β‐Thalassemia major (β‐TM) is a common hereditary hemolytic anemia, which is characterized by a defect in the synthesis of beta-globin chains of hemoglobin [1]. A high prevalence of β‐thalassemia has been reported in certain areas of the world such as the Mediterranean, Middle-East, and Southeast Asia [2]. It is well known that the regular and frequent blood transfusion, as the main treatment for β‐TM, results in the excess levels of iron in the body [3]. In non-transfusion-dependent thalassemia, iron overload can develop owing to ineffective erythropoiesis, which leads to the enhanced intestinal iron absorption by decreasing the serum levels of iron regulatory hormone, hepcidin [4]. Excess iron can be deposited in tissues and organs, leading to the oxidative damage and inflammation [5]. Moreover, iron overload can induce ferroptosis, a type of iron regulated cell death, which plays an important role in the pathogenesis of a variety of diseases [6,7]. Iron accumulation in the body is associated with serious and irreversible damage to various organs, including liver, pancreas, heart, and gonads, which can cause cirrhosis, diabetes, cardiac impairment, and hypogonadism as well as increased mortality [8].

Iron chelation therapy, as a standard clinical strategy, is used to attenuate the excessive levels of iron and prevent the toxic effects related to the iron deposition in tissues [9]. The standard iron chelators such as deferoxamine, deferasirox, and deferiprone have serious adverse reactions, which limit their long-term use in clinical practice [10,11]. Therefore, it is necessary to explore and develop safer and more effective iron chelating agents as alternative or adjuvant for treatment of β‐TM. In recent years, the discovery and development of novel iron chelating agents with high efficacy and low toxicity have been the focus of much research [11,12]. In this sense, polyphenols as natural phytochemicals [13], have drawn much scientific attention due to their significant iron chelating activities with minimal toxicity against healthy tissues [14]. Polyphenols can be categorized into several major classes such as flavonoids, phenolic acids, stilbenes, and lignans [15,16]. Flavonoids are one of the most important polyphenolic compounds [17], which have specific chemical structure with iron chelating affinity [18]. These natural compounds contain chelation sites that can bind iron to form a stable iron-flavonoid complex [18]. Several mechanisms are linked to the role of flavonoids in the treatment of iron overload [19]. Flavonoids can ameliorate iron burden in a direct or indirect way. These natural polyphenols decrease the iron accumulation by iron binding effect, which is a direct way for the attenuation of iron overload. Indirectly, flavonoids reduce the iron burden by modulating a variety of proteins and signaling pathways [19]. Flavonoids also have significant antioxidant and anti-inflammatory effects, which can diminish the iron overload-induced oxidative damage and inflammation [20,21].

In the last few years, one of the phytochemicals, which has been extensively evaluated for its pharmacological effects, is grape seed extract (GSE) [22]. GSE, as a flavonoid-rich supplement, contains several important polyphenolic compounds such as proanthocyanidins, catechin, epicatechin, and gallic acid [23,24]. Numerous experimental and clinical studies demonstrate that GSE has various biological and pharmacological effects, including antioxidant [25,26], anti‐inflammatory [27,28], antibacterial [29], cardioprotective [22], hepatoprotective [30], anticancer [31,32], anticarcinogenic [33], antiviral [34], and neuroprotective effects [35]. Nowadays, GSE is used in the pharmaceutical, cosmetic, and food industries owing to its health beneficial effects [22]. Growing evidence indicates that proanthocyanidins, as the major components of GSE, can remarkably attenuate free radicals concentration and inflammatory mediators by modulating several molecular targets and signaling cascades. These natural compounds have the potential to chelate metals with their o-diphenol groups [36]. Studies have revealed that proanthocyanidins possess marked iron chelating activities in vitro [37]. Proanthocyanidins also have protective influences against iron overload mediated-oxidative damage in vivo [[38], [39], [40]].

To the best of our knowledge, so far, no clinical studies have been conducted to investigate the influence of GSE supplement on iron overload in children with β‐TM. Therefore, the present study aimed to evaluate the iron‐chelating effect and safety of GSE supplement as well as its influences on oxidative stress, inflammation, and liver function in β‐TM pediatric patients receiving deferasirox as the only standard iron chelator.