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Introduction

Iron plays an essential role in many vital body functions; it is the most abundant metal in the human body and is essential for maintaining normal physiological activities.^1-6 Iron is mainly involved in crucial processes such as oxygen transport, electron transfer, DNA synthesis and various enzymatic reactions.^7-8 Of the 3500mg of iron present in the body, erythrocytes contain about 1800mg, while the liver stores 1000mg and another 300mg are associated with proteins to support specific cellular processes. The rest is stored as ferritin.⁹

To compensate for the daily losses associated with epithelial cell desquamation, estimated at 1 to 2mg per day, the human body requires a dietary intake of approximately 15mg of iron per day to ensure effective absorption of 1 to 2mg. However, dietary intake alone is not sufficient to meet these needs, as it represents less than 10% of daily iron requirements. Therefore, the recycling of red blood cells by macrophages allows the release of the iron they contain and plays a crucial role in maintaining this balance.^10,11 Overall, iron homeostasis is preserved when the amounts of iron absorbed and lost are balanced.¹²

Metabolic imbalance, such as iron overload, can lead to severe clinical consequences manifested by excessive accumulation of iron in tissues,far exceeding physiological needs.^1-6,13-15 Iron overload is a complex and multifactorial pathology, requiring rapid and appropriate management to limit its harmful effects on the body. It is of particular concern in the context of beta-thalassemia, where it represents a major complication, as well as a significant cause of morbidity and mortality.^16-18

Thus, the objective of this literature review is to discuss the potential medicinal benefits of plant-derived iron chelators. To this end, we will begin with a brief overview of iron homeostasis, both in normal and pathological conditions, to better understand the regulatory mechanisms and associated disturbances. We then briefly discuss synthetic iron chelators, widely used in current treatments, before exploring natural alternatives. Finally, we discuss the promising prospects offered by plants as potential solutions to mitigate the adverse effects of conventional medications while meeting patient needs.

Pathophysiology of iron overload

Iron metabolism and regulation

The human body regulates the distribution of iron between its two ionic forms through redox reactions:

• Heme iron, of animal origin, is distinguished by its high bioavailability, estimated at between 20 and 30%. It is mainly found in the form of ferrous iron (Fe²⁺)
• On the other hand, non-heme iron, of plant origin, has a significantly lower absorption, limited to 2 or 3%, and is mainly found in the form of ferric iron (Fe³⁺).^19,20

Iron is present in the body in two main forms: the heme form (representing approximately 95% of total iron), which is a component of hemoglobin, myoglobin and certain cytochromes, and the non-heme form. The latter is involved in the functioning of certain enzymes, notably iron-sulfur center proteins, as well as chaperone proteins.^21,22

These forms also differ in their enteral absorption. Although the latter represents only 0.1% of daily needs, it cannot be neglected. A series of complex transformations allows the ingested iron to be assimilated by the body. The enterocytes of the duodenum can only absorb ferrous iron (Fe²⁺); therefore, ferric iron (Fe³⁺) must first be reduced to its ferrous form by the action of cytochrome b reductase (duodenal cytochrome b) or other reducers located in the apical membrane of the enterocytes.²² Once absorbed from the gastrointestinal tract, iron is released into the bloodstream and distributed throughout the body, as no physiological pathway exists for its excretion after absorption.²³

This dynamic balance is generally maintained by precise regulatory mechanisms, mainly influenced by dietary iron intake and hematopoietic activity.^1-23 Hepcidin, a 25-amino acid peptide hormone produced by the liver, plays a central role in this process. Its synthesis is modulated by plasma and intracellular iron concentrations: it increases in case of iron overload and decreases in response to anemia or hypoxia.^17,24,25 In normal erythropoiesis, hepatocytes respond to increased iron levels by intensifying hepcidin production, which is then released into the circulation and binds to its target, ferroportin (FPN-1), the only known iron exporter, expressed on the surface of cells involved in iron absorption, storage and recycling. This binding results in the internalisation and degradation of ferroportin in lysosomes, thereby reducing iron flux to plasma.^26,27

Bone marrow is the primary site of iron utilisation, particularly for the synthesis of hemoglobin by red blood cell precursors. Given the continuous degradation of erythrocytes, iron conservation and recycling are crucial to replenish the stores required for hemoglobin^28,29. This recycling is primarily carried out by macrophages, which phagocytose erythrocytes and release the iron contained in heme through the action of heme oxygenase-1 (HO‑1).^29-32 However, in cases of iron overload, excess iron can accumulate in tissues and organs, inducing lipid peroxidation and cellular damage that can lead to cancers, hematological diseases or other chronic pathologies. Moreover, this iron overload is also a characteristic of ferroptosis, a form of regulated cell death, marked by a lethal accumulation of lipid hydroperoxides.³³

Iron balance imbalance

Abnormalities in hepcidin production are the cause of most iron metabolism-related diseases. A lack or decrease in hepcidin leads to iron overload, while excessive production leads to iron-refractory anemia.

Iron overload can be a severe complication, with a considerable impact on patients’ quality of life. Reactive oxygen species (ROS), naturally produced during cellular metabolic functions, play a key role in this process. In the presence of iron, ROS generate hydroxyl radicals, responsible for significant cellular damage and through the Haber-Weiss and Fenton reactions, iron catalyses the formation of these ROS.^34,35 In this mechanism, ferric iron is reduced to ferrous iron by the superoxide radical, which then reacts with hydrogen to produce highly reactive hydroxyl radicals. These radicals cause increased phospholipid peroxidation, oxidation of amino acid side chains, DNA breaks and protein fragmentation.^36,37

Primary iron overload: genetic hemochromatoses

The genetic mutations responsible for primary hemochromatosis all result in impaired activation of the hepcidin gene, leading to insufficient production of this hormone.⁵¹ This reduction in hepcidin causes excessive intestinal absorption of iron, leading to progressive accumulation of the metal in the tissues. The only exception is the forms of hemochromatosis associated with a mutation in the ferroportin gene, where iron overload results either from a defect in the export of iron from the cells (that forms with loss of function of ferroportin) or from resistance to the action of hepcidin (that forms without loss of function of ferroportin ).³⁹

Secondary or acquired iron overload:

Hematopathies: Any ineffective erythropoiesis or abnormal hemolysis, such as in β-thalassemias, congenital dyserythropoiesis or sideroblastic anemias, disrupts iron homeostasis by decreasing hepcidin production.⁴⁰ This deregulation can lead to iron overload, amplified by intestinal hyperabsorption of the metal, often aggravated by blood transfusions.

Chronic viral hepatitis: Iron overload is observed in 35 to 56% of cases of chronic viral hepatitis, particularly in hepatitis C. This accumulation of iron could be explained by a decrease in hepcidin production.⁴¹

Repeated blood transfusions or high-dose parenteral iron therapy: Although blood transfusions are essential, they can induce secondary morbidity. After 4 to 6 transfusions, transferrin saturation exceeds normal levels. Subsequently, iron, in a non-transferrin-bound form, enters various organs, including the heart, liver, anterior pituitary gland and pancreas, where it can cause cellular damage.^42,43 Transfusion-related iron overload, combined with excessive absorption of the metal, complicates the clinical picture, potentially leading to organ dysfunction if left unmanaged.^44,45,46

As previously reported, excess iron can enter the cells of the liver, heart, endocrine glands and other organs, causing progressive tissue damage through the generation of hydroxyl free radicals that cause oxidative stress.^47-49 However, in the absence of a regulated mechanism for the removal of excess iron, it gradually accumulates in various tissues, which can lead to widespread organ dysfunction and, ultimately, organ failure. Liver cirrhosis, hepatocellular carcinoma, cardiomyopathies, hypogonadism and other complications are commonly observed in patients with iron overload disorders.^50,51

At the liver level

The liver is the main organ affected by oxidative stress caused by iron overload. When transferrin saturation increases by more than 75%, non-transferrin-bound iron (NTBI) begins to accumulate,⁶⁵ which is potentially toxic due to its strong ability to induce ROS and can cause cell damage and liver injury through NTBI and iron deposition.^53,54

Research by Nelson et al⁵⁵ has demonstrated a correlation between the location of iron deposits in the liver and the histological severity of non-alcoholic fatty liver disease (NAFLD). According to their studies, histological samples showing iron staining patterns had higher percentages of advanced fibrosis, portal inflammation, hepatocellular ballooning and definitive non-alcoholic steatohepatitis (NASH).⁵⁵

At the cardiac level: Iron overload cardiomyopathy

The American Heart Association (AHA) defines iron overload cardiomyopathy (IOC) as excessive iron accumulation in cardiomyocytes, resulting from abnormal absorption of the metal. This accumulation causes systolic or diastolic dysfunction of the heart, due to excess iron in the myocardium, in the absence of other associated pathological processes. A dilated form of cardiomyopathy develops, with dilation of the left ventricular chamber, accompanied by paroxysmal atrial fibrillation, leading to myocardial damage and increasing the risk of sudden cardiac death (SCD) in patients with iron overload.

Although in most cases the disease is asymptomatic, severe cardiac distress may occur, particularly in the pericardium.^10,56,57 As the disease progresses, iron deposits accumulate in the ventricular myocardium and patients may experience shortness of breath on exertion, due to left ventricular (LV) systolic dysfunction. In addition, nodal abnormalities, causing arrhythmias, may occur because of iron deposits in the cardiac conduction system.

At the tumor cell level

Although iron can induce the formation of ROS, it is not considered carcinogenic in itself but rather acts as a cofactor promoting tumor progression. In this sense, the deregulation of iron homeostasis contributes to the many dysfunctions that characterise cancer cells. Numerous studies have highlighted the disruption of iron homeostasis in these cells, often in association with the deregulation of several other genes. This phenomenon leads to phenotypic changes that confer a selective advantage to cancer cells, thus promoting their proliferation.⁵⁸

At the skin level

Iron is naturally present in the skin, approximately 20–25% of absorbed iron is eliminated daily by exfoliation of epidermal cells.⁵⁹ To protect against iron toxicity, iron is sequestered in iron-binding or heme-containing proteins, such as ferritin and hemosiderin, the latter currently recognised as a histological marker of excess iron in tissues.^59,60 When there is excess iron, it is deposited in the skin as hemosiderin, resulting in brownish hyperpigmentation visible to the naked eye and promoting melanogenesis.^61,62 Hemosiderin granules are found mainly extracellularly, between the collagen bundles of the dermis and dermal macrophages, as well as in the epidermis, especially in Langerhans cells.

At the joints

Several in vitro and vivo studies have demonstrated that changes in catalytically active intracellular iron levels can play a key role in inducing oxidative stress and activating inflammatory pathways, thereby affecting bone metabolism. Tsay et al⁷⁷ revealed that parenteral iron injections resulted in severe iron overload in bone, with a correlation between the degree of overload and an increase in the number of osteoclasts, causing changes in bone microarchitecture and bone loss.⁶³

At the bone marrow level

At this level, iron toxicity induces the accumulation of ROS, which can cause structural and biochemical damage to stem cells, leading to iron-related dyserythropoiesis. This toxicity affects not only the cells but also the expression of genes regulating hematopoiesis. In vitro studies have shown that iron toxicity causes apoptosis, arrests the cell cycle, and reduces the function of human bone marrow mononuclear cells and umbilical cord-derived mesenchymal stem cells, accompanied by increased ROS levels.^64,65 In a mouse model of iron overload, this toxicity increased ROS production and reduced hematopoietic stem cell numbers, colony-forming capacity, and engraftment capacity after in vivo transplantation.⁶⁶ Iron toxicity has also been shown to inhibit proliferation and bone differentiation capacity.⁶⁷

Current therapeutic approaches and their limitations

We will discuss conventional treatments, although there are also phlebotomy alternatives, which will not be covered in this review. Currently, three drugs are approved for the treatment of iron overload. Although iron chelators vary considerably chemically, they generally share oxygen, nitrogen or sulfur donor atoms that form coordinate bonds with iron.

Before choosing one of these treatments, it is important to assess the current or future toxicity of iron overload. For example, although iron chelation is essential in the treatment of thalassemia major, it must be evaluated on a case-by-case basis in myelodysplastic syndromes, considering hepatic and cardiac overload, as well as the patient’s life expectancy, often limited by underlying cytopenias.⁶⁸

Deferoxamine (DFO )

Figure 1. Iron chelation by deferoxamine

Deferoxamine (DFO) is a non-toxic iron chelator, introduced in the 1960s, clinically approved and widely used for long-term iron chelation in conditions such as beta-thalassemia and other pathologies associated with iron overload.⁶⁹ However, it has low oral bioavailability, mainly due to the limited permeability of intestinal cells, which necessitates its parenteral administration. In addition, DFO has a very short half-life of approximately 10 to 20 minutes in humans, requiring prolonged subcutaneous infusions.^70-72 Typically, it is administered as an infusion lasting 8 to 10 hours, 5 days a week, at doses of 30 to 50mg/kg.⁷³

Despite these limitations, DFO remains effective in maintaining iron levels very close to normal, reducing organ damage, and prolonging life expectancy in patients with thalassemia.⁷⁴ It continues to be the reference active comparator in clinical studies of new iron chelators. However, patient compliance often remains insufficient due to discomfort and the demands of administration schedules.^48,75,76 Deferoxamine also carries an increased risk of infections, which may lead to treatment discontinuation.⁷⁷ In addition, dose-related adverse effects, such as hearing problems, growth retardation, and ocular complications, may occur, particularly in patients with lower iron loading but receiving high doses. These concerns have led to research aimed at developing iron chelators that can be administered orally.

Deferiprone ( DFP )

Figure 2. Iron chelation by deferiprone

Deferiprone (DFP) was developed in the 1980s as an orally absorbed iron chelator, first approved in India and subsequently in the European Union and other countries outside the United States and Canada, including other Asian countries in the late 1990s. Although approved in Europe as early as 1999, its use was not approved in the United States until 2011.⁷⁸ DFP is generally prescribed as a second-line treatment, particularly when DFO is contraindicated or when patients fail to maintain satisfactory adherence to treatment due to the constraints of prolonged and invasive DFO administration.⁷⁹

The most common side effects of DFP include elevated liver enzymes, gastrointestinal disturbances, and arthralgias. The most serious adverse effects associated with its use are agranulocytosis and neutropenia, with an incidence of 0.2% and 2.8%, respectively, over a one-year period. These complications, although serious, are reversible after discontinuation of treatment.^80,81

Deferasirox (DFX)

Figure 3. Iron chelation by deferasirox

Deferasirox (DFX ), a new-generation tridentate oral chelator, was approved by the US Food and Drug Administration (FDA) in October 2005 for first line use in adults and children aged 2 years and older with chronic iron overload due to blood transfusions.^82,83 This drug was designed to overcome the limitations of intravenous administration of deferoxamine.⁸⁴

DFX has good oral bioavailability and a long half-life of 12 to 16 hours, allowing once-daily oral administration at a dose ranging from 10 to 30mg/kg.^73,85 The most common adverse effects include gastrointestinal disturbances such as abdominal pain, nausea, diarrhea and vomiting.⁸⁵ However, since its approval, several reports have highlighted cases of severe hepatic and renal toxicity, highlighting the importance of regular monitoring of renal and hepatic functions during treatment.⁷³

Although effective, conventional treatments for iron overload have significant limitations and notable side effects. Deferoxamine, the first iron chelator introduced, requires prolonged parenteral administration (subcutaneous or intravenous), making patient compliance difficult. In addition, it is associated with serious complications such as ototoxicity, ocular toxicity and growth retardation, in addition to an increased risk of infections. Deferiprone, developed as a second-line alternative, is easier to administer thanks to its oral form, but its use requires close monitoring due to serious side effects such as agranulocytosis and neutropenia. Finally, Deferasirox, designed to overcome the disadvantages of parenteral administration, is administered once daily orally thanks to its good bioavailability and long half-life. However, it is frequently associated with gastrointestinal disturbances and can cause severe renal and hepatic toxicities, requiring systematic monitoring of organ functions.

These therapeutic limitations and adverse effects associated with current treatments highlight the growing interest in the development of safer and better tolerated alternatives, including herbal treatments, which are of particular interest due to their availability, reduced cost ;and potentially advantageous safety profile.

 

Figure 4. Timeline of discovery and approval of iron chelating molecules

 

Natural treatments: literature review

To identify plants with iron chelating properties, we conducted a literature search in the electronic databases PubMed and Scopus. The keywords used for the search included: “chelating agents”, “iron chelators”, “natural chelators”, “medicinal plants”, “herbal iron chelators, “iron overload treatment”, “plant extracts”, and “thalassemia”. Inclusion criteria were articles published in English and French up to March 2025 and including studies on plants with iron chelating properties, their mechanisms of action, efficacy and safety. Irrelevant studies, articles without full text access and non-peer-reviewed publications were excluded. A critical analysis of the selected articles was conducted to synthesise current evidence on plant-derived iron chelators. Thus, the search led to the identification of 11 plants listed in Table 1 below.

 

Table 1. List of plants identified as having iron chelating properties

 

Withania somnifera L. (WS): Ashwagandha of the Solanaceae family is one of the most renowned and revered medicinal plants in India. The root is the useful part of this plant and is harvested in summer and winter. In traditional Indian medicine, five basic pharmaceutical forms are presented in a single form: svarasa (juice), kalka (paste), srita (decoction), sita (cold infusion) and phanta (hot infusion).¹⁰¹ The root extract of WS has high iron chelating properties compared to flavonoids.⁸⁷ A study to examine the radical scavenging and iron chelating properties of WS by Yadav et al⁸⁸ reported that this activity was 82% for radicals and 78.88% for iron chelating.These capabilities of WS ingredients both appear responsible for reducing iron overload in the reproductive organs and brain.⁸⁹ Pal et al⁹⁰ evaluated the iron chelating property of WS, as well as the bioactive ingredients of WS that form a sigma-binding complex with iron for excretion.

Curcuma longa L.: Curcumin is found in curcuma longa, called turmeric in English, it is a tropical perennial plant of the ginger family (zingiberaceae), present mainly in India and Indonesia and can reach one meter in height. The rhizome is the part used at the level of this plant either by taking rhizome extracts with hot water or after drying the rhizomes and grinding them into fine powder. The latter is known as nature’s most powerful medicinal herb.⁹¹ Curcumin is the main compound of turmeric, these chemical properties are consistent with iron chelating activity,⁹² it was observed that liver cells treated with curcumin showed distinctive signs of iron depletion, which included a decrease in ferritin, an increase in TfR1 and the activation of iron regulatory proteins.⁹³ In another study, curcumin also repressed the synthesis of hepcidin, a peptide that plays a central role in regulating systemic iron balance.⁹⁴ Consistent with these reports, curcumin reduced NTBI in a mouse model of β -thalassemia.⁹⁵

Camellia Sinensis L.: Also called green tea, the extract of its leaves or its infusion is rich in flavonoids and the most abundant polyphenolic compound in green tea is epigallocatechin gallate (EGCG) possessing iron chelating properties⁹⁶. Indeed, theaflavins act directly as radical scavengers and exert indirect antioxidant effects through the activation of transcription factors and antioxidant enzymes.^96,97 In addition to their radical scavenging action, green tea catechins possess well-established metal chelating properties, with the structurally important features defining their chelating potential being the 3′,4′-dihydroxyl group in the B ring as well as the gallate group.^98-100 Moreover, dried and purified tea polyphenols from black and green teas have been shown to have a profound protective effect on red blood cells exposed to exogenous oxidants via the formation of a redox-inactive complex with iron.¹⁰⁰

Ginkgo biloba L.: also called maidenhair tree, is an tree native to Asia, now endangered in the wild, although it is now present in many countries. It is a valuable medicinal plant, used for a long time as medicine and food. In China, the first mention of Ginkgo biloba dates back to the Shennong Materia Medica Classic (Han dynasty), and the medicinal introduction of its leaves and seeds began in the Song Dynasty.¹⁰¹ Ginkgo fruit kernels, produced only by female trees, have a long history of use in traditional Chinese medicine. Gholampour et al found that quercetin, a flavonoid widely present in the leaves, could inhibit ferrous sulfate-induced hepatorenal toxicity and reduce the degree of iron injury to liver and kidney tissues in rats.¹⁰² The mechanism of quercetin in the treatment of iron overload mainly depends on its antioxidant properties, which reduce lipid peroxidation and iron chelation.¹⁰³ It also has the characteristic of shuttling iron at a quercetin concentration below 1μM, thus it can facilitate the shuttling of chelatable iron via GLUT1 in any direction on the cell membrane.¹⁰⁴ Quercetin and baicalin can release iron from the liver, which is ultimately excreted in the feces.¹⁰⁵

Scutellaria baicalensis G.: The upper part of the Scutellaria baicalensis is traditionally used as a tea substitute to soothe heat. Later, it was discovered that Scutellaria baicalensis tea had special effects, such as clearing heat and dampness and detoxifying, as well as anti-inflammatory and digestive properties.¹⁰⁶ Baicalein and its glycoside baicalin, are the main bioactive compounds present in the Chinese herb Scutellaria baicalensis Georgi. They strongly inhibit iron-promoted Fenton chemistry via a combination of chelation and radical scavenging mechanisms.¹⁰⁷ Baicalein was shown in one study to increase antioxidant status and decrease iron content and lipid peroxidation in the liver of mice with iron overload-induced hepatic oxidative injury.¹⁰⁸ Although these flavonoids are generally considered to be poorly bioavailable, a study of an orally administered formulation containing S. baicalensis reported an apparent elimination half-life of eight hours for baicalein; thus, baicalein may remain in the body long enough to affect iron homeostasis and reduce oxidative stress.¹⁰⁷ These studies suggest that phenolic compounds with an “iron-binding motif” are potent iron-chelating agents that can modulate iron bioactivity and bioavailability in the body.¹⁰⁹

Triticum aestivum L.: Also called wheatgrass, it is an important medicinal plant used since ancient times to treat various diseases and disorders such as high blood pressure, obesity, cancer, diabetes, gastritis, ulcers, pancreas, fatigue and more. In clinical practice, wheatgrass juice is mainly used for its antioxidant properties.¹¹⁰ This dietary supplement, prepared from the cotyledons of the common wheat plant Triticum aestivum, is sold either as a freeze-dried powder or as juice extracted from the fresh leaves of the plant.¹¹⁰ It contains high concentrations of mugineic acid, a phytosiderophore that has comparable efficacy to deferasirox, in a mouse model of iron overload, and may be a clinically significant iron chelator.¹¹¹ In one study, mugineic acid in wheatgrass was observed to have iron chelating activity in patients with transfusion-associated iron overload.¹¹¹

Moringa oleifera Lam.: From the Moringaceae family, M. oleifera is a perennial tree widely cultivated in many tropical regions and easy to grow even in harsh conditions. Also known as the miracle tree, it has been used for centuries in traditional medicine. The seed and leaf powder have purifying properties by accumulation.¹¹² Studies have revealed that the phenolic extract of M. oleifera leaves was able to chelate Fe2+ in a dose-dependent manner, this chelating capacity could be due to the presence of certain phytochemicals, such as polyphenols. Indeed, phenolic compounds can form a complex with iron, thus facilitating its excretion from body.¹¹³ Furthermore, Akomolafe et al¹¹⁴ suggested that phenolic compounds, such as gallic acid, chlorogenic acid, catechin, kaempferol, quercetin and quercitrin, are capable of interfering with iron metabolism, thereby chelating the metal ion.

Myrtus communis L.: This is an aromatic medicinal plant, typical of Mediterranean coastal areas, such as North Africa or Southern Europe, but it is also present in South America, Australia and some regions of the Himalayas. All the aerial parts, fruits, leaves and essential oil, are medicinal.¹¹⁵ Myrtle is used in cooking, spices and traditional medicine. The decoction of aerial parts of myrtle was used as a hypotensive, hypoglycemic, anti-inflammatory and antidiarrheal in the treatment of bleeding and conjunctivitis.¹¹⁵ One of the types of Myrtus most mentioned in traditional books is Myrtus communis, also called Myrtle. In one study, the iron-chelating activity of zero-valent iron nanoparticles synthesized using Myrtus communis (MC-ZVIN) was evaluated as a potentially safe compound. The results showed that MC-ZVIN significantly reduced serum iron levels and decreased iron accumulation in liver tissue, leading to an attenuation of iron-induced tissue damage. Overall, MC-ZVIN demonstrated a protective effect against iron overload and may represent a promising strategy for preventing, or at least mitigating, the deleterious effects of excess iron in mice.¹¹⁶

Other studies have demonstrated that Myrtle leaf has a high flavonoid content 1.8%, as well as a high total phenolic content (3.6%, 1218.3±26.3mg ml-1 GAE). They can act as antioxidants by donating hydrogen to highly reactive radicals, thus preventing the formation of additional radicals.¹³⁰ The antioxidant effect of natural phenolic components has already been studied by several authors showing the highly positive linear relationship exists between antioxidant activity and total phenolic content in many spices and herbs.^117,118

Capsicum annuum L.: This is the most widely cultivated species of the genus Capsicum in the world, mainly for its fruits, which are used as vegetables or as condiments. The fruits, being rich in capsaicinoids, carotenoids, phenolic compounds and vitamins, are used to make antioxidant and antimicrobial additives and anti-inflammatory pharmaceutical products.

Luteolin is present in the form of glycosides and is found in this plant. It has various pharmacological properties, including reducing lipid oxidation of emulsions by eliminating radicals and chelating iron.¹¹⁹

Rhus semialata Murr.: The fruits of this plant are known to be an important source of antioxidants, soluble fiber, nutrients, phenols, flavones, vitamins and minerals. The fruit pulp can be extracted with methanol and water. Methanol and water extracts were studied for their bioactive properties, such as antioxidant, antihyperglycemic and antihypertensive activity.¹²⁰ The natural compound tannic acid, present in the plant,  provided excellent biological activity, besides its in vitro reducing and chelating activity, the compound revealed an ability to counteract iron overload through its chelating activity. The research results obtained were similar to those of the control substance (desirox, a standard iron chelator). Moreover, it is likely that tannic acid can block L-type calcium channels and reverse iron overload in the body.^121,122

Populus trichocarpa Torr.: Poplar leaves and roots show great variability in chlorogenic content, acid (CGA) and phenolic compounds. Leaf extracts contain five times more phenolic compounds than root extracts and root extracts from iron-deficient plants produce 66% more phenolic compounds than those from iron-normal plants. Compared with leaf extracts, root extracts showed a 4-fold increase in iron-binding activity in vitro.¹²³

The eleven plants identified in Table 1 for their iron-chelating properties have some botanical and phytochemical similarities. In terms of botanical classification, they belong to diverse families such as Solanaceae, Zingiberaceae, Theaceae, Ginkgoaceae, Lamiaceae, Poaceae, Moringaceae, Myrtaceae, Anacardiaceae, and Salicaceae. Among these families, some are known for their richness in bioactive compounds, including Solanaceae ( Withania somnifera L., Capsicum annuum L.) and Lamiaceae ( Scutellaria baicalensis G.).

On the phytochemical level, the active molecules identified are mainly: flavonoids (Withania somnifera L., Scutellaria baicalensis G., Myrtus communis L., Populus trichocarpa Torr.); phenolic acids (gallic acid in Moringa oleifera Lam., tannic acid in Rhus semialata Murr.); alkaloids (curcumin in Curcuma longa L.); and catechins ( epigallocatechin gallate in Camellia sinensis L.). Flavonoids are particularly interesting for their ability to form stable complexes with metal ions, making them potentially effective as iron chelators.

Among the listed plants, some show greater potential for therapeutic application due to their specific properties:

• Camellia sinensis L.: Epigallocatechin gallate (EGCG) is well documented for its ability to bind iron ions through complexation mechanisms, with studies demonstrating its potential to reduce iron accumulation in various models.
• Curcuma longa L.: Curcumin is also known for its antioxidant activity and iron chelating capacity, although its low bioavailability limits its clinical efficacy.
• Scutellaria baicalensis G.: Baicalein, a major flavonoid, exhibits a high affinity for iron ions, warranting further exploration for therapeutic use.
• Moringa oleifera Lam.: Gallic acid present in its extracts has shown interesting effects in terms of metal chelation.
• Rhus semialata Murr.: Rich in tannic acid, which has a significant chelating capacity.
• On the other hand, other plants like Withania somnifera L., Myrtus communis L. and​ Populus trichocarpa Torr., show potential chelating properties but require further studies to evaluate their clinical efficacy.

Thus, plants with the following active molecules: epigallocatechin gallate, curcumin, baicalein, gallic acid and tannic acid, deserve special attention for further therapeutic exploration. The use of these compounds in purified form or in standardised extracts could offer a promising alternative in the treatment of iron overload, particularly in diseases such as thalassemia.

Further studies are needed to evaluate the efficacy, safety, and bioavailability of these compounds in a clinical setting.

Challenges and perspectives

The use of medicinal plants as chelating agents in iron overload represents a promising approach and the outlook in this field remains encouraging. Thus, efforts should be focused on producing plants with a high iron chelating capacity. Studies have shown that plants growing in alkaline soils can be a good source of chelators. Since iron is generally not available in these soils, plant roots develop mechanisms to solubilise iron for absorption, such as soil acidification. They also deploy additional strategies to overcome high alkalinity, such as phenolic compounds, which are known to exhibit strong iron-binding properties at near physiological pH conditions109 supporting their biological relevance in iron overload–related disorders, including thalassemia.¹⁰³ Flavonoids have also demonstrated their ability to chelate iron, but this is affected by their concentration and environmental pH, which has an impact on dosage and conditions of use. These factors should be the subject of further studies.

Thus, a better understanding of the molecular mechanisms of plant chelators could pave the way for their integration with conventional therapies, thus reducing side effects and increasing efficacy.^121,122 Biodiversity exploration and ethnobotanical research into the pharmacology of plants from diverse regions, limited and should be pursued within ethically sound and sustainable frameworks.¹²⁴ Not to mention advances in nanotechnology and pharmaceutical formulation that offer solutions to improve the bioavailability of plant chelators. For example, biopolymer-based nanoparticles could encapsulate active compounds to protect them from degradation and ensure controlled release.⁹¹

Unfortunately, this natural approach still faces many challenges and several obstacles, whether scientific, technical, or societal, such as:

• Variability in the composition of plant extracts is influenced by factors such as geographical origin of plants, cultivation methods, extraction and preservation processes that significantly influence their content of bioactive compounds. For example, polyphenols, flavonoids and phenolic acids, often responsible for chelating activity, can vary significantly from batch to batch.¹²⁵ This variability complicates the reproducibility of results and hinders their integration into standardised clinical protocols.
• The lack of robust clinical data in the studies carried out, although several of them, in vitro and in vivo, have demonstrated the chelating properties of certain plants, few large-scale clinical trials have been conducted to confirm their efficacy and safety in humans. Most of the research focuses on animal models or preclinical approaches, leaving a significant gap in data applicable to humans.⁸⁷
• Side effects and drug interactions of plants that often contain a wide range of bioactive compounds, increases the risk of adverse effects and drug interactions when used in parallel with conventional treatments. For example, cases of interactions between tannin-rich extracts and synthetic chelators have been reported, which could alter the effectiveness of the treatment.⁷²
• Sustainability is also one of the biggest challenges, as the increased use of some medicinal plants for their chelating properties raises concerns about their sustainability. Plants in high demand, especially those from regions rich in biodiversity, are threatened by unsustainable exploitation. Promoting ethical sourcing practices is essential to avoid the depletion of natural resources.¹²⁶

Conclusion

The study indicates that flavonoids and active agents from plants, represented by quercetin, curcumin, baicalein and more, can chelate iron. Thus, our study suggests that the use of these natural compounds could be a promising strategy to combat iron overload. In addition, our research demonstrates the results of studies that open a new avenue for the control and treatment of iron overload by plant extracts that should find their place in the preclinical and clinical context as a type of revolutionary therapy or complementary to traditional treatments.

Authors’ Contributions

NB and MY searched literature and designed the study protocol. BM participated in data collection during work meetings. NB analysed the data and made the synthesis of the study. AAHS checked the initial version before and after revision and approved the final version of the manuscript.

Conflict of interest

The authors declare no conflicts of interest.

Funding

The authors received no funding for this study.

Use of rtificial Intelligence Tools

Large language models (ChatGPT, OpenAI) were used solely for copy-editing purposes, including language refinement and improvement of clarity and grammar. All literature searching, data interpretation, scientific analysis, and citation selection were performed exclusively by the human authors. The authors take full responsibility for the content of the manuscript.

Author(s)

Nihal Bhirich^1,2, Mohamed Yafout¹, Brahim Mojemi², Amal Ait Haj Said^1
1Laboratory of Therapeutic Innovation and Artificial Intelligence in Health, Hassan II University of Casablanca, Morocco
²Laboratory of Analytical Chemistry, Faculty of Medicine and Pharmacy, Mohammed V University, Rabat, Morocco

*Corresponding author email bhirich.nihal@gmail.com

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