Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia that persists over time as a consequence of insufficient insulin secretion, improper insulin action, or a combination of both. As such, it accounts for several diseases, including cardiovascular disease, neuropathy, retinopathy, and nephropathy. The international burden of diabetes has been worsening with projections estimating approximately 830 million diabetes cases in 2022, with a disproportionate focus on low- and middle-income countries ( World health organization, 2024). Diabetes can be classified as Type 1 diabetes, which is an autoimmune condition that results in the destruction of the pancreatic β-cells, and, Type 2 diabetes, which occurs after a person has developed insulin resistance and β-cell dysfunction ( American Diabetes Association, 2023). Currently treatment remains focused on drugs, primarily metformin and insulin, but the adverse effects, expenditure, and adherence problems have increased the attention towards alternative drugs developed from natural resources ( Mooradian et al., 2022).

Some of the natural plants investigated for their anti-diabetic properties include the members of the Cucurbitaceae family like, Cucurbita máxima, Cucurbita ficifolia, and Cucurbita moschata. These plants have bioactive compounds such as phenolics, flavonoids, polysaccharides, cucurbitacins which have hypoglycemic, antioxidant and anti-inflammatory activities ( Suwannapong et al., 2023). For instance, some preclinical studies showed that extracts of Cucurbita ficifolia activated peroxisome proliferator-activated receptors (PPARs) that control lipid and glucose metabolism resulting in significant reduction of blood glucose levels streptozotocin induced diabetic mice ( Rojas et al., 2021). In the same way, some extracts of Cucurbita maxima have been shown to regenerate pancreatic β-cells and augment insulin secretion in alloxan diabetic rats ( Mujtaba et al., 2022). This is the reason why these plants should be investigated further for their potential use in diabetes management.

Alongside their hypoglycemic effects, members of the Cucurbita genus demonstrate the ability to counter oxidative stress, which is a diabetes complication, through strong antioxidant activity. For example, a study conducted on the extracts of Cucumis sativus and Cucurbita maxima found that these extracts were successful in reversing the diabetic rats’ liver and pancreas functionality and normalizing the oxidative stress parameters ( Suwannapong et al., 2023). Moreover, cucurbitacins, a subclass of triterpenes belonging to the family of Cucurbitaceae plants, have been reported to possess insulin-like activity by increasing glucose utilization and the insulin sensitivity ( Bhatti et al., 2021). These multifaceted effects suggest that Cucurbita plants could serve as valuable alternatives to conventional diabetes therapies.

This systematic review intends to scrutinize their mechanisms of action and evaluate therapeutic possibilities and translational avenues by analyzing abundant preclinical studies that verify the anti-diabetic activity of Cucurbita species. By bringing together the findings of recent studies, this review intends to clarify how these plants may be useful in the management of diabetes. Moreover, it points out the insufficiencies of research that need to be conducted to enable the use of these promising natural products in clinical settings.

Results from this systematic review are presented in Tables 1, 2 and Figures 1– 6 below. Figure 1 illustrates the various plant parts of Cucurbita species that were utilized across the included studies for anti-diabetic research. Parts used include: Seeds, Fruit pulp, Leaves, Flowers, and Juice. This reflects the versatility of Cucurbita plants, indicating that multiple parts contain bioactive compounds with potential therapeutic effects against diabetes. Figure 3 shows the specific species of Cucurbita evaluated in the review, which include: Cucurbita maxima, Cucurbita moschata, Cucurbita pepo, and Cucurbita ficifolia. Cucurbita maxima and Cucurbita moschata were the most frequently studied species, indicating their prominence in traditional medicine and potential pharmacological interest.

Table 1 reveals that Cucurbita species possess multiple bioactive compounds with diverse therapeutic effects targeting key pathophysiological aspects of diabetes. The hypoglycemic activity is mediated by stimulating insulin secretion, pancreatic regeneration, antioxidant defenses, and improvement in lipid metabolism. The widespread geographical focus of studies underpins the global relevance and ethnobotanical value of Cucurbita plants in managing diabetes. Table 3 summarizes the experimental protocols of Cucurbita species in diabetes management. Most studies used oral administration of aqueous or ethanol extracts over 2–4 weeks, with doses ranging from 50 mg/kg to 1 g/kg. Streptozotocin was the most common diabetes-inducing agent, while glibenclamide was frequently used as the standard control drug. Rats, particularly Wistar and albino strains, were the predominant animal models. The findings confirm the hypoglycemic potential of Cucurbita species, acting through insulin stimulation, antioxidant effects, and pancreatic protection, supporting their ethnomedicinal use in diabetes management. Figure 4 summarizes mechanisms such as: enhancement of antioxidant enzymes (SOD, CAT, GSH, GR), reduction of oxidative stress markers (MDA), insulin secretion and pancreatic regeneration, lipid profile improvement (lowering LDL, triglycerides), liver enzyme reduction (ALT, AST, ALP). A multi-target approach in diabetes management using Cucurbita species enhances therapeutic outcomes by addressing hyperglycemia, oxidative stress, and lipid metabolism.

Figure 5 illustrates the route of administration. The majority of the included studies administered Cucurbita extracts orally, reflecting the traditional usage and potential for formulation into oral therapeutics. One study employed intraperitoneal (IP) administration. The oral route’s predominance supports its feasibility in human therapeutic applications. Figure 6 summarizes the geographical spread of studies. This figure illustrates a global distribution of research, with notable contributions from: Asia (India, China, Thailand, Iraq, Indonesia), Africa (Egypt, Kenya), South America (Mexico), the Middle East (Iran, Jordan), and Southeast Asia (Vietnam). The wide geographical distribution indicates the global recognition of Cucurbita species as potential anti-diabetic agents. Figure 7 shows the types and numbers of standard Anti-diabetic drugs used. This depicts the various standard anti-diabetic drugs used in comparison across studies, including: Glibenclamide, Metformin, Acarbose, Chlorpropamide and Xiaoke pill (herbal standard). Most studies used glibenclamide as the standard control drug, enabling a comparative evaluation of Cucurbita’s efficacy against established pharmacological agents.

This systematic review provides robust preclinical evidence that various species and parts of the Cucurbita plant possess significant anti-diabetic properties. These effects are mediated through multiple mechanisms, including hypoglycemic activity, antioxidant defense, pancreatic regeneration, and lipid profile modulation. The studies span a wide geographical range, highlighting global interest. Oral administration remains the predominant route, enhancing the clinical translatability of these findings.

Phytotherapy has continued to expand as a readily available and cost-effective management strategy for different diseases worldwide. In this study, the findings highlighted in Figures 1 and 2 present critical insights into the phytomedical use of Cucurbita species in diabetes management. Our study showed diverse plant parts, including seeds, fruit pulp, leaves, flowers, and juice, were used, underscoring the botanical versatility of the genus Cucurbita ( Kushawaha et al., 2017; Yang et al., 2024). Similarly, this broad spectrum of plant parts suggests a widespread distribution of bioactive phytochemicals throughout the plant architecture ( George & Brandl, 2021). According to our findings, such compounds may include flavonoids, polyphenols, saponins, alkaloids, and polysaccharides, many of which have been previously reported to exhibit antidiabetic properties through mechanisms like insulin sensitization, β-cell protection ( Kadhum et al., 2020), inhibition of carbohydrate-hydrolyzing enzymes, and modulation of oxidative stress ( Atta et al., 2020). Additionally, the predominance of Cucurbita maxima and Cucurbita moschata in the reviewed literature reflects their established role in ethnomedicine and greater accessibility in various cultures ( Lu et al., 2019; Farid et al., 2015; Agu et al., 2022). This pattern may also be influenced by their favorable agronomic traits, nutritional value, and broader commercial availability, which make them more attractive for preclinical investigation. Importantly, both species have demonstrated diverse pharmacological actions in diabetic models, reinforcing their candidacy for further translational research and potential development into phytotherapeutic agents. Furthermore, these findings support the rationale for exploring multiple Cucurbita species and plant parts in preclinical diabetes research and emphasize the importance of a holistic phytochemical profiling approach. However, comparative studies that directly evaluate the antidiabetic efficacy of different parts and species under standardized conditions remain sparse and are warranted to guide evidence-based selection for clinical translation.

One of the interests in phytotherapy research is to elucidate the molecular mechanisms of action. In this study, the evidence presented in Table 1 and summarized in Table 2 and Figure 6 robustly affirms the multi-targeted antidiabetic mechanisms of Cucurbita species, substantiating their longstanding use in traditional medicine. According to the available data, the convergence of bioactivity across multiple studies reveals a complex pharmacodynamic profile, with extracts from Cucurbita plants mediating therapeutic effects through both pancreatic and extra-pancreatic pathways ( Suwannapong et al., 2023). Notably, the stimulation of insulin secretion and pancreatic β-cell regeneration suggests the presence of insulinotropic agents within Cucurbita phytoconstituents ( Rorsman and Ashcroft, 2018). This effect is particularly significant in type 1 and late-stage type 2 diabetes models, where β-cell integrity is compromised. Similarly, the improvement in lipid profiles and reduction of hepatic enzymes further indicate systemic metabolic benefits, reinforcing the potential of Cucurbita in managing diabetic dyslipidemia and hepatopathy, which are common comorbidities in poorly controlled diabetes ( Atta et al., 2020). Additionally, the upregulation of endogenous antioxidant enzymes (SOD, CAT, GSH, GR) and suppression of lipid peroxidation marker MDA suggest that Cucurbita extracts confer substantial oxidative stress mitigation ( Elsadek et al., 2024). Invariably, this is especially relevant given the critical role of oxidative stress in the pathogenesis and progression of diabetes and its complications ( Agu et al., 2023a). Again, the multi-target nature of Cucurbita bioactivity, spanning glycemic control, oxidative defense, hepatic protection, and lipid modulation, aligns well with the modern paradigm of polypharmacology in chronic disease management.

From a methodological perspective, as observed in this study, the use of streptozotocin (STZ) to induce diabetes reflects a well-established model for replicating β-cell destruction and mimicking human diabetic pathology ( Kushawaha et al., 2017; Yang et al., 2024). The frequent use of glibenclamide as a standard drug control reinforces the credibility of comparative efficacy assessments ( Njoki et al., 2024). However, variability in extract preparation, dose ranges (50 mg/kg to 1 g/kg), and treatment duration (2–4 weeks) may introduce heterogeneity, underscoring the need for standardized protocols in future investigations. Furthermore, geographical diversity in the studies extracted further emphasized the trans-cultural relevance of Cucurbita in diabetes management, supporting its candidacy for global ethnopharmacological development ( Suwannapong et al., 2023). Therefore, these findings collectively advocate for advancing Cucurbita species into more rigorous pharmacokinetic, toxicological, and eventually clinical evaluations.

In this study, we observed an overwhelming preference by researchers for oral administration of Cucurbita extracts ( Figure 6 and Table 3). This mirrors traditional ethnomedicinal practices and is pharmacologically significant. For instance, oral administration not only ensures ease of delivery and patient compliance but also suggests that the bioactive constituents of Cucurbita are sufficiently stable to survive gastrointestinal conditions and reach systemic circulation in biologically active forms. We maintained that this enhances the plausibility of transitioning these extracts or their active fractions into standardized oral formulations, such as capsules, teas, or nutraceutical supplements ( Agu et al., 2023b). Additionally, the solitary use of the intraperitoneal route, while less relevant for human therapy, may have been employed for mechanistic or absorption-focused studies, but does not detract from the overarching translational value demonstrated by the oral route dominance ( Al Shoyaib et al., 2019).

Furthermore, as shown in Figure 6, a geographically diverse body of literature from Asia, Africa, South America, the Middle East, and Southeast Asia suggests Cucurbita’s global ethnobotanical prominence and research appeal ( World Health Organization, 2024). This broad-based validation points to a rich cross-cultural heritage of therapeutic use. It also suggests ecological and biochemical variability within Cucurbita species that may influence their phytochemical profiles and, consequently, their therapeutic effects. This is a compelling argument for comparative ethnopharmacological studies that examine regional chemovariants and their specific bioactivities. Another interesting observation in Figure 7 was the comparative use of standard antidiabetic agents, most notably glibenclamide, and others like metformin, acarbose, chlorpropamide, and the Xiaoke pill. This multi-standard framework allows for a nuanced benchmarking of Cucurbita’s efficacy across pharmacological classes: sulfonylureas (glibenclamide, chlorpropamide), biguanides (metformin), α-glucosidase inhibitors (acarbose), and polyherbal formulations (Xiaoke pill) ( Spengler et al., 1992; Marre et al., 2002; Mujtaba et al., 2022). We suggest that the repeated use of glibenclamide enhances interpretability across studies, as it serves as a well-characterized reference with known insulinotropic effects ( Garber et al., 2006). Therefore, Cucurbita extracts exhibit comparable or complementary effects to these standards in many studies, indicating their strong pharmacological promise.

This systematic review has provided compelling preclinical evidence that Cucurbita species possess significant antidiabetic potential through a multi-targeted mechanism involving insulin secretion, pancreatic regeneration, antioxidant enhancement, lipid profile improvement, and hepatic protection. Additionally, the use of various plant parts, most commonly administered orally, and the widespread global investigation across diverse geographic regions underscored the ethnomedicinal relevance and translational feasibility of Cucurbita-based phytotherapies. Furthermore, comparative efficacy against standard antidiabetic drugs further validates their pharmacological promise. Collectively, we propose that these findings support the advancement of Cucurbita species into standardized formulations and clinical studies as complementary or alternative agents in diabetes mellitus management.