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Systematic Review

Curcumin Therapy Reduces Iron Overload and Oxidative Stress in Beta-Thalassemia: Findings from a Meta-Analytic Study

by
Kabelo Mokgalaboni
1,*,
Wendy N. Phoswa
1,
Perpetua Modjadji
1,2 and
Sogolo L. Lebelo
1
1
Department of Life and Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Florida Campus, Roodepoort 1709, South Africa
2
Non-Communicable Diseases Research Unit, South African Medical Research Council, Cape Town 7505, South Africa
*
Author to whom correspondence should be addressed.
Thalass. Rep. 2025, 15(3), 7; https://doi.org/10.3390/thalassrep15030007
Submission received: 6 April 2025 / Revised: 28 May 2025 / Accepted: 16 June 2025 / Published: 2 July 2025
(This article belongs to the Special Issue Innovative Therapies and Management of Complications in Hemoglobinopathies)
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Abstract

The risk of anemia and iron overload is a global concern in beta (β)-thalassemia. The β-thalassemia primary treatment includes blood transfusion and iron chelation therapy; however, both are associated with risks such as anemia, iron depletion, overload, and oxidative stress if not adequately monitored. Therefore, this study investigates the effects of curcumin on anemia, iron overload, and oxidative stress in β-thalassemia. In this meta-analysis, search terms including “curcumin,” “Curcuma longa,” “curcuminoids,” “turmeric,” and “thalassemia” were used in Scopus and PubMed to identify studies published from inception to 15 February 2025. The quantitative analysis was performed using a meta-analysis web tool, and the effect estimates were reported as the mean difference (MD) or standardized mean difference (SMD), along with 95% confidence intervals (CI). Our analysis showed no significant effect on hemoglobin (p = 0.1788) and red blood cell count (p = 0.9534). In contrast, there was a significant decrease in serum ferritin [SMD = −0.24 (−0.46, −0.02), p = 0.0335], non–transferrin bound iron (NTBI), [SMD = −0.59 (−0.98, −0.19), p = 0.0039] and serum iron, [SMD = −0.30 (−0.60, −0.01), p = 0.0425]. Furthermore, there was a reduction in reactive oxygen species; [SMD = −0.83 (−1.23, −0.44), p < 0.0001] and malonaldehydes, [MD = −343.85 nmol/g Hb (−465.94, −221.76), p < 0.0001]. A dose of 500 mg of curcumin was found to be more effective in reducing the NTBI. The findings suggest that curcumin may help reduce iron overload and oxidative stress in β-thalassemia; however, its effect on improving anemia appears to be limited. Given the small sample size of the included studies, we recommend that future research involve larger cohorts and employ rigorous methodologies to evaluate the therapeutic potential of curcumin in β-thalassemia thoroughly. Additionally, we recommend using curcumin-enhancing strategies to improve its bioavailability and administer an optimal yet effective dose.

1. Introduction

Thalassemia is an inherited form of hemoglobinopathy characterized by reduced functional hemoglobin (Hb) [1]. There are two main types of thalassemia, beta (β)-thalassemia and alpha (α)-thalassemia. The most common form is β-thalassemia, characterized by a reduced level or absence of the β-globin chain. In contrast, α-thalassemia is associated with a reduced synthesis of the α-globin chain [2,3]. Moreover, acquired cases of α-thalassemia have been reported. A high prevalence of β-thalassemia major has been reported in the Mediterranean and Middle East regions [4,5]. In the Southern part of Asia, the high prevalence is attributed to a high carrier rate and a cultural preference for interfamily marriages [6]. Evidence presents anemia as a significant feature of β-thalassemia, especially its more severe forms, β-thalassemia major, and its prevalence differs based on the population [7].
Anemia remains a health challenge irrespective of age or gender, with a negative impact on economic status, especially in low- and middle-income countries. Therefore, it is crucial to control β-thalassemia and reduce the risk of anemia and associated disorders.
Blood transfusion and iron chelation therapy are two main standard treatments for thalassemia [8,9]. The primary goal of transfusion is to restore Hb and red blood cells (RBCs). On the other hand, iron chelation mitigates iron accumulation from blood transfusion by improving iron excretion in urine and feces [10]. However, it is worth noting that some chelators, such as Deferasirox, have a limited safety profile [11,12]. This increases the risk of secondary complications, including mitochondrial dysfunction, oxidative stress, and organ toxicity. Moreover, frequent blood transfusions and chelation can result in endocrine disorders, oxidative stress, and iron overload [13,14,15]. The latter is characterized by the accumulation of iron within the cells, tissues, and body organs, resulting in liver cirrhosis, diabetes, heart failure, arthritis, and hypogonadism [13,14] (Figure 1).
Iron overload results in the accumulation of iron in mitochondria, thus promoting reactive oxygen species (ROS) production and oxidative stress [17,18]. This impairs mitochondrial function and gene integrity, contributing to cellular damage and the development of ferroptosis. Iron overload is primarily diagnosed by ferritin levels. Therefore, finding alternative treatments for β-thalassemia that target ferritin and associated receptors is important to ameliorate iron overload and its associated complications.
Due to the complications associated with the standard treatments for β-thalassemia, it is essential to investigate alternative therapies that are safer for patients living with β-thalassemia to control and manage anemia, iron overload, and oxidative stress in these patients. Natural remedies are gaining interest from researchers due to their notable efficacy, safety profiles, and wide availability. Among these, natural herbs have shown the potential to reduce β-thalassemia symptoms and form healthy RBCs [19,20]. However;,the findings from different clinical trials are inconsistent, suggesting potential limitations. One promising natural compound that has gained research interest is curcumin, an anti-inflammatory compound produced by Curcuma longa that belongs to the family of Zingiberaceae [21,22,23] (Figure 2). It has been reported to modulate proteins associated with iron metabolism in cells and tissues, thus suggesting that it has chelation properties [24].
Interestingly, its effect against iron overload and oxidative stress has been demonstrated in clinical and preclinical studies [24,25,26]. However, in some cases, the evidence from preclinical studies is not translatable to clinical corroboration. Although evidence has emerged from randomized controlled trials (RCTs) exploring curcumin, the primary concern is the small sample size, varying doses, and short intervention duration, which makes it difficult to draw a conclusion about its effect on iron overload in clinical settings. Additionally, not all studies reported common markers of anemia, iron overload, and oxidative stress, thus creating inconsistencies across the available evidence. Notably, this is the first meta-analysis to explore the effect of curcumin on anemia, iron overload, and oxidative stress in β-thalassemia. Therefore, this study aimed to investigate the effects of curcumin on anemia, iron overload, and oxidative stress in patients with β-thalassemia.

2. Materials and Methods

2.1. Database and Literature Search

The PubMed and Scopus databases were utilized to search for studies exploring curcumin in thalassemia. The Medical Subject Headings (MeSH) terms used included curcumin, curcuminoids, Curcuma longa, turmeric, and thalassemia. The search was conducted by independent researchers (KM and WNP) with the assistance of the third independent researcher (SLL) in the event of any contradiction. The exact search was restricted to studies published in English from inception until 15 February 2025. Additionally, the reference lists of relevant studies were screened to identify any missed relevant studies. The study adhered to the preferred reporting items for systematic review and meta-analysis (PRISMA) [27].

2.2. Eligibility Criteria and Selection Criteria

The inclusion and exclusion criteria adhered to our predefined population, intervention, comparator, and outcome (PICO) strategy. Two independent researchers (KM and WNP) screened all retrieved studies. Studies in patients with β-thalassemia published in English were considered for inclusion. All β-thalassemia patients on curcumin treatment were considered. In studies with multiple curcumin treatments, the dosages were treated as an independent arm of the study. All studies were relevant if they reported at least one of the outcomes of interest, ranging from Hb, RBC count, serum iron, ferritin, non-transferrin-bound iron (NTBI), ROS, and malondialdehyde (MDA). Studies with patients on other treatments, those using the rodent model of β-thalassemia, publications in non–English languages, conference abstracts, letters, reviews, and books were excluded.

2.3. Data Items and Extraction

All studies were comprehensively reviewed, and important information from each study was extracted and presented in a tabular format in ascending order of year of publication. This process was conducted by two independent researchers, KM and WNP. The data extracted from each study included the author’s last name and publication year, the country where the study was conducted, participants’ demographics (mean age and gender distribution expressed as number and percentage), participant conditions, form of curcumin, dosage, and duration of the interventions. Additionally, the researcher’s viewpoints were based on the clinical findings from each study. For one study [28], where the age of the participant was reported as median and range, conversion metrics were used to estimate the mean for consistency [29].

2.4. Methodological Quality and Risk of Bias (ROB)

The methodological quality of the included studies was evaluated following the guidelines stipulated by Down and Black [30]. This checklist considers five main domains comprising twenty-seven items. Among the domains are reporting, external validity, internal validity (bias), internal validity (confounding), and power. Each study’s quality was rated based on the overall scores. The study was deemed to be excellent if it scored 26 and above, good (20–25), moderate (15–19), and poor (less than 15) scores. Notably, the higher the quality, the lower the risk of bias; conversely, the lower the quality, the higher the risk of bias.

2.5. Statistical Analyses

This study utilized a meta-analysis web tool to analyze the data [31]. Data (mean, standard deviation, and sample size) in the curcumin group (baseline and post-treatment) were computed to get the effect size for each outcome measure. We used a fixed-effects model, where heterogeneity was absent, and a random-effects model, where heterogeneity was observed [32]. The effect estimates were reported as mean difference (MD) or standardized mean difference (SMD) and 95% confidence intervals (CI) based on whether the outcomes were reported using the same units or not. Due to the small sample size, the Hedges g estimation was used to quantify the effect estimates. The heterogeneity was assessed using I2 statistics. An I2 > 50% prompted us to conduct subgroup analysis based on dose (<50, 500, and 1000 mg), duration of intervention (2, 3, 6, and 12 months), country (Iran and Thailand), and age of participants (below or above 30). The funnel plots and Egger tests were used to assess the potential publication bias for each outcome [33]. Trim and fill were performed to adjust for publication bias. The significance threshold was set at p of less than 0.05 for all statistical tests.

3. Results

3.1. Search, Screening, and Demographics

The exact search strategy for the 47 studies retrieved from PubMed and Scopus is presented in Supplementary File S1 Table S1. During the first screening phase, eleven studies were identified as duplicates through Mendeley Cite and therefore were excluded. The remaining thirty-six were subjected to further screening of titles and abstracts; eight were found to be irrelevant to the topic of this study and thus excluded. Of the twenty-eight that remained, they were retrieved and assessed for eligibility. Four studies had no relevant outcomes, two were not related to thalassemia, three were not associated with curcumin, three were conducted in animal models, two were reviews, one was an in vitro study, and one was unavailable in full text. Therefore, twelve studies [28,34,35,36,37,38,39,40,41,42,43,44], retrieved from the databases, were relevant. However, only eleven met the criteria for meta-analysis due to the availability of data (Figure 3). The general information of the included studies is presented in Table 1. The presented studies were published between 2010 and 2022 in Asia, with at least six studies from Southeast Asia (Thailand) [35,39,40,41,42,43] and six from Southwest Asia (Iran) [28,34,36,37,38,44]. Among the 470 participants, 231 (49%) were males living with β-thalassemia, and 239 (51%) were females. The patient’s age ranged from 14–35 years. Although all studies use curcumin, one study employed a combination therapy that included curcumin with N-acetylcysteine, and deferiprone [40]. The dosages of curcumin ranged from 17.26 mg to 1500 mg per day. While the duration of the intervention varied across the studies, it ranged between 2 and 12 months.

3.2. Methodological Quality of the Included Studies

The overall methodological quality of the included studies ranged from moderate to Excellent. Briefly, six studies [28,34,36,37,38,44] were considered to be of excellent quality as they scored 26 or above. Additionally, four studies [35,40,41,43] scored between 21 and 23 and were rated as having good methodological quality, and lastly, two were rated as moderate, as they scored 16 [39] and 18 [42] respectively (Supplementary File S2).

3.3. Effect of Curcumin on Hemoglobin and Red Blood Cells in β-Thalassemia

In this study, only nine studies with eleven different treatment arms [35,36,37,38,39,40,41,42,43], reported the effect of curcumin on Hb in β-thalassemia. The effect estimates from the fixed-effects model meta-analysis revealed an observational increase in Hb post-curcumin supplementation in β-thalassemia when compared to baseline data [SMD = 0.13, 95% CI (−0.06, 0.33)]; however, this was not statistically significant, p = 0.18 (Figure 4). Interestingly, these studies showed no evidence of heterogeneity (I2 = 0%). The effect of curcumin on RBCs was assessed from 4 studies, and the evidence revealed no significant effect [SMD = −0.02, 95%CI (−0.64, 0.60), p = 0.9534] (Supplementary File S1 Figure S2).

3.4. Effect of Curcumin on Ferritin, Non-Transferrin Binding Iron (NTBI), and Serum Iron Level in β-Thalassemia

Ferritin was reported in eight studies with nine different doses of curcumin [34,37,38,39,40,41,42,43], and the effect estimates from the fixed-effects model meta-analysis revealed a significant decrease in ferritin level following curcumin treatment (SMD = −0.24, 95% CI (−0.46, −0.02), p = 0.0335; Figure 5A). Most importantly, the studies showed no evidence of statistical heterogeneity (I2 = 0%). NTBI has been reported in seven studies involving nine doses of curcumin [35,38,39,40,41,42,43], with effect estimates from fixed-effect model meta-analysis. The results suggest that curcumin post-treatment reduces NTBI, with SMD = −0.59, a 95% CI (−0.98, −0.19), p = 0.0039 (Figure 5B). These studies revealed moderate heterogeneity (I2 = 58.4%). Only four studies [36,37,38,41] reported enough data on curcumin and serum iron levels in β-thalassemia. The results showed a decrease in serum iron following curcumin treatment, with SMD = −0.30, 95% CI (−0.60, −0.01), and p = 0.0425 (Figure 5C). The evidence from these studies showed no evidence of heterogeneity (I2 = 0%).

3.5. Effect of Curcumin on Oxidative Stress in β-Thalassemia

The data on oxidative stress was pooled for ROS and MDA. The findings from four studies showed that curcumin significantly reduced ROS post-treatment compared to baseline, indicating promising potential for curcumin in reducing oxidative stress, with SMD = −0.83, 95% CI (−1.23, −0.44), and p < 0.0001 (Figure 6A). Similarly, MDA was reduced following curcumin treatment, with an MD = −343.85 nmol/g Hb, 95% CI, (−465.94, −221.76), p < 0.0001 (Figure 6B). While there was a notable heterogeneity (I2 = 65%), subgroup analysis was not conducted due to the small sample size.

3.6. Assessment of Publication Bias

For studies on Hb, visual inspection of the funnel plot indicates a potential publication bias (Figure S3A). This was supported by the Egger’s test (t: −2.56, p = 0.037). In contrast, for ferritin, there was no proof of a potential publication bias (Supplementary File S1, Figure S2B), and Egger’s test excludes a funnel plot asymmetry (t: −0.842, p = 0.428). Similarly, for NTBI, the funnel plot revealed no bias (Figure S3C), which is supported by Egger’s test (t = −0.407, p = 0.696). However, for serum iron, the funnel plot indicates a potential publication bias (Figure S3D). This was further supported by Egger’s test (t: −8.776, p = 0.013). For RBCs, the funnel plot did not show a potential publication bias (Figure S3E). Egger’s test also does not support the presence of funnel plot asymmetry (t: −2.294, p = 0.106). The funnel plot suggests a potential publication bias for ROS (Figure S4F); the Egger’s test supports the presence of funnel plot asymmetry (t = −7.328, p = 0.018). Due to the observed publication bias on Hb, serum iron, and ROS, we conducted a trim and fill test as presented in Figure S4A–C. For Hb, the trim and fill analysis suggested that no studies were missing due to publication bias. The adjusted effect size remained unchanged (Figure S4A), indicating the results are likely robust and not substantially influenced by publication bias. For serum iron, the initial analysis showed a significant negative effect (SMD = −0.30, p = 0.0425), but after adjusting for potential publication bias using the trim and fill method, the effect size was reduced and became non-significant (SMD = −0.23, p = 0.0979 (Figure S4B), suggesting possible overestimation due to publication bias. However, for ROS, the trim and fill results remained constant, with an SMD = −0.83, p < 0.0001 (Figure S4C). Although the funnel plot and Egger’s test suggest the potential publication bias, the trim and fill test indicates that this bias does not significantly affect the effect size. Therefore, the observed effect size remains valid and stable, thus providing confidence in the obtained findings. For RBCs MDA, the funnel plot does not indicate potential publication bias and is supported by the Eggers test (t = −0.175, p = 0.872) (Figure S4G).

3.7. Subgroup Analysis

Due to the observed heterogeneity in the evidence assessing NTBI, we conducted a subgroup analysis to identify potential sources of heterogeneity. When grouped by curcumin dosage, the study suggested that lower doses (17.3 and 35.5 mg) may have contributed to the observed heterogeneity (Figure 7). In contrast, higher doses, particularly 1000 mg, were associated with a substantial reduction in heterogeneity (I2 = 22.4%), while a 500 mg dose resulted in only a modest reduction (I2 = 43.7%) (Figure 7). These findings indicate that curcumin dosage may contribute to the observed heterogeneity. Studies that used curcumin alone, without co-supplementation, were also found to contribute to heterogeneity (Figure S4C). Additionally, studies that used curcumin for six months introduced heterogeneity (Figure S4E). The quality, age, and country did not show any association with heterogeneity (Figure S4A,B,D).
Additional potential sources of heterogeneity are summarized in Supplementary Figure S4A–E. Notably, age did not appear to be a contributing factor. In contrast, studies conducted in Iran and those with a six-month duration of curcumin administration were identified as sources of heterogeneity. For MDA, the results of subgroup analyses are presented in Figure S5A–E. The studies classified as good quality were also associated with substantial decreases in heterogeneity post-subgroup, suggesting that they might have contributed, to some extent, to the observed heterogeneity (Figure S5A). However, age, form of therapy, and dose of curcumin were not associated with heterogeneity (Figure S5B,C,E). The duration of intervention was deemed one of the factors contributing to heterogeneity, especially for studies that administered curcumin for 12 months (Figure S5D).

4. Discussion

Anemia and oxidative stress, in patients living with β-thalassemia, promote iron overload, and altogether, these contribute to cardiovascular disease (CVD) and mortality globally [45,46]. This study comprehensively explores the potential effect of curcumin on anemia, iron overload, and oxidative stress among patients living with β-thalassemia. The evidence from the eleven studies on curcumin in patients with β-thalassemia shows the significant benefits of curcumin and curcuminoids on serum ferritin, iron, and NTBI, indicating a promising potential for curcumin to reduce iron overload without notable effects on Hb and RBC count.
A decrease in RBC count and Hb levels is referred to as anemia, resulting in low oxygen delivery [47,48]. This could be due to impaired endothelial function associated with low nitric oxide bioavailability and increased oxidative stress [49]. As the body tries to compensate for the oxygen delivery, the involved organs, including the heart, become strained, resulting in cardiac hypertrophy and heart failure [50]. Also, the body will respond by activating extramedullary erythropoiesis, thus resulting in splenomegaly [51]. Notably, in this study, while the Hb level was elevated following curcumin supplementation, this was not significant; moreover, this is supported by the null effect on RBCs, suggesting that curcumin might have limitations in ameliorating anemia and associated cardiovascular complications.
The mechanism by which curcumin exerts an effect on Hb levels stems from its anti-inflammatory properties [22,52,53,54,55,56]. Thus, its anti-inflammatory effects stimulate erythropoiesis, increasing Hb production, as previously reported in preclinical studies [57,58]. While the benefits are acknowledged, another study showed no effect on Hb when 17.26 or 35.53 mg of curcumin extract was administered in patients with β-thalassemia [35]. This may be due to the use of curcuminoids in addition to green tea extract, which could interfere with the overall efficacy of curcumin due to herbal-herbal interactions. It has been reported that the concurrent use of multiple natural remedies may lead to an interaction that minimizes their effectiveness and safety [59,60]. On the other hand, another study reported a significant decrease in Hb after 24 weeks of supplementation with 500 or 1000 mg of curcumin [41]. However, this limitation of one Hb seems to be attributed to an extended period of intervention. An extended duration of intervention renders the curcumin treatment less effective due to its low bioavailability and rapid metabolism, making it difficult for the body to absorb it [61]. Moreover, it is quickly removed from the body via bile and urine, thereby reducing its presence in the bloodstream and tissues [62,63]. Therefore, the development of strategies that enhance curcumin bioavailability is necessary to maximize its potential benefits among patients with β-thalassemia.
The ferritin serum levels were found to decrease after treatment with curcumin. Serum ferritin is a protein that stores iron and reflects the body’s iron reserves [64]. However, elevated serum iron levels in the body or tissues demonstrate the state of iron overload [65]. Therefore, therapeutic means to control iron overload may focus on the ferritin protein as a target; this will alleviate the complications associated with iron overload. Findings from the current study are supported by previous reports emerging from other studies showing a significant positive effect of curcumin on serum ferritin levels. A report by Yanpanitch et al., 2015 [40] revealed a significant reduction in serum ferritin following the administration of 500 mg of curcumin at six months (p < 0.05) and 12 months (p < 0.05). However, no difference was observed at the end of the 15 months (p > 0.05) as the patients were not given treatment for 3 months before analysis took place at month fifteen. Once again, it is important to note that curcumin has low bioavailability.
In contrast, other studies showed no significant effect of curcumin on serum ferritin levels [41,42]. For instance, a 12-month administration of 500 mg of curcuminoids demonstrated no difference in serum ferritin levels at 6 and 12 months, 2480 ± 238 pmol/L and 2132 ± 253 pmol/L, respectively, compared to baseline (2417 ± 260 pmol/L), p > 0.05 [42]. Another study supported these results, which revealed that 500 mg of curcumin does not improve serum ferritin in β-thalassemia when administered for six months [41]. Furthermore, there was no effect when 1000 mg of curcumin was administered.
The iron level indicates the status of iron in the body, and its elevation suggests the presence of iron overload, which can predispose patients to secondary complications, including organomegaly and arrhythmia-induced heart failure [66,67]. This study showed a significant decrease in its level following curcumin supplementation. These findings are supported by other studies, which showed that a higher dose of curcumin (1500 mg) per day significantly reduced the serum iron level (p < 0.001) [28]. Similarly, Hatairaktham et al. 2021 showed that administration of 1000 mg of curcuminoids reduced serum iron in β-thalassemia compared to baseline (p = 0.009) [41]. However, the effect of curcumin on serum iron seems to be dose- and duration-dependent. For instance, the smaller doses (17.3 or 35.5 mg) of curcuminoids in green tea extract showed no significant difference in serum iron levels among the patients with β-thalassemia [35]. It is worth noting that the latter study used a combinational therapy approach, which consisted of curcumin, green tea extract, and epigallocatechin-3-gallate. The observed conflicting results may be due to herb-to-herb interaction, which has been reported to affect the efficacy and, in some cases, the safety of the treatment. Moreover, a conflicting result was reported in two trials that used exactly 1000 mg of curcumin for three months and found no difference in serum iron post-treatment when compared to baseline [36,37]. It is worth noting that these two trials used deferoxamine as a chelating agent. Other studies have shown that the use of deferoxamine alongside curcumin reduces curcumin activity, as these agents will be competing for iron binding sites [24].
Curcumin supplementation was associated with a reduction in NTBI levels. This is the amount of iron that is not bound to transferrin [68]. The formation of NTBI depends on the availability of transferrin; thus, when the transferrin level is elevated and its capacity is exceeded, NTBI formation begins [69]. As a labile form of iron, it reacts and contributes to the production of free radicals, which damage cells and tissues, resulting in oxidative stress [70]. An increased level of NTBI contributes to iron overload in the body; therefore, its reduction would reduce iron overload and associated complications [71]. Thus, a decrease in NTBI levels following curcumin administration, as noted in this study, suggests that curcumin has iron-chelating properties [35,38,39,40,41,42,43]. It is through its iron-chelating properties that it reduces NTBI levels. Although the mechanisms are not properly documented, other researchers suggest that curcumin binds to iron through its β-diketone functional group, forming a curcumin-Fe3+ or curcumin-Fe2+ complex in the intestine and tissues [38,72]. These complexes prevent iron absorption and enhance excretion, thus reducing excess intracellular iron and NTBI (Figure 8). Curcumin has also been reported to inhibit signal transducer and activator of transcription (STAT) in in vitro studies [73]. Due to the contribution of STAT in the synthesis of hepcidin, its downregulation following curcumin treatment reduced the production of hepcidin [73,74,75].
The evidence gathered in this study is supported by another trial that used 500 mg for 2, 6, and 15 months. This trial found a decrease in NTBI at two and six months [40]. However, the same trial reported that the administration of curcumin for 15 months had no effect on NTBI (p > 0.05). This is in line with the notion that curcumin has low bioavailability and quick metabolism [76], suggesting a need to improve curcumin bioavailability through other mechanisms such as co-administration with piperine, incorporation into nanoparticles, liposomes, micelles, and spray drying to retain its maximal potential [77].
Oxidative stress has been linked with various conditions due to its contribution to mitochondrial DNA damage [17,18]. It exacerbates existing conditions, in β-thalassemia, it is associated with iron overload, and tissue and organ damage. In this study reduction in ROS and MDA was observed following curcumin treatment. These results support the previous reports that regarded curcumin as an antioxidative agent. As an antioxidative agent, it ameliorates oxidative stress through various mechanisms. One of its actions is by increasing the activity of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase [22,78]. Additionally, it scavenges free radicals, thus preventing lipid peroxidation, one of the pathways that promote MDA generation [22]. Altogether, these decrease ROS and MDA, thus reducing oxidative stress. Curcumin is involved in an anti-inflammatory pathway by activating PPAR-γ, thereby upregulating its mRNA expression [79,80]. An active PPAR-γ translocates into the nucleus where it downregulates the expression of nuclear factor-kappa beta (NF-κβ). The inhibition of the NF-κβ pathway through PPAR-γ reduces the production of enzymes such as nitric oxide synthase (NOS) and xanthine oxidase (XO), which reduces ROS generation and thus ameliorates oxidative stress [81]. It has been reported in animal models of diabetes that curcumin downregulates the expression of NF-κβ by inhibiting the degradation of an inhibitor of kappa beta (Ikβ) [78,82]. This activity inhibits the production of proinflammatory cytokines, including TNF-α and interleukin-6 (IL-6), as well as ROS-generating enzymes, such as NOS and XO, thereby alleviating inflammatory-mediated oxidative stress [81,82,83]. It is also involved in the activation of the nuclear factor-erythroid-related factor 2 (Nrf2) pathway by inhibiting its repressor protein, Kelch-like ECH-associated protein 1 (Keap1) [78,84,85]. Activation of this pathway promotes the translocation of Nrf2 into the nucleus, where it binds to the antioxidant response element (ARE). This upregulates the transcription and expression of antioxidant enzymes, such as heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), and increases the activities of SOD and CAT [81,86]. Altogether, these enzymes prevent the generation of ROS and subsequently reduce oxidative stress (Figure 8).
Thalassrep 15 00007 g008
Figure 8. The proposed mechanism by which curcumin reduces iron overload and oxidative stress [73,74,75,81,84,86]. ARE: Antioxidant response element, DMT1: divalent metal transporter 1, Fe3+: ferrous iron, Fe2+: ferric iron, FPN: ferroportin, HO-1: Heme oxygenase-1, IL-6: interleukin-6, IL-6R: interleukin-6-receptor, IKK: inhibitor of kappa B kinase, Ikβ: inhibitor of kappa beta, JAK: Janus-associated kinase, Keap1: Kelch-like ECH-associated protein 1, NF-kβ: nuclear factor kappa beta, NOS: nitric oxidase, Nrf2: nuclear factor-erythroid related factor 2, NTBI: non-transferrin-bound iron, NQO1: NAD (P) H quinone oxidoreductase 1, P: phosphate ion, PPAR-γ: peroxisome proliferator-activated receptor gamma, ROS: reactive oxygen species, SOD: Superoxide dismutase, STAT: signal transducer and activator of transcription, Tf: transferrin, TfR: transferrin receptor, XO: xanthine oxidase. ↓ decrease, ↑ increase, → activation, ⟞ inhibition. Created through Biorender.
Figure 8. The proposed mechanism by which curcumin reduces iron overload and oxidative stress [73,74,75,81,84,86]. ARE: Antioxidant response element, DMT1: divalent metal transporter 1, Fe3+: ferrous iron, Fe2+: ferric iron, FPN: ferroportin, HO-1: Heme oxygenase-1, IL-6: interleukin-6, IL-6R: interleukin-6-receptor, IKK: inhibitor of kappa B kinase, Ikβ: inhibitor of kappa beta, JAK: Janus-associated kinase, Keap1: Kelch-like ECH-associated protein 1, NF-kβ: nuclear factor kappa beta, NOS: nitric oxidase, Nrf2: nuclear factor-erythroid related factor 2, NTBI: non-transferrin-bound iron, NQO1: NAD (P) H quinone oxidoreductase 1, P: phosphate ion, PPAR-γ: peroxisome proliferator-activated receptor gamma, ROS: reactive oxygen species, SOD: Superoxide dismutase, STAT: signal transducer and activator of transcription, Tf: transferrin, TfR: transferrin receptor, XO: xanthine oxidase. ↓ decrease, ↑ increase, → activation, ⟞ inhibition. Created through Biorender.
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Strengths and Limitations

While the evidence suggests potential benefits, it is essential to acknowledge some of the strengths and limitations when interpreting these findings. To the best of our knowledge, this is the first systematic review and meta-analysis to investigate the effect of curcumin on anemia, iron overload, and oxidative stress in patients with β-thalassemia. A comprehensive search was made on Scopus and PubMed to locate all relevant studies from inception until 15 February 2025. Moreover, this study adhered to the guidelines outlined by the PRISMA (Supplementary File S3). Although the evidence on NTBI showed heterogeneity, we explored this through subgroup analysis. Nonetheless, other outcomes showed no evidence of statistical heterogeneity. Due to the minimal sample size across other outcomes (ROS and MDA), subgroup analysis was not conducted despite visual and statistical evidence of heterogeneity.
However, as noted, the evidence synthesized in this study was gathered from eleven studies with a minimal sample size. Another important limitation observed is that all studies were conducted in the Asian population due to the high β-thalassemia rate; therefore, the results may not be translatable to other populations, especially the African population. The results should be interpreted with caution, particularly for use in patients with β-thalassemia from African and European populations. Different concentrations or doses of curcumin were used in various studies, making it challenging to determine the most effective dose of curcumin in β-thalassemia. Additionally, only one mode of administration was used, oral administration, which is associated with low availability compared to intravenous [76]. Moreover, only two studies adopted a combination therapy using curcumin alongside N-acetylcysteine and deferiprone [40], while another study used curcumin and green tea [35]. However, green tea, as an herbal remedy, can have herb-to-herb interactions, thereby affecting the bioavailability and efficacy of curcumin. Therefore, future studies can incorporate strategies such as co-administration with piperine or formulations such as liposomes, nanoparticles, or micelles nanocarriers, to improve the bioavailability of curcumin [76,77].

5. Conclusions

This study demonstrated that curcumin supplementation in β-thalassemia patients can help alleviate iron overload, as evidenced by reduced serum iron, ferritin, and NTBI levels, as well as decreased levels of ROS and MDA. Moreover, curcumin administration at medium doses (500 mg) was associated with a pronounced reduction in serum NTBI levels in β-thalassemia. However, there was no effect on Hb levels and RBC count. There is sufficient evidence demonstrating the impact of curcumin as an iron-chelating agent in β-thalassemia, as supported by the observation of reduced NTBI, iron, and ferritin. These results suggest that NTBI and iron-related markers can be targeted when developing therapeutic agents against iron overload. Therefore, we recommend that future studies recruit more patients with β-thalassemia and employ additional approaches to enhance the bioavailability of curcumin.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/thalassrep15030007/s1, Supplementary File S1: Supporting materials Figure S1: Effect of curcumin on red blood cells in β-thalassemia; Figure S2: Assessment of publication through visual inspection of funnel plot. A: Hemoglobin; B: ferritin; C: Non-transferrin-binding iron; D: Serum iron; E: Red blood cells; F: Reactive oxygen species; G: Malonaldehydes; Figure S3; Trim and Fill results, A: Hemoglobin, B: Serum iron, C: Reactive Oxygen Species; Figure S4: Subgroup analysis showing the impact of curcumin on non-transferrin-bound iron. A: quality of the studies, B: age, C: form of therapy, D: country of publication, E: duration of intervention; Figure S5: Subgroup analysis showing the impact of curcumin on malondialdehyde. A: quality of studies, B: age, C: form of therapy, D: duration of intervention, E: dose of curcumin; Table S1: Search strategy on Scopus and PubMed; Supplementary File S2: quality assessment by Downs and Black checklist; Supplementary File S3: PRISMA checklist.

Author Contributions

Conceptualization, K.M.; methodology, K.M. and W.N.P.; software, K.M.; validation, K.M., W.N.P. and S.L.L.; formal analysis, K.M.; investigation, K.M. and W.N.P.; resources, K.M.; data curation, K.M. and W.N.P.; writing—original draft preparation, K.M.; writing—review and editing, K.M., W.N.P., S.L.L. and P.M.; visualization, K.M., W.N.P. and S.L.L.; supervision, W.N.P. and S.L.L.; project administration, K.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

We thank the University of South Africa Research Office for handling the article processing charges. The figures presented in this manuscript were created using Biorender.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
AREAntioxidant Response Element
β-thalassemiaBeta-thalassemia
CATCatalase
CIConfidence interval
CVDCardiovascular disease
DMT1Divalent metal transporter one
EGCGEpigallocatechin-3-gallate
FPNFerroportin
GTEGreen-tea extract
HbHemoglobin
HO-1Heme oxygenase-one
IKKInhibitor of kappa B kinase
IKβInhibitor of kappa beta
IL-6Interleukin-6
IL-6RInterleukin-6 receptor
JAKJanus-associated kinase
Keap1Kelch-like ECH-associated protein one
MDMean difference
MDAMalonaldehydes
NADPHNicotinamide adenine dinucleotide phosphate hydrogen
NF-κβNuclear factor-kappa beta
NOSNitric oxidase
Nrf2Nuclear factor-erythroid related factor two
NTBINon-transferrin-bound iron
NQO1NAD (P) H quinone oxidoreductase one
PPhosphate ion
PPAR-γPeroxisome proliferator-activated receptor gamma
PRISMAPreferred reporting items for systematic review and meta-analysis
RBCsRed blood cells
RCTsRandomized controlled trials
ROSReactive oxygen species
SMDStandardized mean difference
SODSuperoxide dismutase
STATSignal transducer and activator of transcription
TfTransferrin
TfRTransferrin receptor
TNF-αTumor necrosis factor alpha
XOXanthine oxidase

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Figure 1. Complications associated with thalassemia [1,16]. α: alpha-globulin chain, β: beta-globin chain, ROS: reactive oxygen species (Created through Biorender).
Figure 1. Complications associated with thalassemia [1,16]. α: alpha-globulin chain, β: beta-globin chain, ROS: reactive oxygen species (Created through Biorender).
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Figure 2. The Curcuma longa root and powder, including the chemical structure of curcumin in a keto form [23].
Figure 2. The Curcuma longa root and powder, including the chemical structure of curcumin in a keto form [23].
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Figure 3. Flow chart showing the screening based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
Figure 3. Flow chart showing the screening based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
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Figure 4. Forest plot showing the effect of curcumin on hemoglobin in β-thalassemia. Hatairaktham (A) et al. [41]; Hatairaktham (B) et al. [41]; Koonyosyin (A) et al. [35]; Koonyosyin (B) et al. [35]; Panachan et al. [39]; Tamaddoni et al. [36]; Mohammadi et al. [38]; Nasseri et al. [37]; Yanpanitch et al. [40]; Weeraphan et al. [43]; Kalpravidh et al. [42]. CI: confidence intervals, SD: standard deviation, SMD: standardized mean difference. The solid vertical line shows the line of no effect, the vertical dashed line shows the effect size, the gray block shows the weight of the study, the horizontal line crossing the gray block shows the confidence intervals (lower and upper), diamond plot shows the combined effect size.
Figure 4. Forest plot showing the effect of curcumin on hemoglobin in β-thalassemia. Hatairaktham (A) et al. [41]; Hatairaktham (B) et al. [41]; Koonyosyin (A) et al. [35]; Koonyosyin (B) et al. [35]; Panachan et al. [39]; Tamaddoni et al. [36]; Mohammadi et al. [38]; Nasseri et al. [37]; Yanpanitch et al. [40]; Weeraphan et al. [43]; Kalpravidh et al. [42]. CI: confidence intervals, SD: standard deviation, SMD: standardized mean difference. The solid vertical line shows the line of no effect, the vertical dashed line shows the effect size, the gray block shows the weight of the study, the horizontal line crossing the gray block shows the confidence intervals (lower and upper), diamond plot shows the combined effect size.
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Figure 5. (A). Forest plot showing the effect of curcumin on ferritin in β-thalassemia. (B). Forest plot showing the effect of curcumin on non-transferring bound iron in β-thalassemia. (C). Forest plot showing the effect of curcumin on serum iron. Koonyosyin (A) et al. [35] Koonyosyin (B) et al. [35]; Hatairaktham (A) et al. [41]; Hatairaktham (B) et al. [41]; Panachan et al. [39]; Tamaddoni et al. [36]; Mohammadi et al. [38]; Nasseri et al. [37]; Yanpanitch et al. [40]; Weeraphan et al. [43]; Kalpravidh et al. [42], Saeidnia et al. [34]. CI: confidence intervals, SD: standard deviation, SMD: standardized mean difference. The solid vertical line shows the line of no effect, the vertical dashed line shows the effect size, the gray block shows the weight of the study, the horizontal line crossing the gray block shows the confidence intervals (lower and upper), diamond plot shows the combined effect size.
Figure 5. (A). Forest plot showing the effect of curcumin on ferritin in β-thalassemia. (B). Forest plot showing the effect of curcumin on non-transferring bound iron in β-thalassemia. (C). Forest plot showing the effect of curcumin on serum iron. Koonyosyin (A) et al. [35] Koonyosyin (B) et al. [35]; Hatairaktham (A) et al. [41]; Hatairaktham (B) et al. [41]; Panachan et al. [39]; Tamaddoni et al. [36]; Mohammadi et al. [38]; Nasseri et al. [37]; Yanpanitch et al. [40]; Weeraphan et al. [43]; Kalpravidh et al. [42], Saeidnia et al. [34]. CI: confidence intervals, SD: standard deviation, SMD: standardized mean difference. The solid vertical line shows the line of no effect, the vertical dashed line shows the effect size, the gray block shows the weight of the study, the horizontal line crossing the gray block shows the confidence intervals (lower and upper), diamond plot shows the combined effect size.
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Figure 6. The effect of curcumin on oxidative stress in patients with β-thalassemia. (A): Reactive oxygen species; (B): Malondialdehyde (MDA). Hatairaktham (A) et al. [41] Hatairaktham (B) et al. [41]; Panachan et al. [39]; Yanpanitch et al. [40]; Kalpravidh et al. [42]. CI: confidence intervals, MD: mean difference, SD: standard deviation, SMD: standardized mean difference. The solid vertical line shows the line of no effect, the vertical dashed line shows the effect size, the gray block shows the weight of the study, the horizontal line crossing the gray block shows the confidence intervals (lower and upper), diamond plot shows the combined effect size.
Figure 6. The effect of curcumin on oxidative stress in patients with β-thalassemia. (A): Reactive oxygen species; (B): Malondialdehyde (MDA). Hatairaktham (A) et al. [41] Hatairaktham (B) et al. [41]; Panachan et al. [39]; Yanpanitch et al. [40]; Kalpravidh et al. [42]. CI: confidence intervals, MD: mean difference, SD: standard deviation, SMD: standardized mean difference. The solid vertical line shows the line of no effect, the vertical dashed line shows the effect size, the gray block shows the weight of the study, the horizontal line crossing the gray block shows the confidence intervals (lower and upper), diamond plot shows the combined effect size.
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Figure 7. Subgroup analysis based on dosage of curcumin on NTBI. Hatairaktham (A) et al. [41] Hatairaktham (B) et al. [41]; Koonyosyin (A) et al. [35] Koonyosyin (B) et al. [35]; Panachan et al. [39]; Mohammadi et al. [38]; Yanpanitch et al. [40]; Weeraphan et al. [43]; Kalpravidh et al., [42]. CI: confidence intervals, SD: standard deviation, SMD: standardized mean difference. The solid vertical line shows the line of no effect, the vertical dashed line shows the effect size, the gray block shows the weight of the study, the horizontal line crossing the gray block shows the confidence intervals (lower and upper), diamond plot shows the combined effect size.
Figure 7. Subgroup analysis based on dosage of curcumin on NTBI. Hatairaktham (A) et al. [41] Hatairaktham (B) et al. [41]; Koonyosyin (A) et al. [35] Koonyosyin (B) et al. [35]; Panachan et al. [39]; Mohammadi et al. [38]; Yanpanitch et al. [40]; Weeraphan et al. [43]; Kalpravidh et al., [42]. CI: confidence intervals, SD: standard deviation, SMD: standardized mean difference. The solid vertical line shows the line of no effect, the vertical dashed line shows the effect size, the gray block shows the weight of the study, the horizontal line crossing the gray block shows the confidence intervals (lower and upper), diamond plot shows the combined effect size.
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Table 1. Effects of curcumin on anemia, iron overload, and oxidative stress in patients living with β-thalassemia.
Table 1. Effects of curcumin on anemia, iron overload, and oxidative stress in patients living with β-thalassemia.
ReferenceCountryStudy DesignPopulation SizeMean Age (Years)Gender, Male n (%)Intervention, PeriodsSummary of FindingsMethodological Quality
Kalpravidh et al., 2010 [42]ThailandProspective, open-label, single-arm clinical studyTwenty-one β-thalassemia/Hb E patients157 (33.3)Two capsules of 250 mg (500 mg) curcuminoids per day for 12 monthsNo significant difference in Hb and serum ferritin was observed between baseline and post-curcumin treatment. The NTBI and MDA decreased at six months of curcumin treatment compared to the baseline.Moderate
Weeraphan et al., 2013 [43]ThailandProspective cohortTen β-thalassemia/Hb E patients27.95 (50)500 mg curcuminoids daily for 12 months.Curcumin led to no significant difference in Hb and serum ferritin at 6 and 12 months compared to baseline.
Curcumin significantly decreased NTBI, ROS, and RBCs MDA.		Excellent
Yanpanitch et al., 2015 [40]ThailandClinical trialTwenty-five β-thalassemia/Hb E patients32.511 (44)500 mg/day curcumin,
200 mg/day N-acetylcysteine and 50 mg/kg/day deferiprone for 12 months		Curcumin levels significantly increased at 6 and 12 months, but returned to baseline levels by the 15th month. Additionally, ferritin, NTBI, ROS, and MDA decreased at 6 and 12 months compared to baseline.Excellent
Nasseri et al., 2017 [37]IranDouble-blind, randomized, controlled clinical trialSixty-one-β-thalassemia major patients (31 curcumin and 30 placebo)25.9714 (45.2)Two capsules of 500 mg (1000 mg) curcumin daily for 12 weeks (≈3 months).Curcumin post-treatment led to no significant difference in Hb. Curcumin showed no significant difference between the serum iron and ferritin groups before and after treatment.Good
Mohammadi et al., 2018 [38]IranDouble-blind randomized
controlled clinical trial		Thirty-one β-thalassemia
major patients on curcumin and 30 on placebo		25.9714 (45.2)500 mg curcumin capsules twice daily for 12 weeks (≈3 months).Curcumin post-treatment led to no significant difference in Hb. Curcumin led to no significant difference in ferritin. The NTBI significantly decreased post-treatment compared to the baseline.Good
Panachan et al., 2019 [39]ThailandInterventional longitudinal studyTen β-thalassemia/Hb E patients35.05 (50)500 mg curcumin per day for 12 months.Significant increase in Hb at six and twelve months of curcumin compared to baseline.
A decrease in ferritin, NTBI, ROS, and MDA was observed compared to baseline.		Excellent
Tamaddoni et al., 2020 [36]IranDouble-blind randomized controlled clinical trialSixty-eight β- thalassemia major patients25.9714 (45.2)Two capsules of 500 mg (1000 mg) curcumin daily for 12 weeks (3 months).Curcumin post-treatment led to no significant difference in Hb. Curcumin showed no difference in serum iron levels between the groups.Excellent
Koonyosying (A) et al., 2020 [35]ThailandProspective controlled interventionTwelve β-thalassemia patients28.34 (33.3)Green tea extract (GTE)-curcumin (17.26 mg epigallocatechin-3-gallate (EGCG)) daily for 60 days (≈2 months).Curcumin post-treatment led to no significant difference in Hb or NTBI.Good
Koonyosying (B) et al., 2020 [35]ThailandProspective controlled interventionEleven β-thalassemia patients26.15 (45.5)Green tea extract (GTE)-curcumin (35.5 mg EGCG) daily for 60 days (≈2 months).Curcumin post-treatment led to no significant difference in Hb. Curcumin significantly decreased NTBI without a difference in serum iron.Good
Saeidnia et al., 2021 [34]IranRandomized double-blind clinical trialThirty patients with β-thalassemia intermedia29.830 (100)500 mg curcumin thrice a day for three months.Curcumin post-treatment significantly decreased serum ferritin compared to baseline and placebo.Excellent
Hatairaktham (A) et al., 2021 [41]ThailandRandomized clinical trialFourteen patients with β-thalassemia/Hb E367 (50)500 mg of curcuminoids per day for 24. weeks (≈6 months).Curcumin post-treatment significantly reduced NTBI, ROS, and RBC MDA. No difference in Hb, iron, and ferritin was observed.Good
Hatairaktham (B) et al., 2021 [41]ThailandRandomized clinical trialFifteen patients with β-thalassemia/Hb E347 (47)1000 mg of curcuminoids per day for 24 weeks (≈6 months).Curcumin post-treatment significantly reduced serum iron, NTBI, ROS, and RBC MDA. No difference in Hb and ferritin was observed.Good
Saeidnia et al., 2022 [28]IranRandomized, controlled, double-blind clinical trialThirty male patients with β-thalassemia intermedia (15 on curcumin and 13 on placebo)28.0630 (100)500 mg curcumin thrice a day for three months.Serum iron and ferritin significantly decreased in the curcumin group compared to the placebo group.Moderate
Eghbali et al., 2023 [44]IranDouble-blind, randomized, controlled clinical trialOne hundred fifty-eight patients with β-thalassemia major14.289 (56.3)500 mg oral curcumin- capsules twice daily for six monthsThe serum ferritin levels remained unchanged throughout curcumin treatment.Excellent
EGCG: epigallocatechin-3-gallate, GTE: green-tea extract, Hb: hemoglobin, MDA: malondialdehyde, NTBI: non-transferrin-bound iron, RBCs: red blood cells, RCT: randomized controlled trial, ROS: reactive oxygen species.
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Mokgalaboni, K.; Phoswa, W.N.; Modjadji, P.; Lebelo, S.L. Curcumin Therapy Reduces Iron Overload and Oxidative Stress in Beta-Thalassemia: Findings from a Meta-Analytic Study. Thalass. Rep. 2025, 15, 7. https://doi.org/10.3390/thalassrep15030007

AMA Style

Mokgalaboni K, Phoswa WN, Modjadji P, Lebelo SL. Curcumin Therapy Reduces Iron Overload and Oxidative Stress in Beta-Thalassemia: Findings from a Meta-Analytic Study. Thalassemia Reports. 2025; 15(3):7. https://doi.org/10.3390/thalassrep15030007

Chicago/Turabian Style

Mokgalaboni, Kabelo, Wendy N. Phoswa, Perpetua Modjadji, and Sogolo L. Lebelo. 2025. "Curcumin Therapy Reduces Iron Overload and Oxidative Stress in Beta-Thalassemia: Findings from a Meta-Analytic Study" Thalassemia Reports 15, no. 3: 7. https://doi.org/10.3390/thalassrep15030007

APA Style

Mokgalaboni, K., Phoswa, W. N., Modjadji, P., & Lebelo, S. L. (2025). Curcumin Therapy Reduces Iron Overload and Oxidative Stress in Beta-Thalassemia: Findings from a Meta-Analytic Study. Thalassemia Reports, 15(3), 7. https://doi.org/10.3390/thalassrep15030007

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