal mechanism of iron(III) reduction. Nature Communications (2018).
5. STEAP2 Knockdown Reduces the Invasive Potential of Prostate Cancer Cells. Scientific Reports (2018).