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

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.

Links between Vitamin K, Ferroptosis and SARS-CoV-2 Infection

“…This NAD(P)H-dependent ubiquinone oxidoreductase plays a significant role in ferroptosis by converting ubiquinone to ubiquinol and utilizing NAD(P)H [ 127 ]. Similar conclusions were reached by Kolbrink et al [ 129 ], who showed that vitamin K 1 is a strong ferroptosis inhibitor and can be used as a medicine in the course of acute kidney damage. Vitamin K 2 has also been shown to inhibit ferroptosis and protect against cell death caused by oxidative stress.…”

Regulated cell death pathways in kidney disease

“…In 2022, vitamin K 1 and a form of vitamin K 2 — menaquinone 4 (MK-4) — were shown to inhibit ferroptosis in cultured cells and improve outcomes in a mouse model of IRI-AKI 204 . By contrast, the vitamin K antagonist phenprocoumon, which is in clinical use in Germany, exacerbated outcomes 204 , 205 . This knowledge may drive the reinterpretation of the reported adverse effects of vitamin K antagonists in kidney disease, which include the development of haematuria-associated AKI during periods of warfarin overdosing 206 – 211 , vascular calcification 212 and an increased risk of CKD progression 213 , 214 .…”

Ferroptosis-Regulated Cell Death as a Therapeutic Strategy for Neurodegenerative Diseases: Current Status and Future Prospects

“…96 Vitamin K1 has also emerged as a possible treatment for acute kidney injury, thanks to its ability to inhibit ferroptosis. 97 Moreover, Nuszkiewicz and colleagues have uncovered a fascinating link between vitamin K, ferroptosis, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. 98 By investigating the relationship between vitamin K and ferroptosis, they discovered that vitamin K supplements could reduce the severity of SARS-CoV-2 infections.…”