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Review
. 2024 Mar 10;13(3):334.
doi: 10.3390/antiox13030334.

Beyond Mortality: Exploring the Influence of Plant Phenolics on Modulating Ferroptosis-A Systematic Review

Nemanja Živanović  1 , Marija Lesjak  1 , Nataša Simin  1 , Surjit K S Srai  2
Affiliations
Review

Beyond Mortality: Exploring the Influence of Plant Phenolics on Modulating Ferroptosis-A Systematic Review

Nemanja Živanović et al. Antioxidants (Basel). .

Abstract

Ferroptosis is a recently discovered type of programmed cell death that is mechanistically different from other types of programmed cell death such as apoptosis, necroptosis, and autophagy. It is characterized by the accumulation of intracellular iron, overproduction of reactive oxygen species, depletion of glutathione, and extensive lipid peroxidation of lipids in the cell membrane. It was discovered that ferroptosis is interconnected with many diseases, such as neurodegenerative diseases, ischemia/reperfusion injury, cancer, and chronic kidney disease. Polyphenols, plant secondary metabolites known for many bioactivities, are being extensively researched in the context of their influence on ferroptosis which resulted in a great number of publications showing the need for a systematic review. In this review, an extensive literature search was performed. Databases (Scopus, Web of Science, PubMed, ScienceDirect, Springer) were searched in the time span from 2017 to November 2023, using the keyword "ferroptosis" alone and in combination with "flavonoid", "phenolic acid", "stilbene", "coumarin", "anthraquinone", and "chalcone"; after the selection of studies, we had 311 papers and 143 phenolic compounds. In total, 53 compounds showed the ability to induce ferroptosis, and 110 compounds were able to inhibit ferroptosis, and out of those compounds, 20 showed both abilities depending on the model system. The most researched compounds are shikonin, curcumin, quercetin, resveratrol, and baicalin. The most common modes of action are in the modulation of the Nrf2/GPX4 and Nrf2/HO-1 axis and the modulation of iron metabolism.

Keywords: ferroptosis; ferroptosis inhibition; ferroptosis initiation; polyphenols.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Mechanism of apoptosis initiation. The activation of the intrinsic pathway triggers the release of Cyt-c from the mitochondrial lumen into the cytosol, facilitated by a pore formed by the proteins BAK and BAX. This event induces the formation of a protein complex involving APAF1 and pro-CASP9, ultimately leading to the release of active CASP9. Subsequently, CASP9 activates CASP3. On the other hand, the extrinsic pathway is initiated by the binding of a ligand to its receptor, as illustrated in the scheme depicting the binding of Fasl to Fas. This binding activates a cascade that culminates in the activation of CASP8, which in turn activates CASP3. The activation of CASP3 serves as a pivotal point of no return, leading to the exposure of PS on the outer layer of the cell membrane, membrane blebbing, and the fragmentation of DNA in the nucleus.
Figure 2
Figure 2
Structure of PE-peroxide containing AA—it is a product of ALOX12/15 enzymes, is very unstable, and can initiate a lipid peroxidation chain reaction leading to damage of cell membrane.
Figure 3
Figure 3
Mechanism of initiation of ferroptosis. The Xct- system is vital for preventing ferroptosis by supplying cystine for GSH synthesis, used by GPX4 to neutralize lipid radicals, as marled with red line. Under intense oxidative stress, depleted GSH and blocked Xct- system hinders sufficient GSH production, leaving the cell vulnerable to oxidative damage. ACSL4 synthesizes phospholipids with unsaturated fatty acids, like AA, prone to oxidation by ALOX12/15 enzymes, inducing lipid peroxidation in the cell membrane. Accumulated free iron in the cytosol generates reactive hydroxyl radicals through the Fenton reaction, triggering highly reactive lipid peroxides and initiating lipid peroxidation in the cell membrane. Iron levels are tightly regulated; in the blood, Fe3+ is transported bound to Tf. Cells with TfR receptors internalize the Tf-iron complex, releasing iron through DMT1. Ferritin stores iron inside cells, shielding them from pro-oxidant free iron. Ferritinophagy releases iron into the cytosol. Excess iron exits cells through FPN1, oxidizes to Fe3+, and binds to Tf. Processes inhibiting Xct-, GPX4, or causing free iron accumulation, along with increased synthesis of unsaturated fatty acid phospholipids and activation of ALOX12/15, can promote ferroptosis.
Figure 4
Figure 4
DHFR/BH4, FSP1/NAD(P)H/CoQ10, and Nrf2 pathways. CoQ10 and BH4 antioxidants help to neutralize harmful lipid radicals and prevent lipid peroxidation. The red line indicates the neutralization of reactive species, which consequently inhibits lipid peroxidation. FSP1 is an enzyme that turns inactive CoQ10 into its active form, ubiquinol. DHFR is another enzyme that converts dihydrobiopterine (BH2) to BH4, acting as an antioxidant and aiding in CoQ10 synthesis. Keap1 inhibits the release of Nrf2. During oxidative stress, Nrf2 is freed from Keap1, moves to the nucleus, and boosts the expression of proteins that inhibit ferroptosis, as marked with red line.
Figure 5
Figure 5
Structures of most common phenolic acids.
Figure 6
Figure 6
Structures of seven flavonoid subclasses’ skeletons and some of their representatives.
Figure 7
Figure 7
Structures of simple coumarin representatives.
Figure 8
Figure 8
Structure of stilbene representative—resveratrol.
Figure 9
Figure 9
Prisma flow diagram. Illustrates search strategy and selection process. Selected databases were searched using keywords which resulted in a collection of 508 papers. After the removal of duplicates, papers outside of scope and not retrieved papers, 311 papers were included in this review.
Figure 10
Figure 10
The distribution of polyphenols with pro-ferroptotic (A) and anti-ferroptotic (B) activity across subclasses.
See this image and copyright information in PMC

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