Metabolic syndrome (MetS) is a condition characterized by a clustering of metabolic risk factors. It is defined by the World Health Organization as a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia (1). Given its high prevalence and severe consequences, MetS has become a global problem, placing a huge economic burden on societies and health systems in the future (2–5).

However, women with MetS bear a greater health burden. Studies show that females have a higher prevalence of MetS than men (5), and female patients tend to experience more severe symptoms than males (6, 7). Previous research suggests that MetS in middle-aged females may contribute to or exacerbate pain, sleep disturbances, sexual dysfunction, and mood alterations, likely due to aging and chronic inflammation (8). A systematic review and meta-analysis further revealed that MetS in females is associated with an increased risk of several malignancies, including endometrial, pancreatic, and breast cancers. The strongest associations were seen in sex-specific cancers like endometrial cancer and postmenopausal breast cancer (6). Remarkably, postmenopausal females with MetS have a twofold higher risk of developing breast cancer than those without MetS (8).

Evidence indicates that females with MetS experience more severe symptoms than men, possibly due to sex-related hormonal factors. Estrogen plays a crucial role in modulating inflammation and metabolic homeostasis in females (9, 10). It regulates insulin resistance (11), energy metabolism (12), and lipid metabolism (13, 14). The hormone exhibits dual functionality in oxidative stress regulation, providing antioxidant protection through receptor-mediated mechanisms (15), while also orchestrating cellular defense systems against oxidative damage (16). Pathologically, the chronic inflammation and oxidative stress characteristic of MetS are well-established contributors to carcinogenesis (8, 15). Recent studies suggest that ERα-mediated mitochondrial energy regulation represents a key pathway underlying estrogen’s metabolic protective effects (16). However, the postmenopausal decline in estrogen levels promotes macrophage infiltration in adipose tissue, worsening insulin resistance via TNF-α/IL-6-JNK pathway activation (17).

Estrogen fluctuations, mediated through cyclic variations in nuclear receptor ERRα-regulated mitochondrial biogenesis (18), constitute an inherent physiological characteristic in females. Targeting the menopausal decline in estrogen through dual strategies—suppressing NADPH oxidase activity to mitigate oxidative stress while enhancing endogenous antioxidant defenses (e.g., superoxide dismutase (SOD) and catalase)—may effectively reduce the risk of MetS (19). Therefore, antioxidant protection may yield significant benefits for females with MetS, offering greater preventive value than treatment alone. Mechanistically, oxidative stress drives MetS pathogenesis via NF-κB-mediated inflammation (20), insulin signaling disruption, and adipocyte dysfunction (21). Several studies have confirmed the role of dietary antioxidants in counteracting oxidative stress (22–25). For instance, serum levels of carotenoids, particularly α and β-carotene, as well as retinyl esters, exhibit an inversely association with MetS (26). Additionally, abnormal vitamin A metabolism contributes to damage and plays a key role in MetS in a gut microbiota-dependent manner (27) while dietary vitamin E levels are inversely correlated with MetS (28, 29).

Therefore, mitigating oxidative stress may represent a viable preventive and therapeutic approach for managing metabolic syndrome (MetS) in female populations. Notably, while previous investigations predominantly focused on isolated antioxidant components, emerging evidence underscores the critical role of holistic dietary patterns in modulating oxidative-inflammatory pathways (30). The Comprehensive Dietary Antioxidant Index (CDAI), a validated metric reflecting synergistic antioxidant capacity, was developed based on its cumulative inhibitory effects on pro-inflammatory mediators, including tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). Its integrates quantitative assessments of multiple dietary antioxidants—vitamins A, C, and E, alongside manganese (Mn), selenium (Se), and zinc (Zn), etc., thereby providing a comprehensive characterization of individual antioxidant profiles (31), and has been applied in several studies (32–34).

Despite emerging evidence suggesting a non-linear association between MetS and the CDAI, critical knowledge gaps remain (35). Existing studies only found sex-specific differences in association between MetS and CDAI (36), and the stratified regression analyses indicate CDAI-MetS associations may be unique to female populations. However, the biological mechanisms underlying this sexual dimorphism, particularly the potential mediating role of estrogen in modulating antioxidant-metabolic interactions, remain inadequately explored. Since antioxidant supplements have shown no effect on MetS prevention, this study focused on dietary antioxidants (excluding supplements) to better reflect real-world nutritional exposures. In summary, this study aimed to quantify the CDAI-MetS association in females and investigate the role of estrogen in this relationship.

Global epidemiological data reveal a striking female preponderance in MetS, affecting over 500 million females worldwide (4, 5, 37). This disparity may stem from estrogen’s role in redox regulation, as estrogen deficiency elevates oxidative stress and inflammation—canonical drivers of metabolic dysregulation (38–40). More critically, estrogen deficiency disrupts the estrogen-antioxidant crosstalk, a novel mechanism identified in this study. Our investigation elucidates a critical interplay between CDAI and estrogenic status in modulating MetS risk among females. We identified a robust inverse association between CDAI and MetS prevalence, characterized by a biphasic dose–response relationship with an inflection point at CDAI = 1.99. Crucially, estrogen status significantly modified this relationship, with higher estrogen levels enhancing the protective capacity of CDAI. These findings underscore the necessity of optimizing antioxidant intake during premenopausal phase to maximize metabolic protection.

MetS is characterized by a heightened pro-oxidative and pro-inflammation (41). Oxidative stress arises owing to an imbalance between the synthesis of antioxidants and pro-oxidants, causing harm to tissues and organs. It primarily results from excessive levels of reactive oxygen species (ROS), which cause damage to damage macromolecules such as DNA, lipids, proteins, and carbohydrates (42, 43). As an extrinsic factor, diet can affect the plasma redox status by reducing ROS and reactive nitrogen species (44). The CDAI serves as an integrative measure of dietary antioxidant vitamins/minerals, indicating the antioxidant potential of individual dietary sources. We analyzed both the individual components of the CDAI and the index as a whole. In separate analyses, no single dietary component was significantly associated with MetS prevalence (p > 0.05), a finding that contrasts with previous studies (45). This may be due to the differences in the cohort samples of our study, which was conducted on females only, and previous population-wide studies. However, when considering the CDAI as a whole, we observed a significant downward trend in MetS prevalence across increasing CDAI quartiles (p < 0.001). The risk of MetS in females decreased significantly with higher CDAI levels, and females in the highest quartile (OR [95% CI] = 0.62[0.49, 0.77], p < 0.001) of the CDAI had an approximately 28% lower risk of MetS than those in the lowest quartile. This is consistent with previous population-wide studies, and such an association was also present in female patients (35, 36, 44). Our analyses revealed a nonlinear association between the CDAI and MetS, with an inflection point identified at 1.99 through threshold effect modeling. Below this critical threshold, each unit increase in CDAI conferred a 2.0% absolute risk reduction (p < 0.001), whereas supra-threshold increments attenuated this protective to 1.0% per unit (p = 0.001), suggesting a biological ceiling effect of dietary antioxidants. In previous studies, a dose–response trend similar to that in our study was observed (36). Therefore, we hypothesized that a high intake of dietary antioxidants and phytochemicals may reduce the risk of developing MetS in females because the combined intake of dietary antioxidants reduces oxidative stress. Intake of exogenous antioxidants can improve patient quality of life by preventing oxidative imbalance and maintaining a stable biochemical redox state (46), thereby avoiding the deleterious effects of chronic oxidative stress in the human body (47). According to a previous study, daily intake of antioxidants can enhance antioxidant defense and mitigate oxidative stress by increasing plasma antioxidant levels (48).

Oxidative stress exhibits sex-related differences, with estrogen conferring protection against its detrimental effects in females (49, 50). This hormonal regulation plays a pivotal role in modulating the protective association between dietary antioxidants (assessed via CDAI) and MetS in females. Estrogen regulates redox homeostasis through multiple molecular mechanisms, including: upregulating the expression of endogenous antioxidant enzymes (51), binding to mitochondrial estrogen receptors to enhance antioxidant defense (52), and suppressing reactive oxygen species (ROS) generation by inhibiting NADPH oxidase activity (52). Epidemiological studies indicate that the prevalence of MetS increases with age (53), a phenomenon largely driven by age-related exacerbation of oxidative stress driven by either excessive ROS production or impaired antioxidant systems (54).

In our study, the mean age of females without MetS was 43.49 ± 16.04 years, significantly lower than that of females with MetS (54.77 ± 15.52 years; p < 0.001). This age disparity aligns with epidemiological evidence showing a higher prevalence of MetS in postmenopausal populations (53, 55). Mechanistically, menopause typically occurs between 45 and 55 years (55), and the subsequent decline in estrogen levels exacerbates oxidative stress and systemic inflammation (38, 39). Estrogen deficiency disrupts redox homeostasis, leading to progressive accumulation of oxidative damage markers (56, 57), which in turn promotes endothelial dysfunction—a key contributor of insulin resistance, hypertension, and dyslipidemia (45, 57). These pathological alterations collectively drive MetS development in aging females.

Meanwhile, our study confirmed this finding, demonstrating a significant downward trend in MetS prevalence with increasing estrogen levels. Regression analysis further revealed that high levels of estrogen exerted a protective effect against MetS (OR[95% CI] = 0.30[0.22, 0.38], p < 0.001). This protective role may be attributed to the loss of estrogen is associated with a diminished defense against oxidative stress (58). The oxidative stress has a pivotal role in some components of MetS, including abdominal obesity, hypertension, insulin resistance, and dyslipidemia (44, 59–61).

This was the first large-sample study to investigate the association between the CDAI and MetS in females, while also considered the role of estrogen. Our findings provide epidemiological evidence supporting the implementation of preemptive nutritional strategies aimed at optimizing composite dietary antioxidant optimization during the estrogen depletion phase (specifically the premenopausal transition window) as a prophylactic measure against MetS development. A public health priority for the prevention of disease is consuming an optimal diet that can reduce or suppress inflammation owing to its composition and thereby modulate the risk of various diseases (62). As a new paradigm in the prevention and treatment of MetS, dietary interventions should include advice on antioxidant-rich diets given by nutritional professionals as well as increased promotion of these diets and specific antioxidant dietary modifications for menopausal females. Increased dietary intake of vitamins A, C, and E together with selenium, zinc, and carotenoid-rich foods may improve the current status of MetS among females globally.

This study benefits from methodological rigor through utilization of the nationally representative NHANES sampling framework and comprehensive adjustments for established demographic, anthropometric, and metabolic covariates, enhancing internal validity. Notwithstanding these strengths, several methodological constraints warrant consideration: (1) The observational cross-sectional design precludes temporal sequence determination and causal inference; (2) Sex-specific analytic focus limits external validity to male populations; (3) The moderate sample size relative to population-level epidemiological standards constrains statistical power for detecting modest effect sizes; (4) Potential residual confounding persists despite multivariable adjustments, including unmeasured lifestyle determinants (e.g., chrononutrition patterns, physical activity gradients) and epigenetic regulatory mechanisms influencing redox homeostasis.