1. Academic Validation
  2. Vitamin K1 inhibits ferroptosis and counteracts a detrimental effect of phenprocoumon in experimental acute kidney injury

Vitamin K1 inhibits ferroptosis and counteracts a detrimental effect of phenprocoumon in experimental acute kidney injury

  • Cell Mol Life Sci. 2022 Jun 28;79(7):387. doi: 10.1007/s00018-022-04416-w.
Benedikt Kolbrink  # 1 Friedrich Alexander von Samson-Himmelstjerna  # 1 Maja Lucia Messtorff 1 Theresa Riebeling 1 Raphael Nische 1 Jessica Schmitz 2 Jan Hinrich Bräsen 2 Ulrich Kunzendorf 1 Stefan Krautwald 3
Affiliations

Affiliations

  • 1 Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, Campus Kiel, Fleckenstr. 4, 24105, Kiel, Germany.
  • 2 Nephropathology Unit, Institute of Pathology, University of Hannover, 30625, Hannover, Germany.
  • 3 Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, Campus Kiel, Fleckenstr. 4, 24105, Kiel, Germany. krautwald@nephro.uni-kiel.de.
  • # Contributed equally.
Abstract

Ferroptosis, a type of iron-dependent programmed cell death distinct from Apoptosis, Necroptosis, and other types of cell death, is characterized by lipid peroxidation, Reactive Oxygen Species production, and mitochondrial dysfunction. Accumulating evidence has highlighted vital roles for Ferroptosis in multiple diseases, including acute kidney injury. Therefore, Ferroptosis has become a major focus for translational research. However, despite its involvement in pathological conditions, there are no pharmacologic inhibitors of Ferroptosis in clinical use. In the context of drug repurposing, a strategy for identifying new uses for approved drugs outside the original medical application, we discovered that vitamin K1 is an efficient inhibitor of Ferroptosis. Our findings are strengthened by the fact that the vitamin K antagonist phenprocoumon significantly exacerbated ferroptotic cell death in vitro and also massively worsened the course of acute kidney injury in vivo, which is of utmost clinical importance. We therefore assign vitamin K1 a novel role in preventing ferroptotic cell death in acute tubular necrosis during acute kidney injury. Since the safety, tolerability, pharmacokinetics, and pharmacodynamics of vitamin K1 formulations are well documented, this drug is primed for clinical application, and provides a new strategy for pharmacological control of Ferroptosis and diseases associated with this mode of cell death.

Keywords

Acute kidney injury; Ferroptosis; Ischemia–reperfusion injury; Vitamin K.

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