Ferroptosis Mechanisms in Diabetic Nephropathy

Diabetic nephropathy is a leading cause of end-stage renal disease and is characterised by progressive glomerular and tubular injury driven by chronic hyperglycaemia. Ferroptosis, an iron-dependent form of regulated cell death marked by unchecked lipid peroxidation and reactive oxygen species accumulation, has emerged as a critical pathway in the pathogenesis of diabetic kidney injury. In the diabetic milieu, dysregulation of iron homeostasis—through increased transferrin receptor 1 expression and ferritin degradation—coupled with depletion of glutathione and inactivation of glutathione peroxidase 4 (GPX4) precipitates lethal lipid hydroperoxide build-up in renal tubular epithelial cells. Key signalling axes such as Nrf2/HO-1, HIF-1α/HO-1 and TLR4/NF-κB intersect with ferroptotic cascades to modulate antioxidant defences, iron uptake and mitochondrial integrity. Therapeutic strategies that bolster the cystine/glutamate antiporter system Xc−, restore GPX4 activity or chelate excess iron have shown renoprotective effects in preclinical diabetic models, highlighting ferroptosis as a promising target for intervention.

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Ferroptosis Mechanisms in Diabetic Nephropathy publication trend

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

Technical terms

Ferroptosis: iron-dependent regulated cell death characterised by lipid peroxidation and reactive oxygen species accumulation.

Diabetic nephropathy: chronic kidney disease resulting from prolonged hyperglycaemia, leading to glomerular and tubular injury.

Glutathione peroxidase 4 (GPX4): selenoenzyme that neutralises lipid hydroperoxides, preventing membrane damage and ferroptosis.

Glutathione (GSH): intracellular antioxidant tripeptide essential for GPX4-mediated detoxification of lipid peroxides.

Transferrin receptor 1 (TFR1): cell surface protein facilitating iron import, whose overexpression fuels iron accumulation and lipid peroxidation.

References

1. VDR Activation Attenuates Renal Tubular Epithelial Cell Ferroptosis by Regulating Nrf2/HO‐1 Signaling Pathway in Diabetic Nephropathy. Advanced Science (2023).
2. Iron metabolism and ferroptosis in type 2 diabetes mellitus and complications: mechanisms and therapeutic opportunities. Cell Death & Disease (2023).
3. San-Huang-Yi-Shen capsule ameliorates diabetic nephropathy in mice through inhibiting ferroptosis. Biomedicine & Pharmacotherapy (2023).
4. Ferroptosis Enhanced Diabetic Renal Tubular Injury via HIF-1α/HO-1 Pathway in db/db Mice. Frontiers in Endocrinology (2021).
5. Characterization of ferroptosis in kidney tubular cell death under diabetic conditions. Cell Death & Disease (2021).
6. Glabridin, a bioactive component of licorice, ameliorates diabetic nephropathy by regulating ferroptosis and the VEGF/Akt/ERK pathways. Molecular Medicine (2022).