Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Diverse biological functions of vitamin K: from coagulation to ferroptosis

Nature Metabolism volume 5, pages 924–932 (2023)Cite this article

Subjects

Abstract

Vitamin K is essential for several physiological processes, such as blood coagulation, in which it serves as a cofactor for the conversion of peptide-bound glutamate to γ-carboxyglutamate in vitamin K-dependent proteins. This process is driven by the vitamin K cycle facilitated by γ-carboxyglutamyl carboxylase, vitamin K epoxide reductase and ferroptosis suppressor protein-1, the latter of which was recently identified as the long-sought-after warfarin-resistant vitamin K reductase. In addition, vitamin K has carboxylation-independent functions. Akin to ubiquinone, vitamin K acts as an electron carrier for ATP production in some organisms and prevents ferroptosis, a type of cell death hallmarked by lipid peroxidation. In this Perspective, we provide an overview of the diverse functions of vitamin K in physiology and metabolism and, at the same time, offer a perspective on its role in ferroptosis together with ferroptosis suppressor protein-1. A comparison between vitamin K and ubiquinone, from an evolutionary perspective, may offer further insights into the manifold roles of vitamin K in biology.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: History of vitamin K research.
Fig. 2: Vitamin K cycle for carboxylation of vitamin K-dependent proteins and chemical structures of vitamin K.
Fig. 3: Metabolism and biological function of vitamin K.
Fig. 4: Mechanisms of ferroptosis and its suppression pathways.

Similar content being viewed by others

References

  1. Mladenka, P. et al. Vitamin K—sources, physiological role, kinetics, deficiency, detection, therapeutic use, and toxicity. Nutr. Rev. 80, 677–698 (2022).

    Article  PubMed  Google Scholar 

  2. Tabb, M. M. et al. Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR. J. Biol. Chem. 278, 43919–43927 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Nowicka, B. & Kruk, J. Occurrence, biosynthesis and function of isoprenoid quinones. Biochim. Biophys. Acta 1797, 1587–1605 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Mishima, E. et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 608, 778–783 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mishima, E. & Conrad, M. Nutritional and metabolic control of ferroptosis. Annu. Rev. Nutr. 42, 275–309 (2022).

    Article  PubMed  Google Scholar 

  7. Dam, H. The antihaemorrhagic vitamin of the chick. Biochem. J. 29, 1273–1285 (1935).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dam, H. et al. Isolierung des vitamins K in hochgereinigter form. Helv. Chim. Acta 22, 310–313 (1939).

    Article  CAS  Google Scholar 

  9. McKee, R. W., Binkley, S. B., MacCorquodale, D. W., Thayer, S. A. & Doisy, E. A. The isolation of vitamins K1 and K2. J. Am. Chem. Soc. 61, 1295–1295 (1939).

    Article  CAS  Google Scholar 

  10. Lehmann, J. Vitamin K as a prophylactic in 13,000 infants. Lancet 243, 493–494 (1944).

    Article  Google Scholar 

  11. Esmon, C. T., Sadowski, J. A. & Suttie, J. W. A new carboxylation reaction. The vitamin K-dependent incorporation of H-14-CO3− into prothrombin. J. Biol. Chem. 250, 4744–4748 (1975).

    Article  CAS  PubMed  Google Scholar 

  12. Stenflo, J., Fernlund, P., Egan, W. & Roepstorff, P. Vitamin K-dependent modifications of glutamic acid residues in prothrombin. Proc. Natl Acad. Sci. USA 71, 2730–2733 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stenflo, J. A new vitamin K-dependent protein. Purification from bovine plasma and preliminary characterization. J. Biol. Chem. 251, 355–363 (1976).

    Article  CAS  PubMed  Google Scholar 

  14. Stenflo, J. & Jonsson, M. Protein S, a new vitamin K-dependent protein from bovine plasma. FEBS Lett. 101, 377–381 (1979).

    Article  CAS  PubMed  Google Scholar 

  15. Villa, J. K. D., Diaz, M. A. N., Pizziolo, V. R. & Martino, H. S. D. Effect of vitamin K in bone metabolism and vascular calcification: a review of mechanisms of action and evidences. Crit. Rev. Food Sci. Nutr. 57, 3959–3970 (2017).

    Article  CAS  PubMed  Google Scholar 

  16. Bouckaert, J. H. & Said, A. H. Fracture healing by vitamin K. Nature 185, 849 (1960).

    Article  CAS  PubMed  Google Scholar 

  17. Walker, C. S. et al. On a potential global role for vitamin K-dependent gamma-carboxylation in animal systems. Evidence for a gamma-glutamyl carboxylase in Drosophila. J. Biol. Chem. 276, 7769–7774 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Brown, M. A. et al. Precursors of novel Gla-containing conotoxins contain a carboxy-terminal recognition site that directs gamma-carboxylation. Biochemistry 44, 9150–9159 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Li, T., Yang, C. T., Jin, D. & Stafford, D. W. Identification of a Drosophila vitamin K-dependent gamma-glutamyl carboxylase. J. Biol. Chem. 275, 18291–18296 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Schofield, F. W. A brief account of a disease in cattle simulating hemorrhagic septicaemia due to feeding sweet clover. Can. Vet. J. 3, 3274–3278 (1922).

    Google Scholar 

  21. Campbell, H. A. & Link, K. P. Studies on the hemorrhagic sweet clover disease: iv. The isolation and crystallization of the hemorrhagic agent. J. Biol. Chem. 138, 21–33 (1941).

    Article  CAS  Google Scholar 

  22. Overman, R. S. et al. Studies on the hemorrhagic sweet clover disease: xiii. Anticoagulant activity and structure in the 4-hydroxycoumarin group. J. Biol. Chem. 153, 5–24 (1944).

    Article  CAS  Google Scholar 

  23. Holmes, R. W. & Love, J. Suicide attempt with warfarin, a bishydroxycoumarin-like rodenticide. JAMA 148, 935–937 (1952).

    Article  CAS  Google Scholar 

  24. Whitlon, D. S., Sadowski, J. A. & Suttie, J. W. Mechanism of coumarin action: significance of vitamin K epoxide reductase inhibition. Biochemistry 17, 1371–1377 (1978).

    Article  CAS  PubMed  Google Scholar 

  25. Berkner, K. L. Vitamin K-dependent carboxylation. Vitam. Horm. 78, 131–156 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Bell, R. G. & Matschiner, J. T. Warfarin and the inhibition of vitamin K activity by an oxide metabolite. Nature 237, 32–33 (1972).

    Article  CAS  PubMed  Google Scholar 

  27. Sherman, P. A. & Sander, E. G. Vitamin K epoxide reductase: evidence that vitamin K dihydroquinone is a product of vitamin K epoxide reduction. Biochem. Biophys. Res. Commun. 103, 997–1005 (1981).

    Article  CAS  PubMed  Google Scholar 

  28. Tie, J. K. & Stafford, D. W. Structural and functional insights into enzymes of the vitamin K cycle. J. Thromb. Haemost. 14, 236–247 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wu, S. M., Cheung, W. F., Frazier, D. & Stafford, D. W. Cloning and expression of the cDNA for human gamma-glutamyl carboxylase. Science 254, 1634–1636 (1991).

    Article  CAS  PubMed  Google Scholar 

  30. Li, T. et al. Identification of the gene for vitamin K epoxide reductase. Nature 427, 541–544 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Rost, S. et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427, 537–541 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Wallin, R. & Hutson, S. Vitamin K-dependent carboxylation. Evidence that at least two microsomal dehydrogenases reduce vitamin K1 to support carboxylation. J. Biol. Chem. 257, 1583–1586 (1982).

    Article  CAS  PubMed  Google Scholar 

  33. Shearer, M. J. & Okano, T. Key pathways and regulators of vitamin K function and intermediary metabolism. Annu. Rev. Nutr. 38, 127–151 (2018).

    Article  CAS  PubMed  Google Scholar 

  34. Chu, P. H., Huang, T. Y., Williams, J. & Stafford, D. W. Purified vitamin K epoxide reductase alone is sufficient for conversion of vitamin K epoxide to vitamin K and vitamin K to vitamin KH2. Proc. Natl Acad. Sci. USA 103, 19308–19313 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wallin, R., Patrick, S. D. & Ballard, J. O. Vitamin K antagonism of coumarin intoxication in the rat. Thromb. Haemost. 55, 235–239 (1986).

    Article  CAS  PubMed  Google Scholar 

  36. Lowenthal, J. & Macfarlane, J. A. The nature of the antagonism between vitamin K and indirect anticoagulants. J. Pharmacol. Exp. Ther. 143, 273–277 (1964).

    CAS  PubMed  Google Scholar 

  37. Ingram, B. O., Turbyfill, J. L., Bledsoe, P. J., Jaiswal, A. K. & Stafford, D. W. Assessment of the contribution of NAD(P)H-dependent quinone oxidoreductase 1 (NQO1) to the reduction of vitamin K in wild-type and NQO1-deficient mice. Biochem. J. 456, 47–54 (2013).

    Article  CAS  PubMed  Google Scholar 

  38. Ross, D. et al. NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chem. Biol. Interact. 129, 77–97 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693–698 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688–692 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kaye, J. B. et al. Warfarin pharmacogenomics in diverse populations. Pharmacotherapy 37, 1150–1163 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nutescu, E., Chuatrisorn, I. & Hellenbart, E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J. Thromb. Thrombolysis 31, 326–343 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Jin, D. Y. et al. A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase. Nat. Commun. 14, 828 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Napolitano, M., Mariani, G. & Lapecorella, M. Hereditary combined deficiency of the vitamin K-dependent clotting factors. Orphanet J. Rare Dis. 5, 21 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Brenner, B. et al. A missense mutation in gamma-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors. Blood 92, 4554–4559 (1998).

    Article  CAS  PubMed  Google Scholar 

  46. De Vilder, E. Y., Debacker, J. & Vanakker, O. M. GGCX-associated phenotypes: an overview in search of genotype–phenotype correlations. Int. J. Mol. Sci. https://doi.org/10.3390/ijms18020240 (2017).

  47. Oldenburg, J. et al. Congenital deficiency of vitamin K-dependent coagulation factors in two families presents as a genetic defect of the vitamin K-epoxide-reductase-complex. Thromb. Haemost. 84, 937–941 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Pauli, R. M., Lian, J. B., Mosher, D. F. & Suttie, J. W. Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: clues to the mechanism of teratogenicity of coumarin derivatives. Am. J. Hum. Genet. 41, 566–583 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Azuma, K. et al. Liver-specific gamma-glutamyl carboxylase-deficient mice display bleeding diathesis and short life span. PLoS ONE 9, e88643 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Zhu, A. et al. Fatal hemorrhage in mice lacking gamma-glutamyl carboxylase. Blood 109, 5270–5275 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Shiba, S. et al. Vitamin K-dependent gamma-glutamyl carboxylase in sertoli cells is essential for male fertility in mice. Mol. Cell Biol. https://doi.org/10.1128/MCB.00404-20 (2021).

  52. Azuma, K. et al. Osteoblast-specific gamma-glutamyl carboxylase-deficient mice display enhanced bone formation with aberrant mineralization. J. Bone Miner. Res. 30, 1245–1254 (2015).

    Article  CAS  PubMed  Google Scholar 

  53. Spohn, G. et al. VKORC1 deficiency in mice causes early postnatal lethality due to severe bleeding. Thromb. Haemost. 101, 1044–1050 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. LeBlanc, J. G. et al. Bacteria as vitamin suppliers to their host: a gut microbiota perspective. Curr. Opin. Biotechnol. 24, 160–168 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Shearer, M. J., McBurney, A. & Barkhan, P. Studies on the absorption and metabolism of phylloquinone (vitamin K1) in man. Vitam. Horm. 32, 513–542 (1974).

    Article  CAS  PubMed  Google Scholar 

  56. Narushima, K., Takada, T., Yamanashi, Y. & Suzuki, H. Niemann-pick C1-like 1 mediates alpha-tocopherol transport. Mol. Pharmacol. 74, 42–49 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Takada, T. et al. NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy. Sci. Transl. Med. 7, 275ra223 (2015).

    Article  Google Scholar 

  58. Goncalves, A. et al. Intestinal scavenger receptors are involved in vitamin K1 absorption. J. Biol. Chem. 289, 30743–30752 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hirota, Y. et al. Menadione (vitamin K3) is a catabolic product of oral phylloquinone (vitamin K1) in the intestine and a circulating precursor of tissue menaquinone-4 (vitamin K2) in rats. J. Biol. Chem. 288, 33071–33080 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Nakagawa, K. et al. Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature 468, 117–121 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Okano, T. et al. Conversion of phylloquinone (vitamin K1) into menaquinone-4 (vitamin K2) in mice: two possible routes for menaquinone-4 accumulation in cerebra of mice. J. Biol. Chem. 283, 11270–11279 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Thijssen, H. H. & Drittij-Reijnders, M. J. Vitamin K status in human tissues: tissue-specific accumulation of phylloquinone and menaquinone-4. Br. J. Nutr. 75, 121–127 (1996).

    Article  CAS  PubMed  Google Scholar 

  63. Shearer, M. J. Vitamin K in parenteral nutrition. Gastroenterology 137, S105–S118 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Araki, S. & Shirahata, A. Vitamin K deficiency bleeding in infancy. Nutrients https://doi.org/10.3390/nu12030780 (2020).

  65. Zipursky, A. Prevention of vitamin K deficiency bleeding in newborns. Br. J. Haematol. 104, 430–437 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Shea, M. K. et al. Vitamin K status and cognitive function in adults with chronic kidney disease: the chronic renal insufficiency cohort. Curr. Dev. Nutr. 6, nzac111 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Berkner, K. L. & Runge, K. W. Vitamin K-dependent protein activation: normal gamma-glutamyl carboxylation and disruption in disease. Int. J. Mol. Sci. https://doi.org/10.3390/ijms23105759 (2022).

  68. Hayes, D. M. Neonatal anemia due to water-soluble vitamin K analogue: case report. N. C. Med. J. 22, 270–271 (1961).

    CAS  PubMed  Google Scholar 

  69. Ansbacher, S., Corwin, W. C. & Thomas, B. G. H. Toxicity of menadione, menadiol and esters. J. Pharmacol. Exp. Ther. 75, 111 (1942).

    CAS  Google Scholar 

  70. Loor, G. et al. Menadione triggers cell death through ROS-dependent mechanisms involving PARP activation without requiring apoptosis. Free Radic. Biol. Med. 49, 1925–1936 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Goto, S. et al. Prodrugs for skin delivery of menahydroquinone-4 an active form of vitamin K2(20) could overcome the photoinstability and phototoxicity of vitamin K2(20). Int. J. Mol. Sci. 20, 2548 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ichikawa, T., Horie-Inoue, K., Ikeda, K., Blumberg, B. & Inoue, S. Vitamin K2 induces phosphorylation of protein kinase A and expression of novel target genes in osteoblastic cells. J. Mol. Endocrinol. 39, 239–247 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Ohsaki, Y. et al. Vitamin K suppresses the lipopolysaccharide-induced expression of inflammatory cytokines in cultured macrophage-like cells via the inhibition of the activation of nuclear factor kappaB through the repression of IKKalpha/beta phosphorylation. J. Nutr. Biochem. 21, 1120–1126 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Hirota, Y. & Suhara, Y. New aspects of vitamin K research with synthetic ligands: transcriptional activity via SXR and neural differentiation activity. Int. J. Mol. Sci. https://doi.org/10.3390/ijms20123006 (2019).

  75. Jiang, X., Stockwell, B. R. & Conrad, M. Ferroptosis: mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 22, 266–282 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Friedmann Angeli, J. P. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 16, 1180–1191 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. Vervoort, L. M., Ronden, J. E. & Thijssen, H. H. The potent antioxidant activity of the vitamin K cycle in microsomal lipid peroxidation. Biochem. Pharmacol. 54, 871–876 (1997).

    Article  CAS  PubMed  Google Scholar 

  78. Li, J. et al. Novel role of vitamin k in preventing oxidative injury to developing oligodendrocytes and neurons. J. Neurosci. 23, 5816–5826 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kolbrink, B. et al. Vitamin K1 inhibits ferroptosis and counteracts a detrimental effect of phenprocoumon in experimental acute kidney injury. Cell. Mol. Life Sci. 79, 387 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Viswanathan, V. S. et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547, 453–457 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Misima, E. et al. DHODH inhibitors sensitize cancer cells to ferroptosis via FSP1 inhibition. Res. Sq. https://doi.org/10.21203/rs.3.rs-2190326/v1 (2022).

    Article  Google Scholar 

  82. Hiratsuka, T. et al. An alternative menaquinone biosynthetic pathway operating in microorganisms. Science 321, 1670–1673 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Meganathan, R. & Kwon, O. Biosynthesis of menaquinone (vitamin K2) and ubiquinone (coenzyme Q). EcoSal Plus https://doi.org/10.1128/ecosalplus.3.6.3.3 (2009).

  84. Brettel, K. & Leibl, W. Electron transfer in photosystem I. Biochim. Biophys. Acta 1507, 100–114 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Wang, L. et al. The phytol phosphorylation pathway is essential for the biosynthesis of phylloquinone, which is required for photosystem I stability in Arabidopsis. Mol. Plant 10, 183–196 (2017).

    Article  CAS  PubMed  Google Scholar 

  86. Vos, M. et al. Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency. Science 336, 1306–1310 (2012).

    Article  CAS  PubMed  Google Scholar 

  87. Cerqua, C. et al. Vitamin K2 cannot substitute coenzyme Q10 as electron carrier in the mitochondrial respiratory chain of mammalian cells. Sci. Rep. 9, 6553 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Hirota, Y. et al. Functional characterization of the vitamin K2 biosynthetic enzyme UBIAD1. PLoS ONE 10, e0125737 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Nashimoto, S., Takekawa, Y., Takekuma, Y., Sugawara, M. & Sato, Y. Transport via Niemann–Pick C1 Like 1 contributes to the intestinal absorption of ubiquinone. Drug Metab. Pharmacokinet. 35, 527–533 (2020).

    Article  CAS  PubMed  Google Scholar 

  90. Ilbert, M. & Bonnefoy, V. Insight into the evolution of the iron oxidation pathways. Biochim. Biophys. Acta 1827, 161–175 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Bergdoll, L., Ten Brink, F., Nitschke, W., Picot, D. & Baymann, F. From low- to high-potential bioenergetic chains: thermodynamic constraints of Q-cycle function. Biochim. Biophys. Acta 1857, 1569–1579 (2016).

    Article  CAS  PubMed  Google Scholar 

  92. Distefano, A. M. et al. Heat stress induces ferroptosis-like cell death in plants. J. Cell Biol. 216, 463–476 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Aguilera, A. et al. C-ferroptosis is an iron-dependent form of regulated cell death in cyanobacteria. J. Cell Biol. https://doi.org/10.1083/jcb.201911005 (2022).

  94. Bogacz, M. & Krauth-Siegel, R. L. Tryparedoxin peroxidase deficiency commits trypanosomes to ferroptosis-type cell death. Elife https://doi.org/10.7554/eLife.37503 (2018).

  95. Shen, Q., Liang, M., Yang, F., Deng, Y. Z. & Naqvi, N. I. Ferroptosis contributes to developmental cell death in rice blast. New Phytol. 227, 1831–1846 (2020).

    Article  CAS  PubMed  Google Scholar 

  96. Perez, M. A., Magtanong, L., Dixon, S. J. & Watts, J. L. Dietary lipids induce ferroptosis in Caenorhabditis elegans and human cancer cells. Dev. Cell 54, 447–454 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Conrad, M. et al. Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev. 32, 602–619 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Vats, K. et al. Keratinocyte death by ferroptosis initiates skin inflammation after UVB exposure. Redox Biol. 47, 102143 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Singhal, R. & Shah, Y. M. Oxygen battle in the gut: hypoxia and hypoxia-inducible factors in metabolic and inflammatory responses in the intestine. J. Biol. Chem. 295, 10493–10505 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

M.C. acknowledges funding from the Deutsche Forschungsgemeinschaft (CO 291/9-1, 461385412; and the Priority Program SPP 2306 (CO 291/9-1, 461385412; CO 291/10-1, 461507177)), the German Federal Ministry of Education and Research (BMBF) FERROPath (01EJ2205B), the Else Kröner-Fresenius-Stiftung (projects 2019_T12 and 2020_EKTP19) and the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. GA 884754). E.M. is funded by JSPS KAKENHI (20KK0363 and 18K08198).

Author information

Author notes

  1. These authors contributed equally: Eikan Mishima, Adam Wahida.

Authors and Affiliations

  1. Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, Germany

    Eikan Mishima, Adam Wahida, Tobias Seibt & Marcus Conrad

  2. Division of Nephrology, Rheumatology and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Eikan Mishima

  3. Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany

    Adam Wahida

Authors
  1. Eikan Mishima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adam Wahida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tobias Seibt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marcus Conrad
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E.M., A.W., T.S. and M.C. jointly wrote this article.

Corresponding authors

Correspondence to Eikan Mishima or Marcus Conrad.

Ethics declarations

Competing interests

E.M. has filed a patent related to the treatment of ferroptosis-associated diseases with vitamin K (WO2022075444A1). M.C. is a cofounder and shareholder of ROSCUE Therapeutics, which is developing ferroptosis inhibitors. The other authors declare no competing interests.

Peer review

Peer review information

Nature Metabolism thanks Martin Shearer and Yoshihisa Hirota for their contribution to the peer review of this work. Primary Handling Editor: Christoph Schmitt, in collaboration with the Nature Metabolism team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mishima, E., Wahida, A., Seibt, T. et al. Diverse biological functions of vitamin K: from coagulation to ferroptosis. Nat Metab 5, 924–932 (2023). https://doi.org/10.1038/s42255-023-00821-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s42255-023-00821-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing