Can an epilepsy drug stop cisplatin kidney ferroptosis?
Valproic acid, like ferrostatin-1, improved cisplatin AKI in mice by reversing GPX4 loss and ACSL4-linked lipid peroxidation; GPX4 siRNA wiped out VPA’s protection in tubular cells.
Source
VPA improves ferroptosis in tubular epithelial cells after cisplatin-induced acute kidney injury
Study at a glance
- Design
- Animal / in-vitro — Cisplatin AKI in C57BL/6 mice (5 groups, n=5) plus HK-2 cells and 3 human AKI biopsies vs 3 tumor-adjacent controls; VPA vs ferrostatin-1
- N
- N=25 · 25 mice (5 per group); human histology n=3 AKI + 3 controls; in vitro HK-2 with VPA/Fer-1 and GPX4 siRNA
- Population
- Male C57BL/6 mice with cisplatin AKI, HK-2 tubular cells, and human AKI biopsy vs renal-cancer adjacent tissue
- Outcome
- Kidney function (creatinine, BUN), histology, lipid peroxidation, ACSL4/GPX4, and rescue by VPA or Fer-1
Structured fields used in claim comparison tables when every cited study has a complete layer.
What they did
Documented ferroptosis marks in 3 human AKI biopsies, then randomized mice to sham, cisplatin 20 mg/kg, VPA, cisplatin+VPA, or cisplatin+Fer-1 (n=5 each), and tested VPA/Fer-1 and GPX4 knockdown in HK-2 cells.
What they found
Ferroptosis appeared in human and mouse injured tubules. VPA or Fer-1 lowered creatinine, BUN, tissue injury, cell death, lipid peroxidation, and ACSL4 while restoring GPX4. GPX4 siRNA significantly weakened VPA’s benefit after cisplatin.
The limits
What it doesn't show
n=5 mice per arm and 3 human biopsies cannot establish VPA as clinical AKI therapy; cisplatin nephrotoxicity still affects ~30% of treated patients and this is not a human trial.
Key terms
- Ferroptosis
- Iron-dependent lipid-peroxidation cell death distinct from apoptosis; central here in cisplatin AKI.
- Valproic acid (VPA)
- HDAC1/2 inhibitor and antiepileptic tested as a ferroptosis-modulating AKI protectant.
- GPX4
- Glutathione peroxidase 4 that suppresses ferroptosis; VPA helps restore it.
- ACSL4
- Lipid-metabolizing enzyme that promotes ferroptosis; rose with injury and fell with VPA/Fer-1.
- Ferrostatin-1
- Ferroptosis inhibitor used as a positive-control protectant (1 mg/kg in mice).
- Cisplatin AKI
- Acute kidney injury from platinum chemotherapy; clinically common (~30%) and modeled at 20 mg/kg in mice.
Flashcards
Research intelligence for this paper
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Quiz yourself
VPA is classically:
Common questions
Mouse grouping?
Five groups, n=5 each, including cisplatin, VPA, and Fer-1 arms.
Human samples?
3 AKI biopsies and 3 renal-cancer adjacent controls.
Did GPX4 knockdown matter?
Yes—siRNA significantly weakened VPA protection after cisplatin.
Functional readouts?
Lower serum creatinine, BUN, and tissue damage with VPA or Fer-1.
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