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Review
. 2021 Dec 1;10(12):2952.
doi: 10.3390/foods10122952.

The Regulatory Effects and the Signaling Pathways of Natural Bioactive Compounds on Ferroptosis

Shenshen Zhang  1 , Ruizhe Hu  1 , Yaping Geng  1 , Ke Chen  1 , Ling Wang  1 , Mustapha Umar Imam  2
Affiliations
Review

The Regulatory Effects and the Signaling Pathways of Natural Bioactive Compounds on Ferroptosis

Shenshen Zhang et al. Foods. .

Abstract

Natural bioactive compounds abundantly presented in foods and medicinal plants have recently received a remarkable attention because of their various biological activities and minimal toxicity. In recent years, many natural compounds appear to offer significant effects in the regulation of ferroptosis. Ferroptosis is the forefront of international scientific research which has been exponential growth since the term was coined. This type of regulated cell death is driven by iron-dependent phospholipid peroxidation. Recent studies have shown that numerous organ injuries and pathophysiological processes of many diseases are driven by ferroptosis, such as cancer, arteriosclerosis, neurodegenerative disease, diabetes, ischemia-reperfusion injury and acute renal failure. It is reported that the initiation and inhibition of ferroptosis plays a pivotal role in lipid peroxidation, organ damage, neurodegeneration and cancer growth and progression. Recently, many natural phytochemicals extracted from edible plants have been demonstrated to be novel ferroptosis regulators and have the potential to treat ferroptosis-related diseases. This review provides an updated overview on the role of natural bioactive compounds and the potential signaling pathways in the regulation of ferroptosis.

Keywords: ferrroptosis; glutathione peroxidase 4; health-promoting; lipid peroxidation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic view of the molecular pathways of ferroptosis regulation. Three main metabolic pathways are GSH/GPX4 pathway, lipid peroxidation and iron metabolism pathways. Ferroptosis is initiated by the suppression of system Xc− and depletion of GSH, or inhibition of GPX4, which results in cell death. Lipid ROS is in charge of the process of ferroptosis. The peroxidation of PUFAs is identified as a vital contributor. Excess iron is the basis for ferroptosis execution. In addition, the latest researches have revealed that the FSP1-CoQ10-NAD(P)H pathway with its unique mechanistic properties engages in ferroptosis. AA: Arachidonic acid, ACSL4: Acyl-CoA Synthetase Long Chain Family Member 4), AdA: Adrenoyl, DMT1: Divalent metal transporter 1, FSP1: Ferroptosis suppressor protein 1, FPN1: Ferroportin 1, GPX4: Glutathioneperoxidase 4, GSH: glutathione, GSSG: Oxidized GSH; LPCAT3: Lysophosphatidylcholine acyltransferase 3, lipoxygenases: LOXs, NCOA4: Nuclear receptor coactivator 4, GR: Glutathione reductase. PL: Phospholipids, Tf: Transferrin.
Figure 2
Figure 2
The dual function of p53 on ferroptosis. P53 can promote ferroptosis through regulating SLC7A11, GLS2, SAT1/ALOX15, ALOX12 and PTGS2. Meanwhile, p53 also could restrain ferroptosis via the mediation of p21 and DPP4. ALOX12: Arachidonate 12-Lipoxygenase, ALOX15: Arachidonate 15-Lipoxygenase, DPP4: Dipeptidyl peptidase 4, GLS2: Glutaminase 2, SLC7A11: Solute carrier family 7 member 11, SAT1: Spermidine/spermine N1-acetyltransferase 1.
See this image and copyright information in PMC

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