Pumpkin Seeds as a Natural Remedy for Anemia: Nutritional Insights and Therapeutic Potential

Abstract

Anemia is a widespread global health concern characterized by reduced hemoglobin levels and diminished oxygen-carrying capacity of the blood. According to the World Health Organization, anemia affects 40% of children aged 6 to 59 months, 37% of pregnant women, and 30% of women aged 15 to 49 years globally. The condition is primarily linked to iron deficiency, particularly in low- and middle-income countries, although other factors such as vitamin B12 insufficiency, parasitic infections, chronic diseases, and genetic disorders also contribute. The socioeconomic and health impacts of anemia highlight the need for effective prevention and management strategies. Dietary interventions play a critical role in addressing iron deficiency, with functional foods gaining prominence for their sustainable and cost-effective potential. Among these, pumpkin seeds (Cucurbita spp) stand out due to their rich nutrient profile and potential health benefits. This review explores the global and Indian prevalence of anemia, the nutritional complexity of the condition, and the therapeutic potential of pumpkin seeds. It discusses their nutritional composition, mechanisms of action, and current evidence supporting their role in combating anemia while identifying research gaps and future directions for establishing standardized dietary recommendations. Much literature and scientific research underscore the importance of nutrient-dense foods such as pumpkin seeds, which are rich in essential micronutrients such as iron, zinc, magnesium, and bioactive compounds that support hematopoiesis and overall health. Leveraging the therapeutic potential of these natural alternatives, alongside fortified food programs and precise monitoring methods, can significantly contribute to anemia reduction and improve public health outcomes.

Introduction

Anemia is characterized by reduced hemoglobin (Hb) levels and insufficient oxygen-carrying capacity of the blood, making it a prevalent global health issue. It affects individuals across all age groups, with women of reproductive age, children, and the elderly being particularly vulnerable. The World Health Organization (WHO) defines anemia as the condition of having a low concentration of blood Hb, that is, <110, <120, and <130 g/L for children aged 6 to 59 months, nonpregnant women, and men, respectively,¹ although Ghosh et al² have recently reported that a cutoff value of 110 g/L may be more suitable for childbearing age of Indian women. World Health Organization³ reports that, worldwide, 40% of children aged 6 to 59 months, 37% of pregnant women, and 30% of women aged 15 to 49 years are affected by anemia. Also, in 2019, anemia caused 50 million years of healthy life to be lost.⁴ High anemia prevalence is a big worry in India and other nations, especially industrialized ones. The WHO wants to reduce anemia in women of reproductive age by 50% by 2025. However, worldwide anemia prevalence has remained stable over the previous 20 years, and the objective may not be realized by 2030.⁵

The etiology of anemia is multifactorial, with iron deficiency being the most common cause. Iron is a vital component that serves as a cofactor for both hemoproteins and nonheme iron proteins. It is found in the hemoprotein’s Hb in red blood cells (RBCs) and myoglobin, which carry and store oxygen throughout the body. Iron has a crucial role in the heme iron center of cytochrome C oxidase, which promotes adenosine triphosphate (ATP) generation during mitochondrial respiration.⁶ There is a growing concern that iron shortage may impair this process, which is critical for brain development.⁷ Low iron intake is the leading cause of anemia, particularly in low- and middle-income countries.³ Recent research suggests that Hb levels may not accurately predict iron insufficiency.⁸ According to WHO,³ anemia can also be caused by non–iron-related causes such as vitamin B12 insufficiency and digestive tract worm infection. Other contributing factors include vitamin deficiencies, chronic diseases, and genetic disorders such as thalassemia and sickle cell anemia.⁹ The socioeconomic and health burdens associated with anemia underscore the urgent need for effective prevention and treatment strategies.

Dietary interventions are a cornerstone of anemia management, especially in addressing iron deficiency. Functional foods, rich in bioavailable micronutrients, have gained attention as sustainable and cost-effective solutions. Among these, pumpkin seeds (Cucurbita spp) have emerged as a promising natural remedy due to their exceptional nutrient profile and health benefits.¹⁰ These seeds are a rich source of nonheme iron, essential fatty acids, amino acids, and trace minerals such as zinc and magnesium. They also contain bioactive compounds, including phytosterols, tocopherols, and polyphenols, which contribute to their antioxidant and anti-inflammatory properties.¹¹ Iron bioavailability is a critical factor in combating anemia. While many plant-based sources of iron are limited by low absorption rates due to the presence of phytates and oxalates, studies suggest that certain preparation methods for pumpkin seeds, such as roasting or fermentation, can reduce these inhibitors and enhance iron bioavailability.¹² Additionally, the zinc content in pumpkin seeds plays a vital role in hematopoiesis by supporting the function of erythropoietin and other enzymes involved in RBC synthesis.

Anemia often coexists with oxidative stress, particularly in cases related to chronic inflammation or hemolytic conditions. The antioxidants present in pumpkin seeds help mitigate oxidative damage to RBCs, thus improving their lifespan and functionality.¹³ Furthermore, pumpkin seeds have been found to have immunomodulatory effects, which may indirectly benefit anemic patients by addressing underlying inflammatory or infectious causes.¹⁴ Another significant advantage of pumpkin seeds is their accessibility and cultural acceptance. Widely consumed as a snack or incorporated into traditional recipes, they present an appealing option for public health interventions aimed at reducing anemia prevalence, especially in resource-limited settings.¹⁵ With their versatility and potential to address multiple facets of anemia, pumpkin seeds align with the growing interest in plant-based functional foods for disease prevention and management. This review delves into the global burden of anemia, Indian prevalence of anemia, nutritional complex of anemia, nutritional composition, mechanisms of action, and therapeutic potential of pumpkin seeds in combating anemia. It highlights existing evidence, identifies gaps in research, and paves the way for future studies to validate their efficacy and establish standardized dietary recommendations.

Anemia

Anemia is a multifaceted condition characterized by a deficiency in RBCs or Hb, affecting oxygen delivery to body tissues. It affects approximately one-third of the global population. Anemia has been linked to higher rates of morbidity and death in women and children, poor birth outcomes, lower productivity in adults, and poorer cognitive and behavioral development in children. Preschool children and women of reproductive age are especially vulnerable. Establishing adequate Hb thresholds is crucial for accurately identifying anemia and preventing detrimental effects. Understanding the complicated etiology of anemia is vital for devising effective therapies and assessing the performance of control strategies.¹⁶

Global Burden of Anemia

Anemia is a pervasive global health issue, affecting nearly 25% of the world’s population, with a particularly high burden among women, children, and individuals in low- and middle-income countries.¹⁷ It is most prevalent in sub-Saharan Africa and South Asia, where rates exceed 40%, driven by factors such as poor nutrition, iron and vitamin deficiencies, parasitic infections, and chronic diseases.¹⁸ In 2019, anemia affected 30% (539 million) of nonpregnant women and 37% (32 million) of pregnant women aged 15 to 49 years, with the highest prevalence in the WHO Regions of Africa and South-East Asia. Anemia is estimated to impact 106 million women and 103 million children in Africa and 244 million women and 83 million children in South-East Asia.^4,19

The condition significantly affects cognitive development in children, increases maternal and infant mortality rates, and exacerbates chronic illnesses among the elderly. In young children, pregnant and postpartum mothers, and adolescent girls, anemia leads to a range of health complications, including impaired physical and cognitive development. Socioeconomically, anemia reduces workforce productivity and imposes a substantial health care burden, particularly in regions where labor-intensive industries are vital.²⁰ In 2019 alone, anemia resulted in the loss of 50 million years of healthy life due to incapacity. The main causes of anemia include dietary iron deficiency, thalassemia, sickle cell trait, and malaria, which disproportionately affect populations in rural areas, poorer households, and those with limited education.⁴ Addressing this issue requires comprehensive strategies, including iron supplementation, dietary diversification, food fortification, and improved health care interventions for underlying conditions such as gastrointestinal disorders and malaria.²¹ Research into targeted interventions is essential to mitigate anemia’s health and economic impacts, particularly for high-risk groups. The present study aims to contribute valuable evidence to inform public health approaches for anemia management.

Anemia Prevalence in India

Table 1 summarizes prevalence statistics for anemia in adults and children from the Indian National Family Health Surveys (NFHS)-3 (2005–2006),²² NFHS-4 (2015–2016),²³ and NFHS5 (2019–2021).²⁴ Over 58% of children aged 6 to 59 months were anemic, with Hb values below 11 g/dL. Children in rural settings are more likely to have anemia, which is linked to low-income households and moms with less education. Rural children may have higher intestinal worm burdens due to lower sanitation and undernutrition compared with urban children. Early childbirth is more prevalent in rural settings, where moms are more likely to be anemic compared with older urban mothers.⁹ Similar findings have been observed in Africa, with rural Ethiopian children having a 23% higher incidence of anemia compared with urban children for the same reasons as in India.²⁵

Table 1.

Definition of anemia in NFHS 3.²²

S: no	Population particulars	Reports of NFHS	Percentage of anemic in residence			References
			Rural	Urban	All
1	Men 15–49 y	3: 2005–2006	NG	NG	24.2	22–24
		4: 2015–2016	25.3	18.5	22.7
		5: 2019–2021	27.4	20.4	25.0
2	Women 15–48 y not pregnant	3: 2005–2006	NG	NG 2	53.2
		4: 2015–2016	54.4	51.0	53.2
		5: 2019–2021	58.7	54.1	57.2
3	Women 15–48 y pregnant	3: 2005–2006	NG	NG	58.7
		4: 2015–2016	52.2	45.8	50.4
		5: 2019–2021	54.3	45.7	52.2
4	Children 6–59 mo	3: 2005–2006	71.5	63.0	69.5
		4: 2015–2016	59.5	56.0	58.6
		5: 2019–2021	68.3	64.2	67.1

2005 to 2006 hemoglobin: men, <13 g/dL; women, <12 g/dL; children, <11.0 g/dL. NFHS 4²³: 2015 to 2016 hemoglobin: men, <13 g/dL; nonpregnant women, <12 g/dL; pregnant women, <11 g/dL; children, <11.0 g/dL. NFHS 5²⁴: 2019 to 2021 hemoglobin: men <13.2 g/dL; nonpregnant women <12 g/dL; pregnant women <11 g/dL; children <11.0 g/dL.

NFHS = National Family Health Surveys; NG = not given.

The lower values in the 2015–2016 survey compared with 2005–2006 have increased in 2019–2021, which is worrying. In comparison with 2015–2016, there was a rise in mild (Hb, 10.0–10.9 g/dL), moderate (Hb, 7.0–9.9 g/dL), and severe anemia (Hb, <7.0 g/dL). However, the prevalence of severe and moderate anemia remained lower than in NFHS-2 (1998–1999).²⁶ Childhood anemia rates varied among Indian states, with Gujarat having the highest frequency (79.7%), followed by Jammu and Kashmir (72.7%) and Madhya Pradesh (72.7%), and Kerala having the lowest (39.4%).²⁶ Additionally, the number of states with anemia prevalence over 60% increased from 5 in 2015–2016 to 11 in 2019–2021.²⁶

According to Singh et al,²⁶ the increased frequency in 2019–2021 was primarily due to mothers' low anemia status, socioeconomic status, and education level. To lower the high prevalence of pediatric anemia in India, food supplementation programs should use rigorous technology-based monitoring methods. Anemia was more common among women and men aged 15 to 48 years in rural areas compared with urban areas (Table 1). Women had higher anemia rates in 2019–2021 compared with 2015–2016, indicating a correlation with higher childhood prevalence during that period.²⁶ Concerns were raised that the greater anemia rates observed in NFHS-5 (2019–2021) were due to the use of capillary blood, which has been found to produce lower Hb values than venous blood.²⁷ The Diet and Biomarkers Survey in India will employ venous blood to quantify Hb.²⁸

Kumari et al²⁹ investigated the prevalence of anemia among 200 adolescent girls at a tertiary care hospital in Bihar, Northeast India. The study indicated that 50% of girls aged 10 to 19 years had anemia (Hb concentrations, <12 g/dL), which is consistent with the NFHS-4 findings. The study found that adolescent girls require more dietary iron, indicating a higher risk of iron deficiency anemia (IDA).

A recent study³⁰ analyzed data from 116,117 and 109,400 adolescent women (aged 15–19 years) from NFHS-4 (2015–2016) and NFHS-5 (2019–2021), respectively, to identify factors contributing to an increase in adolescent anemia in the second study compared with the first. Targeted treatments for teenage females, particularly in states with high anemia prevalence, are needed, as agreed upon in the following study.²⁶ The study found that socioeconomic factors like money and education can increase the risk of anemia among adolescent women in India. Poor dietary status and adolescent parenthood are significant risk factors for adolescent anemia in this population. The study emphasizes the need for a concerted approach to eliminate anemia, especially among vulnerable populations. The study by Chakrabarty et al³⁰ identified low dietary intakes of iron, vitamin B12, and folate as contributing to anemia. However, data on these nutrients was not accessible to the participants getting involved. Data on female teenagers, as well as other segments of the population, is badly needed.

Dietary Iron and Anemia: A Complex Connection

Anemia manifests in various types, including IDA, which results from inadequate iron intake, blood loss, or malabsorption; vitamin deficiency anemia, caused by insufficient vitamin B12 or folate; hemolytic anemia, marked by premature RBC destruction; and anemia of chronic disease, associated with long-term conditions such as cancer and kidney disease. The association between dietary iron intake and anemia remains complex and multifactorial, with IDA commonly cited as a significant contributor, particularly in India, where dietary patterns often lack heme iron–rich sources.³¹ However, anemia's etiology encompasses other nutritional deficiencies, parasitic infections such as hookworm, malaria, and chronic conditions, including gastrointestinal bleeding.³² Despite IDA being a prevalent cause globally,³³ studies suggest that low dietary iron may not always have a strong association with anemia, with factors like maternal anemia, poverty, and food insecurity playing more critical roles. Investigations in rural India reported that improving iron intake reduced anemia risk only marginally.³⁴

Nutritional supplementation plays a crucial role in managing anemia. Iron-rich foods, vitamin C to enhance iron absorption, and adequate intake of B12 and folate are essential in RBC production. Protein, zinc, and copper further contribute to Hb synthesis and overall hematopoiesis. Biofortification strategies and targeted supplementation are especially beneficial in addressing micronutrient deficiencies, while malabsorption conditions necessitate tailored nutritional interventions. Effective prevention and management of anemia through nutrition can significantly improve health outcomes and quality of life.^1,31

Importance of Natural Iron Sources and Their Utilization in Value-Added Food Products

Scientists are increasingly exploring natural sources of iron due to their favorable tolerability, enhanced bioavailability, and added nutritional benefits. Natural iron sources, particularly from plant-based foods, provide a balanced composition of micronutrients, antioxidants, and dietary fibers that contribute to overall metabolic health. Unlike synthetic supplements, which may lead to iron overload and oxidative stress, natural sources promote regulated absorption and utilization.³⁵

Advantages of natural iron sources

Better bioavailability with synergistic nutrients

Natural iron sources contain bioavailability enhancers such as vitamin C, polyphenols, and organic acids, which facilitate iron absorption in the gut.³⁶

Reduced gastrointestinal side effects

Unlike synthetic iron supplements, natural sources are less likely to cause nausea, constipation, or gastric discomfort, making them more tolerable for long-term consumption.

Antioxidant and anti-inflammatory properties

Plant-based iron sources often contain polyphenols, flavonoids, and essential fatty acids that provide antioxidant and anti-inflammatory benefits, which help reduce oxidative stress associated with iron metabolism.³⁷

Regulated absorption

Unlike synthetic iron supplements, which may lead to excessive iron accumulation and toxicity, natural sources allow for better regulation through hepcidin-mediated pathways, reducing the risk of iron overload.³⁸

Gut microbiota support

Natural iron sources, especially from plant-based foods, contribute to a healthy gut microbiome, which plays a critical role in iron metabolism and absorption.³⁹

Sustainable and eco-friendly

Many plant-based iron sources, such as pumpkin seeds, legumes, and leafy greens, offer a sustainable and environmentally friendly alternative to synthetic iron supplementation.

Integration into functional foods

Natural iron sources can be incorporated into value-added food products such as fortified cereals, bread, and dairy alternatives, making iron intake more accessible and convenient.

Natural Iron Sources Versus Synthetic Iron Supplements

Iron is an essential micronutrient that plays a crucial role in oxygen transport, energy metabolism, and enzymatic functions. The sources of dietary iron can be broadly classified into natural food-based sources and synthetic supplements. Each has its advantages and limitations concerning bioavailability, side effects, and overall impact on health in Table 2.

Table 2.

The efficiency of iron absorption depends on multiple dietary and physiologic factors.

Iron source	Bioavailability (%)	Advantages	Disadvantages
Heme iron (animal)	15–35	High absorption, not affected by dietary inhibitors	Expensive, linked to high cholesterol, and ethical concerns
Nonheme iron (plant)	2–20	Rich in fiber, polyphenols, and essential micronutrients	Lower absorption, influenced by inhibitors such as phytates
Synthetic iron	Varies (5–40)	Rapid correction of iron deficiency	Gastrointestinal distress, oxidative stress, and poor regulation

Natural iron sources

Natural iron sources include heme iron, predominantly found in animal products, and nonheme iron, which is derived from plant-based foods. Common dietary sources include the following: heme iron sources and nonheme iron sources.

Heme iron sources

Red meat, poultry, fish, and organ meats. Heme iron is more readily absorbed by the body, with an estimated bioavailability of 15% to 35%.³⁶

Nonheme iron sources

Pumpkin seeds, legumes, spinach, nuts, whole grains, and fortified cereals. The bioavailability of nonheme iron is significantly lower, ranging from 2% to 20%, due to the presence of natural inhibitors such as phytates, polyphenols, and oxalates.³⁵

Despite lower bioavailability, plant-based iron sources are increasingly favored due to their additional health benefits, such as high fiber content, antioxidant properties, and essential micronutrients that support metabolic functions.

Synthetic iron supplements

Synthetic iron supplements, such as ferrous sulfate, ferrous gluconate, and ferric citrate, are widely used for treating IDA. These supplements provide a concentrated dose of iron but are associated with several limitations:

Gastrointestinal side effects

Synthetic iron can cause nausea, constipation, diarrhea, and stomach cramps, leading to poor compliance among patients.³⁷

Oxidative stress

Excessive iron intake from supplements may generate free radicals, promoting oxidative damage and inflammation, particularly in individuals with hemochromatosis or metabolic disorders.⁴⁰

Absorption efficiency

The absorption of synthetic iron is highly variable, influenced by gastric pH, dietary inhibitors, and systemic iron regulation. Ferric iron (Fe³⁺) requires reduction to the more soluble ferrous (Fe²⁺) form before absorption, adding an extra biochemical step that reduces efficiency.³⁸

Iron overload risk

Unlike dietary iron, which is naturally regulated by body stores, synthetic iron can bypass hepcidin-mediated control mechanisms, leading to toxicity in cases of excessive supplementation.⁴¹

Mechanism of Iron Bioavailability in the Body

Dietary iron sources

Iron exists in 2 primary dietary forms: heme and nonheme iron. Heme iron, primarily found in animal-based sources such as red meat, poultry, and fish, is highly bioavailable, with an absorption efficiency of 15% to 35%. This is because heme iron remains in the Fe²⁺ form, which can be directly absorbed by intestinal enterocytes. In contrast, nonheme iron, which is abundant in plant-based foods such as spinach, legumes, nuts (eg, pumpkin seeds), and fortified cereals, has lower bioavailability (2%–20%) due to its presence in the ferric (Fe³⁺) state. Before absorption, nonheme iron must be converted to Fe²⁺, making its uptake less efficient. The bioavailability of nonheme iron is influenced by dietary enhancers and inhibitors, making it more susceptible to external factors compared with heme iron.⁴²

Gastric processing and iron reduction

Iron absorption begins in the stomach, where hydrochloric acid plays a crucial role in solubilizing iron and breaking down food matrices to release bound iron. The acidic environment of the stomach prevents iron precipitation and enhances its solubility. Fe³⁺, which is less absorbable, is converted into ferrous iron (Fe²⁺) by ferric reductase (Dcytb), an enzyme located on the duodenal brush border. This enzymatic reduction is essential for the subsequent uptake of iron into intestinal cells. Individuals with low stomach acid (eg, those on proton pump inhibitors or with atrophic gastritis) may have reduced iron absorption due to impaired solubilization and conversion of nonheme iron.⁴³

Iron absorption in the duodenum

Iron absorption predominantly occurs in the duodenum, where the divalent metal transporter 1 facilitates the uptake of Fe²⁺ into enterocytes. Within intestinal cells, iron follows 2 primary pathways; it is either stored in ferritin if immediate utilization is not required or transported into circulation via ferroportin, the only known iron exporter in enterocytes. Upon release into the bloodstream, Fe²⁺ is oxidized back to Fe³⁺ by hephaestin before binding to transferrin (Tf), the primary iron transport protein. This process ensures efficient iron delivery to various tissues, particularly the bone marrow, where it is used for erythropoiesis.³⁸

Factors influencing iron absorption

Enhancer

Several dietary components significantly influence iron absorption. Enhancers include vitamin C (ascorbic acid), which reduces Fe³⁺ to Fe²⁺ and prevents the formation of insoluble iron complexes, thereby increasing absorption. In addition, vitamin C prevents the formation of insoluble iron-phytate and iron-polyphenol complexes, thus improving absorption in plant-based diets.⁴⁴ This is particularly relevant for individuals relying on plant-based iron sources, such as pumpkin seeds, because the bioavailability of nonheme iron can be significantly increased by co-consuming vitamin C-rich foods such as citrus fruits, bell peppers, and tomatoes. Organic acids such as citric and lactic acid chelate iron, maintaining its solubility and preventing precipitation. Additionally, meat proteins and peptides enhance the absorption of both heme and nonheme iron by stimulating gastric acid secretion and forming soluble iron complexes.

Mechanistic interplay of vitamin C in iron absorption

Under normal physiologic conditions, nearly all plasma iron is tightly bound to Tf.⁴⁵ Iron absorbed by enterocytes is released into the bloodstream and oxidized to its ferric state, a process primarily facilitated by the transmembrane multicopper ferroxidase, hephaestin, located in the basolateral membrane of enterocytes.⁴⁶ Additionally, ceruloplasmin, a homologous soluble multicopper ferroxidase abundant in plasma, may also contribute to this oxidation process.⁴⁷ The resulting Fe³⁺ binds specifically to serum Tf, glycoprotein predominantly synthesized by the liver.⁴ Each Tf molecule can bind 1 or 2 Fe³⁺ ions, forming monoferric or diferric Tf (holo-Tf).^48,49 Iron binding occurs with high affinity at physiologic pH (7.4), with an affinity constant of approximately 10²⁰ M⁻¹ at atmospheric partial pressure of carbon dioxide (pCO₂).⁵⁰ Holo-Tf then interacts with Tf receptor 1 (TfR1), an integral membrane protein that mediates iron uptake by cells.^45,51 TfR1 is a glycoprotein that forms via disulfide bonds, enabling it to bind 2 holo-Tf molecules.^52,53 Most cells express TfR1, except mature erythrocytes,⁵⁴ and possibly oligodendrocytes, microglia, and astrocytes in vivo.⁵⁵ Its affinity for diferric Tf at pH 7.4 is about 2000 times higher than for apo-Tf and approximately 20 times greater than for monoferric Tf.56, 57 The holo-Tf–TfR1 complex undergoes receptor-mediated endocytosis through clathrin-coated pits. Inside the endosome, an ATP-dependent proton pump, vacuolar-type H⁺-ATPase, lowers the lumen pH to approximately 5.3 to 5.6,58, 59, 60 triggering the release of Fe³⁺ from Tf, whereas apo-Tf remains bound to TfR1.⁶¹

Before iron can be transported into the cytoplasm via divalent metal transporter 1,^4,19 Fe³⁺ must first be reduced to Fe²⁺.62, 63 The only known ferrireductase involved in this step is 6-transmembrane epithelial antigen of the prostate-364, 65 though its activity may be primarily limited to erythroid precursors. Other transporters, such as ZIP14, have been suggested to contribute to iron mobilization from Tf-cycle endosomes, but their relative importance across different cell types remains uncertain.⁶⁶ Finally, the apo-Tf–TfR1 complex is recycled back to the plasma membrane, where the slightly alkaline extracellular pH promotes the dissociation of apo-Tf from TfR1, allowing the cycle to continue⁶⁷ (Figure 1).

Fig. 1.

Model of vitamin C–dependent stimulation of transferrin (Tf)–iron uptake. (A) In ascorbate-depleted cells, iron is released from holo-Tf in acidified endosomes and transported into the cytosol by divalent metal transporter 1 (DMT1)/Zip14 (Zrt- and Irt-like Protein 14, a metal-ion transporter involved in non-transferrin-bound iron uptake), entering the labile iron pool (LIP). (B) Intracellular ascorbate enhances Tf-dependent iron uptake, LIP size, and ferritin synthesis and storage via intracellular ferri reduction. Ascorbate may act directly or through endosomal ferrireductases, possibly by entering the endosome to facilitate iron release from Tf.

Ascorbate (Asc) enhances iron uptake through an intracellular reductive mechanism. Physiologic plasma levels of Asc can increase iron uptake from Tf by up to 100% in Asc-enriched cells, which is accompanied by a corresponding rise in cellular ferritin expression and ferritin-iron accumulation.⁶⁸ While Asc has been reported to elevate ferritin levels either by stimulating de novo synthesis⁶⁹ or by preventing ferritin autophagy⁷⁰ (as discussed later), studies have confirmed that neither of these processes accounts for Asc’s ability to enhance Tf-dependent iron uptake.⁶⁸ These findings reinforce the concept that ferritin itself does not directly participate in Tf-dependent iron acquisition but primarily functions as the main storage site for newly internalized iron. Ascorbate appears to enhance iron uptake at the level of Tf-cycle endosomes. To understand its role in stimulating Tf-dependent iron uptake, a comparative study was conducted to identify key differences between iron uptake from iron–citrate complexes and holo-Tf.⁶⁸ Unlike iron–citrate,71, 72, 73 iron uptake from Tf was found to be largely independent of both extracellular Asc’s reductive action and the extracellular release of iron from Tf.⁶⁸ Experiments using membrane-impermeable and membrane-permeable Asc-oxidizing reagents strongly indicated that Asc functions intracellularly to enhance Tf-dependent iron uptake.⁶⁸ Given that most biological functions of Asc rely on its reducing activity,74, 75 findings reported that its reducing enediol moiety was essential for stimulating iron uptake.⁶⁸

Inhibitors

On the other hand, inhibitors include phytates, which are present in whole grains and legumes and bind iron, forming insoluble compounds that limit its absorption. Polyphenols, found in tea, coffee, and cocoa, also reduce iron bioavailability by forming stable complexes with iron. Calcium, a major component of dairy products, competes with iron for intestinal absorption sites, further decreasing bioavailability.³⁵ Additionally, emerging research highlights the role of gut bacteria in iron metabolism, where beneficial microbes like Lactobacillus spp enhance iron solubility and absorption.³⁹

Iron transport and systemic distribution

Once iron enters the bloodstream, it binds to Tf, which facilitates its transport to various tissues. Most of the iron is directed to the bone marrow, where it is used in Hb synthesis for RBC production. Excess iron is stored in the liver, spleen, and bone marrow as ferritin or hemosiderin, preventing free iron toxicity. The body has no active mechanism for iron excretion, so iron balance is maintained through regulated absorption rather than elimination. Excessive iron accumulation, as seen in conditions like hemochromatosis, can lead to oxidative stress and tissue damage due to free radical formation.³⁸

Hepcidin regulation of iron homeostasis

Iron homeostasis is tightly controlled by hepcidin, a peptide hormone produced by the liver. When iron stores are sufficient or excessive, hepcidin levels increase, leading to the internalization and degradation of ferroportin, thereby reducing iron absorption and release from storage sites. Conversely, during iron deficiency, hypoxia, or increased erythropoiesis, hepcidin production is suppressed, allowing greater iron absorption and mobilization from stores. Dysregulation of hepcidin is implicated in several iron-related disorders, including IDA (low hepcidin) and iron overload disorders (high hepcidin).⁴⁰

Understanding the mechanisms governing iron bioavailability is essential for addressing IDA and optimizing dietary strategies. Improving dietary iron intake, enhancing absorption through bioavailability-promoting strategies, and minimizing inhibitory factors are crucial for effective anemia management and public health interventions. Given these complexities, integrating natural iron sources with bioavailability enhancers in value-added food products presents a promising strategy for combating IDA. The growing interest in natural iron sources, such as pumpkin seeds, stems from their superior bioavailability, added health benefits, and reduced side effects compared with synthetic iron supplements. Their immunomodulatory, anti-inflammatory, and gut health-enhancing properties make them a promising dietary intervention for anemia management. Future research should focus on developing functional foods incorporating pumpkin seeds to optimize iron intake and overall health outcomes.

Pumpkin Seeds—A Nutrient-Rich Alternative

Pumpkin has attracted increasing attention from scientists due to its nutritional profile. It is a nutritious and inexpensive food from the Cucurbitaceae family. Cucurbita pepo L., Cucurbita maxima Duchesne, and Cucurbita moschata Duchesne are widely harvested due to their cost-effective and eco-friendly features. Pumpkin is widely used in medicine for its anti-inflammatory, antioxidant, antiviral, and anti-diabetic effects in countries such as Austria, Hungary, Mexico, Slovenia, China, Spain, and various other European, Asian, and African nations. Pumpkins are farmed globally for their peel, flesh, and seeds. Seeds are typically big and contain significant levels of polyunsaturated and monounsaturated fatty acids. Pumpkin contains significant amounts of linoleic acid, oleic acid, palmitic acid, ECN-44, ECN-46, tocopherols, β-sitosterol, and δ-7-sterols.⁷⁶

Essential Micronutrients and Bioactive Compounds in Pumpkin Seeds

Pumpkin seeds (Cucurbita spp) are nutrient-dense, providing a variety of essential micronutrients critical for overall health and anemia prevention. Key nutrients include iron, zinc, magnesium, potassium, selenium, and phosphorus, each playing a distinct role in supporting physiologic functions, as represented in Figure 2. Pumpkin seeds possess a range of therapeutic properties that promote health and aid in managing various disease conditions.

Fig. 2.

Essential micronutrient, bioactive compounds, and medicinal properties of pumpkin seeds. CVD = cardiovascular disease.

Iron

A vital component of Hb and myoglobin, iron in pumpkin seeds supports oxygen transport in the blood and energy metabolism. A 100-g serving provides approximately 8.8 mg of iron, fulfilling about 49% of the recommended daily allowance (RDA) for adult men and 27% for women.⁷⁷ This makes pumpkin seeds a valuable source of iron, especially for individuals at risk of IDA, such as vegetarians and vegans.

Zinc

Essential for immune function, protein synthesis, and cell division, zinc plays a crucial role in erythropoiesis (RBC production). Pumpkin seeds provide about 7 to 9 mg of zinc per 100 g, covering a significant portion of the RDA for adults.⁷⁸ Zinc also influences the activity of enzymes like δ-aminolevulinic acid dehydratase, which are critical in the heme biosynthesis pathway.

Magnesium

Known as the “relaxation mineral,” magnesium is involved in over 300 enzymatic reactions, including those related to cellular energy production and DNA synthesis. Magnesium stabilizes RBC membranes and supports their production, contributing around 262 mg per 100 g, which meets about 62% of the RDA for adults.⁷⁹

Potassium

An essential electrolyte, potassium maintains fluid and acid–base balance, which indirectly supports healthy erythropoiesis. It also plays a key role in muscle function and cardiovascular health, ensuring efficient oxygen delivery to tissues.⁸⁰

Phosphorus

Vital for ATP formation, phosphorus supports energy production necessary for RBC formation and function. Additionally, pumpkin seeds contain small amounts of copper and manganese, which are essential for iron metabolism and antioxidant defense systems.

Bioactive Compounds and Their Health Benefits

Bioactive compounds discovered in pumpkin seeds, which are commonly considered agricultural trash, offer intriguing nutraceutical properties. Pumpkin seeds contain zinc, phosphorus, magnesium, potassium, and selenium, making them a nutritional powerhouse that can combat ailments such as arthritis and inflammation. Pumpkin seeds were often considered a waste of labor and resources, but their nutritional potential may now play an important part in food supply. They are safe to eat on a daily basis and do not have any negative impact on human health. These compounds include phytosterols, tocopherols, polyphenols, and essential fatty acids, which collectively contribute to their therapeutic potential (Table 3). A detailed view of the nutritional composition, bioactive profile, and health benefits of pumpkin bioactive compounds is shown in Table 3.

Table 3.

The nutritional composition, bioactive profile, and health benefits of pumpkin bioactive compounds.

S. no	Nutrition’s	Pumpkin seed		References
		Nutrition’s	Values
1.	Basic nutrition	Carbohydrates	3.45 g	80
		Lipids	15.82g
		Dietary fiber	1.94 g
		Proteins	9.75 g
2.	Minerals	Magnesium	190.92
		Iron	2.84
		Phosphorus	397.64
		Calcium	14.84
		Zinc	2.52
		Manganese	1.47
		Copper	0.43
		Potassium	260.90
3.	Vitamins	Vitamin C	0.0015
		Vitamin B1	0.61
		Vitamin B2	0.09
		Vitamin B3	0.05
		Vitamin B5	1.61
		Vitamin B6	0.24
		Vitamin B9	0.05

Phytosterols

Phytosterols, such as β-sitosterol, help reduce cholesterol levels and support cardiovascular health, which is essential for efficient oxygen transport in the blood.⁸¹ They also exhibit anti-inflammatory properties, which may help mitigate chronic inflammation associated with anemia of chronic disease.

Tocopherols (vitamin E)

Tocopherols act as potent antioxidants, protecting RBCs from oxidative damage caused by free radicals. This is especially beneficial in hemolytic anemia, where oxidative stress shortens RBC lifespan.⁸²

Polyphenols

Pumpkin seeds contain phenolic compounds, including flavonoids and phenolic acids, which exhibit strong antioxidant and anti-inflammatory activities. These compounds enhance vascular health and reduce oxidative stress, indirectly supporting erythropoiesis.⁸²

Essential fatty acids

Rich in omega-6 (linoleic acid) and omega-9 (oleic acid) fatty acids, pumpkin seeds support membrane integrity and fluidity in RBCs. These fatty acids also possess anti-inflammatory properties, which can improve overall blood health and reduce inflammation-related anemia.⁸³

Proteins and amino acids

Pumpkin seeds provide high-quality protein and essential amino acids such as lysine and arginine, which are critical for Hb synthesis and maintaining muscle mass, especially in anemic individuals experiencing fatigue and weakness.

Other compounds

Pumpkin seeds also contain carotenoids, saponins, and lignans, which contribute to their antioxidant capacity and potential to modulate immune responses. These properties make them beneficial for addressing anemia caused by infections or autoimmune conditions.

The combination of these nutrients and bioactive compounds positions pumpkin seeds as an exceptional dietary remedy for anemia. Their therapeutic potential, affordability, and availability make them an ideal candidate for dietary interventions targeting anemia prevention and management.

Impact of Pumpkin Seed Supplementation on Anemia

Enhancing iron absorption and bioavailability

Pumpkin seeds (Cucurbita spp) are an excellent source of nonheme iron, providing approximately 8.8 mg per 100 g, which is significant for addressing IDA, especially in individuals with restricted access to animal-based iron sources. Nonheme iron, while less bioavailable than heme iron, can be enhanced through dietary strategies. The natural oils and organic acids in pumpkin seeds create a favorable gastrointestinal environment that enhances iron absorption.⁸⁴ Additionally, pumpkin seeds contain compounds such as citric acid, which improve iron solubility, and amino acids such as histidine, which form complexes with iron, increasing its bioavailability.⁸⁵ Furthermore, pumpkin seeds have lower concentrations of phytates compared with other seeds, minimizing their inhibitory effect on iron absorption.⁸⁶ Combining pumpkin seeds with vitamin C-rich foods can further amplify iron absorption, making them an essential component of a diet for preventing and managing IDA.⁸⁷

Role of zinc and other micronutrients in hematopoiesis

Pumpkin seeds are rich in zinc, an essential trace element involved in regulating erythropoiesis (the production of RBCs). Zinc acts as a cofactor for numerous enzymes, including δ-aminolevulinic acid dehydratase, which is crucial in heme biosynthesis, and supports erythropoietin production, a hormone vital for RBC production.⁸⁸ Zinc also plays a role in stabilizing cell membranes and mitigating oxidative stress, ensuring the longevity of RBCs. Zinc deficiency impairs immune responses and disrupts hematopoietic processes, often leading to anemia. Supplementing zinc through pumpkin seeds can restore these processes and improve Hb levels.⁸⁹ Other micronutrients in pumpkin seeds, such as magnesium, copper, and phosphorus, further enhance hematological health. Magnesium facilitates energy production required for erythropoiesis by supporting ATP synthesis, whereas copper acts as a cofactor for enzymes like ceruloplasmin, which is critical for iron metabolism.⁹⁰ Copper deficiency can lead to secondary iron deficiency by impairing iron mobilization from storage sites. Phosphorus contributes to cellular energy storage and utilization, supporting RBC metabolism.⁹¹

Antioxidant properties and RBC protection

Pumpkin seeds are abundant in antioxidants, including vitamin E, polyphenols, carotenoids, and phytosterols, which protect RBCs from oxidative damage. Oxidative stress leads to lipid peroxidation of the RBC membrane, compromising its integrity and shortening the cell’s lifespan, a common issue in hemolytic anemia.

Vitamin E (tocopherols)

Pumpkin seeds contain tocopherols that neutralize free radicals, protecting RBCs from oxidative damage. This is particularly beneficial in conditions such as sickle cell anemia and β-thalassemia, where oxidative stress is a key factor in hemolysis.⁹²

Polyphenols and flavonoids

Polyphenolic compounds in pumpkin seeds, such as flavonoids and phenolic acids, enhance antioxidant defenses by scavenging reactive oxygen species.⁹² These compounds also exert anti-inflammatory effects, reducing systemic inflammation that often accompanies anemia of chronic disease.

Carotenoids

Carotenoids in pumpkin seeds enhance immune function and erythropoiesis by reducing inflammation and protecting hematopoietic stem cells from oxidative stress.⁹³

Essential fatty acids

Pumpkin seeds are rich in omega-6 and omega-9 fatty acids, which stabilize RBC membranes and prevent hemolysis by reducing lipid peroxidation. These fatty acids also improve the fluidity and functionality of the RBC membrane, optimizing oxygen transport.⁹⁴

Immunomodulatory and anti-inflammatory effects

Hakeem et al⁹⁵ studied the treatment with pumpkin seed oil significantly reduced parasite burden, achieving a 75% decline in adult worms and a 66% reduction in encysted larvae. Moreover, infected mice receiving pumpkin oil exhibited a notable decrease in intestinal inflammation, accompanied by a progressive increase in goblet cells. Additionally, pumpkin seed oil treatment substantially lowered MMP-9 (matrix metalloproteinase-9) levels in both intestinal and muscular tissues, demonstrating its potent anti-inflammatory properties. These findings highlight the therapeutic potential of pumpkin seed oil in mitigating parasitic infections and inflammation.⁹⁵ Bardaa et al⁹⁶ revealed that the pumpkin seed oils, possessing potent radical-scavenging properties, significantly enhanced superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities in carrageenan-induced skin inflammation by mitigating lipid peroxidation and protein oxidation (TBARS and AOPP). Their anti-inflammatory efficacy was strongly linked to both their antioxidant potential and bioactive constituents, including polyunsaturated fatty acids, vitamin E, and phytosterols. Notably, this study provides the first in vivo evidence of the anti-inflammatory effects of pumpkin, linseed, and prickly pear oils. These oils effectively modulated inflammatory mediators and oxidative stress markers in carrageenan-induced acute inflammation. Their dual action antioxidant and anti-inflammatory highlights their therapeutic significance.⁹⁶ According to Dong et al⁹⁷ oleic acid ester of hydroxy oleic acid (OAHOA), which can be extracted from pumpkin seeds, has anti-inflammatory properties by dose-dependently inhibiting dendritic cells from secreting interleukin (IL)-12, IL-1β, and tumor necrosis factor-α in response to lipopolysaccharide (LPS). Compared with OA and LOA, OAHOA found the strongest reduction of IL-12 and a moderate inhibitory effect on tumor necrosis factor-α among the substances studied. Because lower blood levels of OAHOA have been seen in obesity and insulin resistance, it is also linked to insulin sensitivity. OAHOA may use GPCR signaling pathways to activate its anti-inflammatory actions by acting as a GPR120 ligand. OAHOA level variations may provide new therapeutic potential for the treatment of inflammatory and metabolic diseases. To investigate further anti-inflammatory actions of pumpkin seed components, more research into the isomers of OAHOA is important (Figure 3).⁹⁷

Fig. 3.

Anti-inflammatory effect of pumpkin seed. IL = interleukin; TNF-α = tumor necrosis factor-α. MMP-9 (matrix metalloproteinase-9), SOD (superoxide dismutase), CAT (catalase), and GPx (glutathione peroxidase) are antioxidant enzymes. LPS (lipopolysaccharide) is a component of the outer membrane of Gram-negative bacteria that induces strong inflammatory responses.

Gut health and microbiota modulation

Recent studies reported the effect of pumpkin seeds in the modulation of gut microbiome and gut health. Agarkova et al⁹⁸ found that the prebiotic effect of commercial and experimental mouse samples was studied in male Wistar rats with antibiotic-induced dysbiosis, using untreated rats as an intact control. After antibiotic treatment, the negative-control group received only water, whereas the experimental groups received commercial or experimental mouse samples. Antibiotic treatment caused a decrease in Lactobacillus spp and Bifidobacterium spp populations. Compared with the intact control, Lactobacillus spp decreased by 2.2 times and Bifidobacterium spp decreased by 9 times (P < 0.01). Both mouse samples increased Lactobacillus spp counts to (5.0 ± 0.7) × 10⁸ and (5.6 ± 0.4) × 10⁸ CFU/g, compared with (4.0 ± 0.4) × 10⁸ CFU/g in the negative control. The experimental mouse increased Bifidobacterium spp by 3.7 times, whereas the commercial mouse had no such effect. A significant bifidogenic effect was observed in the mouse containing whey protein hydrolysate and pumpkin pectin.⁹⁸ Wu et al⁹⁹ study reported that whey protein concentrate peptides (W-CPP) and rice protein peptides (RPPs) exhibited significant functions with free radical scavenging and significant inhibitory effects on α-glucosidase and α-amylase. RPP-3 specifically inhibited glucose uptake in the Caco-2 monolayer and promoted glucose excretion, whereas RPP-2 had no inhibitory effect. In the animal experiment, W-CPP treatment significantly enhanced type 2 diabetes mellitus symptoms in mice by decreasing fasting blood glucose, reducing insulin resistance, and lowering blood lipid levels. Also, it enhanced the diversity of intestinal flora while eliminating the populations of harmful bacteria, including Clostridium, Thermoanaerobe, Symbiotic bacteria, Deinococcus, Vibrio haematococcus, Proteus gamma, and Corio. At the family level, treatment with W-CPP (1200 mg/kg) significantly decreased the abundance of Erysipelotrichaceae, while Akkermansia developed as a biomarker. The findings indicate that pumpkin polysaccharides altered the intestinal flora, leading to enhancements in blood glucose and lipid metabolism in type 2 diabetes mellitus mice (Figure 4).⁹⁹

Fig. 4.

Effects of pumpkin seed on gut health and microbiota modulation.

The optimized pumpkin polysaccharide extraction was used in in vitro digestion, showing a significant decrease in polysaccharide molecular weight after 30 minutes of gastric digestion due to glycosidic bond breakdown, while intestinal fluid had little effect within 240 minutes. Biodistribution analysis in mice revealed that polysaccharides appeared in the duodenum, jejunum, and ileum within 30 to 60 minutes. Absorption occurred mainly in the jejunum and ileum between 60 and 360 minutes. These findings enhance the understanding of digestion, absorption, and biodistribution of pumpkin polysaccharides.¹⁰⁰

Conclusion

Anemia remains a significant global health concern, particularly among women, children, and populations in low- and middle-income countries, including India. The multifactorial etiology of anemia necessitates a comprehensive approach to its management, incorporating nutritional interventions, iron supplementation, and strategies to address parasitic infections and chronic diseases. The high prevalence in rural and socioeconomically disadvantaged communities highlights the critical need for targeted interventions, particularly for adolescent girls and women of reproductive age. Emerging research underscores the importance of nutrient-dense foods such as pumpkin seeds, which are rich in essential micronutrients such as iron, zinc, magnesium, and bioactive compounds that support hematopoiesis and overall health. Leveraging the therapeutic potential of these natural alternatives, alongside fortified food programs and precise monitoring methods, can significantly contribute to anemia reduction and improve public health outcomes.

Funding

The authors state that the work presented in this article received no associated funding.

CRediT authorship contribution statement

Andugula Swapna Kumari: Conceptualization, Formal analysis, Investigation, Writing – original draft. Gowrishankar Arumugam: Conceptualization, Writing – review & editing, Supervision, Project administration. Shyamaladevi Babu: Conceptualization, Writing – original draft, Writing – review & editing, Supervision, Project administration. Madhan Krishnan: Data curation, Formal analysis, Investigation. Nohini Sandhya Singampalli: Data curation, Writing – review & editing. Jayanthi Chandramohan: Writing – review & editing.

Declaration of competing interest

The authors declare no conflicts of interest and assume sole responsibility for both the content and the writing of the article.