Polyphenols are organic chemicals containing several phenol groups, which determine the chemical’s properties. Most polyphenols occur naturally as secondary metabolites in plants, where their primary role is to protect the plant from ultraviolet radiation and pathogens [90
]. Interestingly, polyphenols can functionally counteract the effects of oxidative stress, making them suitable for therapeutic purposes. Moreover, polyphenols are reported to confer protection against the development of certain types of cancer, cardiovascular disease, diabetes, osteoporosis, and neurodegenerative disease [91
]. Four main classes of polyphenols have been identified: flavonoids, phenolic acids, lignans, and stilbenes.
3.1.1. The Flavonoids: Tea Catechins, Black Soy Bean Seed Anthocyanins and Myricetin, Citrus Flavonoids, Grape Seed Extract, Curcumin, Quercetin, Genistein, and Silymarin
Flavonoids are the most common class of polyphenols and are present in a wide variety of plants, imparting many of these plants with their specific colors. Their primarily functions are to protect the plant and to act as chemical messengers, physiological regulators, and cell cycle inhibitors. However, because flavonoids are relatively non-toxic to animal cells, humans and other animals can safely ingest them, thereby benefiting from their positive properties [92
]. Examples of flavonoids include quercetin, catechins, curcumin, and kaempferol, which are abundant in fruits, vegetables, legumes, red wine, and green tea.
summarizes the flavonoids and other antioxidants that regulate both iron homeostasis and redox state, in some cases via independent mechanisms. A flavonoid-rich extract of orange and bergamot juice has been shown to chelate iron in iron-overloaded A549 cells (a human lung epithelial cell line); in addition, this extract was shown to activate the antioxidant enzyme catalase, leading to a decrease in ROS production and membrane lipid peroxidation [65
]. Based on these effects, the authors suggested that this flavonoid-rich extract is a promising candidate for regulating both iron homeostasis and oxidative stress [65
]. Similarly, the tea-derived catechin epigallocatechin-3-gallate (EGCG) and grape seed extract (GSE)—both of which have potent antioxidant properties—are good candidates for chelating iron, given their ability to reduce basolateral iron export in Caco-2 cells [66
]. Moreover, because EGCG can activate Nrf2—a master transcriptional regulator of antioxidant genes [67
]—it may also help restore a balanced redox state in patients with iron overload. GSE is rich in anthocyanins, which are believed to be the bioactive compounds responsible for GSE’s ability to modulate iron homeostasis and oxidative stress [68
]. Specifically, GSE-derived anthocyanins prevent sodium fluoride-induced oxidative damage in human embryo-derived hepatic cells by decreasing iron content and increasing antioxidants, including GPx, SOD, and total antioxidant capacity, by decreasing hepcidin expression and increasing ferroportin expression [68
Another potent flavonoid antioxidant, curcumin, can also chelate iron in addition to modulating redox state [93
]. Curcumin decreases iron levels in the bone marrow, spleen, and liver, and it can induce signs of iron deficiency anemia in mice by activating hepatic IRP and TfR1, as well as by repressing hepatic ferritin and hepcidin expression. Interestingly, curcumin can also reduce oxidative stress‒related inflammation induced by lipopolysaccharides (LPS) [69
]. As discussed above, inflammation can activate hepcidin expression, which can reduce iron absorption, ultimately leading to iron deficiency. However, the fact that curcumin can reduce inflammation and hepcidin expression while inducing signs of iron deficiency suggests that this compound has iron chelation properties that are independent of hepcidin.
Recently, Tang et al. [70
] reported that quercetin can reduce hepatic iron deposition in mice that were exposed to either ethanol or excess iron. They found that quercetin increased BMP6, intranuclear SMAD4, SMAD4 binding to the HAMP
promoter, and hepcidin expression, which led to decreased hepatic iron levels and reduced iron-related damage. Conversely, we reported that an anthocyanin-rich extract of black soybean seed coat extract can decrease hepatic hepcidin expression, resulting in decreased splenic iron and increased serum iron via reduced SMAD1/5/8 phosphorylation [71
]. In a follow-up study, we found that myricetin is the principal bioactive compound in black soybean seed coat extract responsible for suppressing hepcidin expression [72
]. Although myricetin is structurally similar to quercetin [94
], unlike quercetin it inhibits hepcidin expression by modulating the BMP/SMAD signaling pathway in both in vitro and in vivo systems [72
]. Specifically, myricetin decreases hepcidin expression by inhibiting the HAMP
promoter; in addition, myricetin reduces SMAD1/5/8 phosphorylation in HepG2 cells, even in the presence of potent stimulators of hepcidin such as BMP6 and interleukin (IL)-6. In mice, myricetin also suppresses hepatic hepcidin expression, decreases splenic iron levels, and increases serum iron levels [72
Genistein, another flavonoid that has potent antioxidant and anti-inflammatory properties, reduces ethanol-induced inflammation and oxidative stress in mice [95
]. However, similar to quercetin, genistein increases HAMP
promoter activity in both zebrafish and human hepatocytes via a Stat3- and Smad4-dependent process [73
]. This suggests that genistein’s ability to induce hepcidin expression may be independent of its inflammation-reducing properties. Silymarin, another flavonoid, is present in milk thistle plant extract and may have iron-chelating properties [74
]. Silymarin is actually a mixture of flavonolignans, including silibinin, isosilibinin, silicristin, and silidianin; silibinin has both antioxidant and hepatoprotective properties. Silymarin is a safe, well-tolerated, cost-effective alternative to currently available iron-chelation therapies for treating patients with β-thalassemia [74
Flavonoids have already been shown to have both anti-inflammatory and antioxidant effects [96
]. Recently, Bayele et al. reported that the transcription factor Nrf2 regulates hepcidin expression as part of an antioxidant regulatory network, whereas several flavonoids modulate iron homeostasis by blocking Keap1-mediated transcriptional repression, providing further evidence that Nrf2 modulates the activity of the HAMP
promoter when activated as part of an antioxidant response [97
]. However, the physicochemical properties of flavonoids can influence their pharmacokinetics, which can affect their bioavailability in vivo, thereby determining their ability to exert biological activities relevant to human health [98
]. Thus, on one hand, flavonoids such as EGCG and curcumin can chelate iron, prevent the basolateral export of iron across Caco-2 cells, and induce signs of iron deficiency by increasing hepcidin expression and depleting iron stores, thereby providing clinical value during iron overload conditions and eventually restoring redox state; on the other hand, their iron-chelating property can also be detrimental and may even lead to iron deficiency.