Ferroptosis Mechanisms in Acute Kidney Injury

Acute kidney injury (AKI) is a critical clinical syndrome with high morbidity and mortality, often precipitated by ischaemia–reperfusion, nephrotoxic agents or sepsis. Ferroptosis, characterised by iron-dependent lipid peroxidation, has emerged as a central mechanism driving tubular epithelial cell death in AKI. In this process, free iron catalyses the formation of lipid hydroperoxides in polyunsaturated membrane phospholipids. Under normal conditions, glutathione peroxidase 4 (GPX4) detoxifies lipid peroxides, while ferroptosis suppressor protein 1 (FSP1) regenerates coenzyme Q10 to intercept lipid radicals. Disruption of these defence systems—through diminished glutathione synthesis, proteolytic degradation of GPX4 or impaired FSP1 activity—leads to unchecked lipid peroxidation, mitochondrial dysfunction and plasma membrane rupture. Ferroptotic cell death also releases damage-associated molecular patterns, amplifying inflammatory and fibrotic programmes that contribute to AKI progression and the transition to chronic kidney disease. Preclinical studies demonstrate that iron chelators, antioxidants and inhibitors of ferroptosis pathways can significantly attenuate renal injury, offering promising therapeutic avenues to preserve renal function and improve patient outcomes.

Research from Nature Portfolio

Recent studies have delineated autophagy-dependent mechanisms that regulate ferroptosis in ischaemia–reperfusion injury. Spatial transcriptomics identified a hyperactive ferroptosis niche at the corticomedullary junction, coinciding with reduced GPX4 expression. OTU deubiquitinase 5 (OTUD5) was shown to bind and stabilise GPX4 under basal conditions; upon ischaemic stress, mTORC1-driven autophagy degrades OTUD5, triggering GPX4 decay and tubular cell ferroptosis. Restoration of OTUD5 in vivo attenuates lipid peroxidation and accelerates functional recovery. Complementary genetic evidence demonstrated that loss of ferroptosis suppressor protein 1 (FSP1), or targeted alteration of the GPX4 active site, hypersensitises kidneys to acute tubular necrosis. A dual receptor interacting protein kinase 1 (RIPK1) and ferroptosis inhibitor was shown to protect primary renal tubules and improve survival in ischaemia–reperfusion models, underscoring the therapeutic potential of concurrent modulation of regulated necrosis pathways.

Ferroptosis Mechanisms in Acute Kidney Injury publication trend

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

Technical terms

Ferroptosis: iron-dependent regulated cell death driven by lipid peroxidation.
GPX4: glutathione peroxidase 4, a selenoenzyme that reduces lipid hydroperoxides.
FSP1: ferroptosis suppressor protein 1, which regenerates coenzyme Q10 to prevent lipid radical propagation.
Autophagy: intracellular degradation process that can modulate protein stability and stress responses.
Lipid peroxidation: oxidative degradation of polyunsaturated lipids, central to ferroptotic membrane damage.
Nrf2: nuclear factor erythroid 2–related factor 2, a transcription factor orchestrating antioxidant gene expression.

References

1. Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury. Nature Communications (2023).
2. Polyacrylic Acid‐Coated Selenium‐Doped Carbon Dots Inhibit Ferroptosis to Alleviate Chemotherapy‐Associated Acute Kidney Injury. Advanced Science (2024).
3. Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury. Nature Communications (2021).
4. Targeting ferroptosis in acute kidney injury. Cell Death & Disease (2022).
5. Post-treatment With Irisin Attenuates Acute Kidney Injury in Sepsis Mice Through Anti-Ferroptosis via the SIRT1/Nrf2 Pathway. Frontiers in Pharmacology (2022).