Nutrient vitamins enabled metabolic regulation of ferroptosis via reactive oxygen species biology

Abstract

Vitamins are dietary components necessary for cellular metabolic balance, especially redox homeostasis; deficient or excessive supply may give rise to symptoms of psychiatric disorders. Exploring the nutritional and metabolic pathways of vitamins could contribute to uncovering the underlying pathogenesis of ferroptosis-associated diseases. This mini-review aims to provide insights into vitamins closely linked to the regulation of ferroptosis from the perspective of cellular reactive oxygen species biology. The mainstream reprogramming mechanisms of ferroptosis are overviewed, focusing on unique biological processes of iron metabolism, lipid metabolism, and amino acid metabolism. Moreover, recent breakthroughs in therapeutic interventions targeting ferroptosis via fully utilizing vitamin-based pharmacological tools were overviewed, covering vitamins (B, C, E, and K). Finally, mechanism insight related to vitamin-associated nutrient signaling was provided, highlighting the pharmacological benefits of metabolically reprogramming ferroptosis-associated diseases.

Keywords: ferroptosis; metabolic regulation; nutrient signaling; reactive oxygen species; vitamins.

FIGURE 1

Schematic representation of metabolic processes of ferroptosis modulated by nutrient vitamins. The modulation of the ferroptosis process can be facilitated by the presence of vitamin B, C, E, and K, which exert a multifaceted influence towards iron deposition, ROS accumulation, and radical-trapping. Abbreviation: TFRC, transferrin receptor; NCOA4, nuclear receptor coactivator 4; LIP, labile iron pool; PUFA, polyunsaturated fatty acid; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; LOX, lipoxygenase.

FIGURE 2

Schematic illustration of VFNC-based ferroptosis therapy towards triple-negative breast cancer. (A) Schematic of the preparation process and therapeutic mechanism of the VFNC nanoplatform. (B) Immunofluorescence staining of GPX4. (C) CLSM images of LPO accumulation. Adapted with permission from Zhou M. et al. (2023). Copyright (2023) John Wiley & Sons, Inc.

FIGURE 3

(A) Mechanism of action of early-life B12 in programming of adult health. (B,C) Heatmap and quantification of lipid species with maternal B12 supplementation. Reproduced with permission (Qin et al., 2022). Copyright 2022, Cell Press.

FIGURE 4

(A) Schematic illustration of the tumoricidal effect of combination therapy of VF/S/A@CaP and AHP-DRI-12. (B) The cryo-electron microscope images of H1975/AR cells from the control group or Vc–Fe(II)@CaP group. The red triangle serves as a marker for healthy mitochondria, whereas the yellow triangle signifies vacuolated mitochondria that have sustained severe oxidative damage. (C) The expression levels of GPX4 and COX2 in both H1975 and H1975/AR cells have been assayed. Reproduced with permission (Wang et al., 2022). Copyright (2022), John Wiley & Sons, Inc.

FIGURE 5

The schematic illustration outlines the process of enhancing ROS-mediated lysosomal membrane permeabilization for cancer ferroptosis therapy. (A) The design methods of VC@^N3AMcLAVs. (B) The various molecular structures from the composition of VC@^N3AMcLAVs. (C) Lysosome-targeting process of VC@^N3AMcLAVs and the specific mechanism to promote ROS-mediated lysosomal membrane permeabilization for efficient ferroptosis therapy. Adapted with permission from Chen et al. (2022). Copyright (2023) John Wiley & Sons, Inc.

FIGURE 6

The anti-ferroptotic mechanism of non-canonical vitamin K cycle. (A) Mechanism of vitamin K supplying VKH2 to GGCX via the alternative vitamin K reduction pathway. (B) The possible recycling pathway of α-tocopherol via the CoQ10/VK-hydroquinone transformation process. (C) The cell viability and (D) lactate dehydrogenase (LDH) release from GPX4-KO mouse embryonic fibroblasts (Pfa1 cells) treated with different conditions (three forms of vitamin K and liproxstatin-1 (Lip1) as a ferroptosis inhibitor). (E) The cellular morphology images of RSL3-treated HT-1080 cells were observed irrespective of whether MK4 was present. (F) Proportional levels of oxidized phospholipids are visualized through heatmaps during an 8-h exposure to RSL3 in Pfa1 cells (Mishima et al., 2022). Copyright (2021) Springer Nature.

FIGURE 7

The preparation and action mechanism of Fe-NQA for augmenting tumor ferroptotic therapy. (A) Schematic illustration of Fe-NQA NPs induced ferroptotic therapy. (B) The LSCM images of LPO and Fe²⁺ detected in CT26 cells after incubation of cells with saline, FeCl₃, NQA, and Fe-NQA NPs (scale bar: 50 μm). Adapted with permission from Zhang Z. et al. (2020). Copyright (2020) Springer Nature.