Mechanisms of Vitamins Inhibiting Ferroptosis

Overview

Journal Antioxidants (Basel)

Date 2025 Jan 8

PMID 39765898

Authors

Meng Zhang

Xin Chen

Yumei Zhang

Affiliations

Soon will be listed here.

Abstract

Ferroptosis is an iron-dependent form of cell death, which is characterized by the uncontrolled and overwhelming peroxidation of cell membrane lipids. Ferroptosis has been implicated in the progression of various pathologies, including steatotic liver, heart failure, neurodegenerative diseases, and diabetes. Targeted inhibition of ferroptosis provides a promising strategy to treat ferroptosis-related diseases. Multivitamins, including vitamins A, B, C, D, E, and K, have shown a good ability to inhibit ferroptosis. For example, vitamin A significantly upregulated the expression of several key ferroptotic gatekeepers genes through nuclear retinoic acid receptors and retinoic X receptors (RAR/RXR). Vitamin B6 could compensate for the impaired glutathione (GSH) levels and restore Glutathione peroxidase 4 (GPX4) expression in cells, ultimately inhibiting ferroptosis. Vitamin D could up-regulate the expression of several anti-ferroptosis proteins by activating vitamin D receptors. Vitamin E and hydroquinone vitamin K (VKH) can directly inhibit the propagation of lipid peroxidation, thereby inhibiting ferroptosis. In this review, we summarize the currently understood mechanisms by which vitamins inhibit ferroptosis to provide reference information for future research on the development of ferroptosis inhibitors.

References

Yang X, Wang Z, Zandkarimi F, Liu Y, Duan S, Li Z . Regulation of VKORC1L1 is critical for p53-mediated tumor suppression through vitamin K metabolism. Cell Metab. 2023; 35(8):1474-1490.e8. PMC: 10529626. DOI: 10.1016/j.cmet.2023.06.014. View

Matsushita M, Freigang S, Schneider C, Conrad M, Bornkamm G, Kopf M . T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J Exp Med. 2015; 212(4):555-68. PMC: 4387287. DOI: 10.1084/jem.20140857. View

Wirth J, Petry N, Tanumihardjo S, Rogers L, McLean E, Greig A . Vitamin A Supplementation Programs and Country-Level Evidence of Vitamin A Deficiency. Nutrients. 2017; 9(3). PMC: 5372853. DOI: 10.3390/nu9030190. View

Rerolle D, Wu H, de The H . Acute Promyelocytic Leukemia, Retinoic Acid, and Arsenic: A Tale of Dualities. Cold Spring Harb Perspect Med. 2024; 14(9). PMC: 11368190. DOI: 10.1101/cshperspect.a041582. View

Dugger B, Dickson D . Pathology of Neurodegenerative Diseases. Cold Spring Harb Perspect Biol. 2017; 9(7). PMC: 5495060. DOI: 10.1101/cshperspect.a028035. View

Maniam S, Mohamed N, Shuid A, Soelaiman I . Palm tocotrienol exerted better antioxidant activities in bone than alpha-tocopherol. Basic Clin Pharmacol Toxicol. 2008; 103(1):55-60. DOI: 10.1111/j.1742-7843.2008.00241.x. View

Peng Y, Zheng W, Chen Y, Lei X, Yang Z, Yang Y . POLQ inhibition attenuates the stemness and ferroptosis resistance in gastric cancer cells via downregulation of dihydroorotate dehydrogenase. Cell Death Dis. 2024; 15(4):248. PMC: 10995193. DOI: 10.1038/s41419-024-06618-5. View

Qin S, Wang Y, Li L, Liu J, Xiao C, Duan D . Early-life vitamin B12 orchestrates lipid peroxidation to ensure reproductive success via SBP-1/SREBP1 in Caenorhabditis elegans. Cell Rep. 2022; 40(12):111381. DOI: 10.1016/j.celrep.2022.111381. View

Mason R, Libby P, Bhatt D . Emerging Mechanisms of Cardiovascular Protection for the Omega-3 Fatty Acid Eicosapentaenoic Acid. Arterioscler Thromb Vasc Biol. 2020; 40(5):1135-1147. PMC: 7176343. DOI: 10.1161/ATVBAHA.119.313286. View

10.

Younossi Z . Non-alcoholic fatty liver disease - A global public health perspective. J Hepatol. 2018; 70(3):531-544. DOI: 10.1016/j.jhep.2018.10.033. View

11.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

12.

Tappel A . Studies of the mechanism of vitamin E action. II. Inhibition of unsaturated fatty acid oxidation catalyzed by hematin compounds. Arch Biochem Biophys. 1954; 50(2):473-85. DOI: 10.1016/0003-9861(54)90063-6. View

13.

Cimmino L, Neel B, Aifantis I . Vitamin C in Stem Cell Reprogramming and Cancer. Trends Cell Biol. 2018; 28(9):698-708. PMC: 6102081. DOI: 10.1016/j.tcb.2018.04.001. View

14.

Hanel A, Carlberg C . Vitamin D and evolution: Pharmacologic implications. Biochem Pharmacol. 2019; 173:113595. DOI: 10.1016/j.bcp.2019.07.024. View

15.

Liu Y, Lu S, Wu L, Yang L, Yang L, Wang J . The diversified role of mitochondria in ferroptosis in cancer. Cell Death Dis. 2023; 14(8):519. PMC: 10425449. DOI: 10.1038/s41419-023-06045-y. View

16.

Dovinova I, Kvandova M, Balis P, Gresova L, Majzunova M, Horakova L . The role of Nrf2 and PPARgamma in the improvement of oxidative stress in hypertension and cardiovascular diseases. Physiol Res. 2021; 69(Suppl 4):S541-S553. PMC: 8603703. View

17.

Wang F, Li W, Shen L, Jiang T, Xia J, You D . Crocin Alleviates Intracerebral Hemorrhage-Induced Neuronal Ferroptosis by Facilitating Nrf2 Nuclear Translocation. Neurotox Res. 2022; 40(2):596-604. DOI: 10.1007/s12640-022-00500-y. View

18.

Traber M, Cross C . Alpha-Tocopherol from People to Plants Is an Essential Cog in the Metabolic Machinery. Antioxid Redox Signal. 2023; 38(10-12):775-791. DOI: 10.1089/ars.2022.0212. View

19.

He Z, Song C, Li S, Dong C, Liao W, Xiong Y . Development and Application of the CRISPR-dcas13d-eIF4G Translational Regulatory System to Inhibit Ferroptosis in Calcium Oxalate Crystal-Induced Kidney Injury. Adv Sci (Weinh). 2024; 11(17):e2309234. PMC: 11077677. DOI: 10.1002/advs.202309234. View

20.

Wu J, Shi Y, Zhou M, Chen M, Ji S, Liu X . Nutrient vitamins enabled metabolic regulation of ferroptosis via reactive oxygen species biology. Front Pharmacol. 2024; 15:1434088. PMC: 11291210. DOI: 10.3389/fphar.2024.1434088. View