Ferroptosis and Acute Kidney Injury (AKI): Molecular Mechanisms and Therapeutic Potentials Original paper

What was reviewed?

This review summarized how ferroptosis contributes to acute kidney injury (AKI) and why this iron-dependent, lipid peroxidation–driven cell-death program matters clinically in settings such as ischemia–reperfusion, sepsis, rhabdomyolysis, and nephrotoxic drug exposure. The authors focused on the defining biology of ferroptosis—iron overload, reactive oxygen species accumulation, and membrane lipid peroxidation—and connected these mechanisms to renal tubular epithelial injury, inflammation, and AKI progression risk toward chronic kidney disease.

Who was reviewed?

The paper did not study a new patient cohort; instead, it reviewed mechanistic and therapeutic evidence drawn mainly from experimental AKI models and renal tubular epithelial cell systems. The authors discussed representative AKI etiologies used in research, including rhabdomyolysis-associated AKI, ischemia–reperfusion injury, sepsis-associated AKI, and folic acid or cisplatin nephrotoxicity, to explain how ferroptosis emerges in kidney tubules and how blocking it can preserve renal structure and function in animals.

What were the most important findings?

The review emphasized that ferroptosis in AKI centers on disrupted iron handling and runaway lipid peroxidation, with polyunsaturated phospholipids acting as key substrates for lethal oxidative damage. It described major regulatory nodes clinicians may recognize as actionable pathways: system Xc− (SLC7A11/SLC3A2) supports cystine uptake and glutathione synthesis; glutathione enables GPX4 to detoxify lipid hydroperoxides; p53 can tilt cells toward ferroptosis by suppressing SLC7A11; and parallel defenses such as FSP1–CoQ10 and Nrf2 transcriptional programs modulate susceptibility, while ACSL4 shapes membrane lipid composition and ferroptosis sensitivity. The review also underscored crosstalk with inflammation and autophagy-related ferritin turnover, which can amplify injury once ferroptosis starts. For a microbiome signatures database, the paper did not report microbiome sampling or taxa-level associations, so major microbial associations are not applicable.

What are the greatest implications of this study/ review?

This review positions ferroptosis as a plausible unifying injury mechanism in AKI because it directly links iron dysregulation to membrane damage and tubular cell loss, which standard supportive care cannot specifically reverse. It also argues that anti-ferroptosis strategies deserve translational attention, since multiple inhibitors reduced renal lipid peroxidation and structural injury in AKI models, including radical-trapping agents (such as ferrostatin-1 and liproxstatin-1), iron chelation approaches (such as deferoxamine), and antioxidant or pathway-targeting interventions that reinforce GPX4 or Nrf2 signaling. At the same time, it makes clear that the field still lacks validated, specific clinical biomarkers of ferroptosis and that therapy development will require better pharmacology, dosing windows, and human-focused testing before clinicians can reliably deploy ferroptosis-targeted treatments in AKI care.