Gastric cancer (GC) is the fifth most prevalent malignancy globally and stands as the fourth leading cause of death. Particularly, the prevalence of GC is high in Asian countries, including South Korea [1]. Several previous studies consider Helicobacter pylori (H. pylori), male sex, diet, smoking, and alcohol as risk factors for GC [2-5]. Metabolic syndrome (MetS) was initially defined by Reaven in 1988 and has since been recognized as a set of risk factors associated with cardiovascular diseases [6]. These factors include hypertension, dyslipidemia, insulin resistance, glucose intolerance, and abdominal obesity. The World Health Organization established the initial diagnostic criteria for MetS [7]. MetS is a condition defined by the presence of a minimum of three out of five factors., including abdominal obesity, elevated triglyceride (TG), decreased high-density lipoprotein cholesterol (HDL-C), hypertension, and higher fasting glucose (Table 1) [8]. Recognized as a universal and serious health concern worldwide, MetS poses a significant risk to individuals’ health [9]. Based on the Korea National Health and Nutrition Examination Survey, criteria for abdominal obesity in Korean adults were established. The Korean Society for the Study of Obesity referenced a study from the 1998 survey and set the waist circumference (WC) cutoff at ≥90 cm for males and ≥85 cm for females [10]. The prevalence of MetS in South Korea has been steadily increasing, rising from 24.9% in 1998 to 29.2% in 2001, 30.4% in 2005, and reaching 31.3% in 2007 [11]. MetS and its components have been shown to increase the incidence of various types of cancer, including pancreatic [12,13], small intestine [14], colorectal [15-19], breast [20,21], and liver cancer [22,23]. The research results regarding the connection between MetS and cancer mortality rates are particularly fascinating. In a study that delved into the relationship between MetS and cancer mortality, involving 33,230 males aged 20 to 88, it was discovered that 28% of the participants exhibited signs of MetS [24]. During an average observation period of 14 years, 685 participants faced mortality due to cancer, and the presence of MetS correlated with a 56% higher risk of cancer-related death [24]. In 2012, a meta-analysis was published reporting the association between various types of cancer, such as liver, colorectal, and bladder cancers, and MetS [25]. Particularly in males, a correlation was observed with colorectal, bladder, and liver cancers. In females, associations were identified with pancreatic, postmenopausal breast, endometrial, and colorectal cancers [25]. The relationship between MetS and GC has garnered increasing interest, driven by numerous studies exploring the complex mechanisms and associations. Such clinical research involves various designs including case series, prospective, retrospective cohort studies, case-control, and cross-sectional, each with its own strengths and limitations [26], thus requiring careful consideration by clinicians for application in real-world clinical practice. This review explores various aspects of this complex relationship, including the role of MetS in GC.

MetS has connections to diverse types of cancers, and each specific risk factor contributing to MetS is also linked to the development of cancer [27]. As previously mentioned, MetS is a conglomerate of various risk factors, with abdominal adipocytes, particularly situated in the abdominal region, emerging as crucial contributors to cancer development [28]. Additionally, it includes insulin-like growth factor (IGF-I), estrogen signaling, hyperinsulinemia, hyperglycemia, and inflammation [28]. Located mainly in the abdominal region, these cells centrally contribute to malignancy by releasing inflammatory cytokines such as tumor necrosis factor-α and interleukin-6, along with hormones like leptin, thereby fostering the development of malignant tumors [29]. Specifically, leptin, a key player in this intricate interplay, is implicated in promoting neoplastic transformations, cancer cell proliferation, and the facilitation of tumor vasculature [29,30]. Abdominal adipose tissue serves as a significant site for estrogen production, particularly influencing cell proliferation, differentiation, and apoptosis in males and postmenopausal females [28,31]. The interplay among MetS, insulin resistance, and hyperinsulinemia establishes an environment favorable to cancer cells, characterized by increased levels of growth factors, adhesion factors, and inflammatory cytokines [28]. Furthermore, increased blood glucose are associated with the risk of various types of cancer [32]. Diverse mechanisms underlie the association between MetS and cancer. In this review, I will systematically unravel how this applies to GC and explore if there are additional factors that can explain the relationship between GC and MetS (Table 2).

GC can be divided based on location into cardia GC and non-cardia GC. Recent advancements have been achieved through epidemiological studies examining environmental risk factors for GC. Cardia GC exhibits potential connections with gastroesophageal reflux, white ethnicity, male sex, and smoking [33], Conversely, the predominant factors contributing to non-cardia GC include H. pylori infection [34], the intake of salt-preserved foods [35], and alcohol abuse [36]. In a meta-analysis assessing the correlation between GC incidence and body mass index (BMI), elevated BMI demonstrated a positive association with the risk of cardia GC [37]. However, there was no significant association observed with non-cardia GC [37]. In the meta-analysis, obesity (BMI ≥30 kg/m²) exhibited an elevated risk (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.03–1.24) for GC compared to individuals with normal weight (BMI 18.5–25 kg/m²), whereas overweight individuals (BMI 25–30 kg/m²) did not show a statistically significant association [38]. Based on the location of GC, both overweight (OR, 1.22; 95% CI, 1.05–1.42) and obesity (OR, 1.61; 95% CI, 1.15–2.24) were correlated with an elevated risk for cardia GC [38]. Among the proposed hypotheses regarding the correlation between obesity and cardia GC, the reflux theory holds widespread acceptance. Obesity is suggested to contribute to the development of gastroesophageal reflux disease by elevating intra-abdominal pressure [39].

In addition, there have been reports that approached the perspective of sex and WC. In a previous study, higher WC (relative risk [RR], 1.48; 95% CI, 1.24–1.78) was significantly associated with increased risk of total gastroesophageal cancer [40]. Notably, the association is pronounced in cardia GC, displaying a positive correlation with WC. However, the link with non-cardia GC does not reach statistical significance. This nuanced observation suggests that the impact of WC on GC risk may vary depending on the anatomical location of the cancer. In line with this, a case-control study nested in the General Practitioner Research Database in the United Kingdom indicates that being overweight (BMI >25 kg/m²) is positively linked with esophageal adenocarcinoma (OR, 1.67; 95% CI, 1.22–2.30) and cardia GC (OR, 1.46; 95% CI, 0.98–2.18) [41]. However, no significant association was observed in non-cardia GC [41]. These studies suggest that the impact of BMI or WC might vary depending on the location of GC.

An intriguing study has explored the impact of hormones on the location of GC. A thorough examination utilizing data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study reveals compelling associations between hormonal factors and specific subtypes of GC [42]. IGF-1 emerges as a significant factor, exhibiting a positive association with both cardia and non-cardia GC [42]. Specifically, in EPIC males, IGF-1 demonstrated a positive association with cardia GC (OR, 1.94) and non-cardia GC (OR, 1.63) [42]. Similar findings were observed in UK-Biobank females, where IGF-1 (hazard ratio, 1.76) was positively associated with cardia GC [42]. Leptin (OR, 2.72) in EPIC males and C-peptide (OR, 2.17) in EPIC females exhibited positive associations with non-cardia GC [42]. Moreover, sex hormone-binding globulin (HR, 1.29) demonstrated a positive association with cardia GC in UK-Biobank males. In contrast, ghrelin showed an inverse association with non-cardia GC in both EPIC and ATBC males, and dehydroepiandrosterone exhibited an inverse association with cardia GC in EPIC and ATBC males combined [42]. These findings underscore the complexity of the relationship between hormonal factors and different subtypes of GC, providing valuable insights into the nuanced interplay that may contribute to the diverse etiology of this malignancy.

Pathologically, it can be categorized into intestinal, diffuse, mixed, and indeterminate types based on the Lauren classification system [43]. Diffuse-type GC is known to occur more commonly in younger individuals and females compared to intestinal-type GC [44,45]. Additionally, it is typically detected at more advanced stages, leading to a poorer prognosis [46]. In a large retrospective cohort study investigating the correlation between BMI and the Lauren classification of GC, findings indicated that among females classified as underweight (BMI <18.5 kg/m²), there was a higher incidence of diffuse-type GC. Conversely, in females classified as overweight (BMI >30 kg/m²), intestinal-type GC was more commonly observed [47]. In contrast, intestinal-type GC was more common regardless of weight among males [47]. In premenopausal females, there is a higher prevalence of diffuse-type GC, and research indicates that female reproductive function might contribute to preventing intestinal-type GC. The incidence of intestinal-type GC tends to rise after menopause [48,49]. Estrogen is not only produced in the ovaries but also in adipose tissue, playing a significant role in the etiology and outcomes of female obesity [50]. The influence of BMI is apparent in the development of both diffuse-type and intestinal-type GC, suggesting a complex interplay with intricately involved mechanisms.

Recent large-scale studies aim to unravel the intricate connections between high-risk behaviors, including obesity, MetS and physical activity. Diving into this wealth of information, the relationship between GC and MetS sparks ongoing debates.

In a retrospective analysis of data from the National Health Insurance Corporation of Korea, the association between MetS and the incidence of GC was explored among approximately 7.8 million patients [51]. Relative to the control group, both the pre-MetS group (HR, 1.08; 95% CI, 1.04–1.12) and the MetS group (HR, 1.26; 95% CI, 1.20–1.32) exhibited a significantly increased risk of GC [51]. In another analysis, males with obesity (BMI ≥30 kg/m²) showed an increased risk of GC (HR, 1.31; 95% CI, 1.05–1.64), not in females [52]. The Health Examinees-Gem study specifically explores the impact of early adulthood obesity (BMI ≥30 kg/m² at age 35) on the risk of GC [53]. Compared to individuals with normal weight (BMI 18.5–23.0 kg/m²), those with obesity (HR, 1.94; 95% CI, 1.26–2.97) in early adulthood faced a high risk of GC [53]. When stratified by sex, obesity at the age of 35 was significantly linked to an elevated risk of GC in both males (HR, 1.79; 95% CI, 1.02–3.13) and females (HR, 2.35; 95% CI, 1.21–4.60) [53]. However, in late adolescence, there were no significant associations between obesity and the risk of GC, regardless of sex [53]. In the MetS and Cancer Project conducted in Austria, Norway, and Sweden, elevated glucose levels (HR, 1.58; 95% CI, 1.14–2.20) and TG (HR, 1.20; 95% CI, 1.06–1.36 per mmol) were significantly correlated with an increased risk of GC in females, not males [54]. In another meta-analysis, diabetes (RR, 1.11; 95% CI, 1.00–1.24) showed a significant association with the occurrence of GC [55]. Subgroup analyses within Asian studies demonstrated a more pronounced correlation between diabetes and the incidence of GC (RR, 1.19, 95% CI, 1.07–1.32). Moreover, individuals with diabetes experienced an elevated mortality rate from GC (RR, 1.29; 95% CI, 1.04–1.59) compared to those without diabetes [55]. In the Cohort of Norway and the third Nord-Trøndelag Health Study, MetS significantly increased the risk of GC incidence (HR, 1.44; 95% CI, 1.14–1.82) [56]. In females, elevated WC (HR, 1.71; 95% CI, 1.05–2.80), hypertension (HR, 2.41; 95% CI, 1.44–4.03), and non-fasting blood glucose (HR, 1.74; 95% CI, 1.18–2.56) were associated with an increased risk of GC, while no such association was observed in males [56].

Intricacies in the relationship between factors of MetS and GC emerge from a comprehensive study conducted in China [57]. GC patients exhibit distinctive metabolic profiles, including altered lipid levels, hypertension, and increased WC, with notable gender-specific impacts. In a study, involving 808 GC patients and 1,146 healthy controls, brings forth significant findings. Compared to the control group, GC patients exhibit elevated TG, decreased HDL-C, and a higher prevalence of hypertension [57]. Subgroup analyses reveal distinct patterns for males and females. In the male subgroup, elevated BMI (OR, 1.97; 95% CI, 1.47–2.66), hypertension (OR, 1.86; 95% CI, 1.35–2.58), and diabetes (OR, 2.06; 95% CI, 1.41–3.40) increase the risk of GC. Conversely, in the female subgroup, lower HDL-C (OR, 2.53; 95% CI, 1.58–4.13), hypertension (OR, 2.75; 95% CI, 1.50–5.04), and diabetes (OR, 1.81; 95% CI, 1.47–2.38) are linked to an increased risk of GC [57]. Furthermore, MetS is correlated with poorly differentiated tumors and an advanced pathological TNM stage [57], adding a layer of complexity to our understanding of how metabolic factors influence GC progression.

In a South Korean cohort study, postmenopausal females showed an inverse correlation between total cholesterol (TC) (HR, 0.88; 95% CI, 0.84–0.92), HDL-C (HR, 0.89; 95% CI, 0.85–0.92), low-density lipoprotein cholesterol (LDL-C) (HR, 0.92; 95% CI, 0.89–0.97), and the risk of GC [58]. In recent research, components of MetS, including elevated TG (HR, 1.16; 95% CI, 1.00–1.36), low HDL-C (HR, 1.17; 95% CI, 1.01–1.37), and high blood glucose (HR, 1.17; 95% CI, 1.00–1.37), were independently linked to GC [59].

A epidemiological meta-analysis suggested that overweight could exhibit a protective effect against GC risk in Asian adult [60]. However, analyzing weight without considering various body compositions can introduce biases. A recent population-based prospective cohort study reported that male (HR, 1.70; 95% CI, 1.01–2.89) and female (HR, 2.47; 95% CI, 1.15–5.32) with higher levels of body mass that excludes fat had a higher risk of GC [61]. Interestingly, fat mass was recognized as a factor providing protection against GC in female [61]. This may be associated with the secretion of estrogen, known to have a protective effect against GC, especially in females [62]. Taken together the research on the impact of BMI and physical activity should be regarded sex/gender factor differently. Contrarily, a recent meta-analysis considering 14 studies found no association between MetS and GC risk [63]. Nevertheless, the analysis observed an increased risk of GC in Western females with MetS (HR, 1.24; 95% CI, 1.05–1.47) [63]. This complex interplay underscores the importance of considering both overall weight and body composition when exploring the link between obesity-related factors and GC risk.

A South Korean study delves into the intricate relationship between MetS, physical activity, and GC risk, shedding light on the nuances of these interconnected factors. Korean individuals diagnosed with MetS have a higher risk of GC (HR, 1.26; 95% CI, 1.07–1.47) [59]. Notably, the risk escalates (HR, 1.33; 95% CI, 1.10–1.60) among individuals with MetS who are obese (BMI ≥25.0 kg/m²). Interestingly, the risk of GC does not show a notable increase among those with MetS who maintain a normal weight [59]. Adding another layer of complexity, the study explores the impact of exercise on GC risk within the context of MetS. Both regular exercisers (HR, 1.37; 95% CI, 1.09–1.72) and irregular exercisers (HR, 1.32; 95% CI, 1.05–1.65) exhibit elevated risks of GC in the presence of MetS [59]. A case-control study evaluating the association between physical activity and GC incidence reported a 20% to 40% reduction in the risk of developing GC when comparing engaging in strenuous activity at least three times a week to less than once a month [64].

This highlights the intricate interplay between physical activity patterns, MetS, and the development of GC, emphasizing the necessity for a nuanced comprehension of these elements for effective risk assessment and prevention strategies. The intertwined relationship between weight, body composition, physical activity and metabolic factors in GC risk demands a nuanced perspective. The protective and risk-associated roles of different components emphasize the importance of considering sex as major factors for unraveling the complex web of obesity-related factors and their influence on GC risk.

H. pylori eradication has been well-established to reduce the incidence of GC (RR, 0.54; 95% CI, 0.40–0.72) and GC-related mortality (RR, 0.61; 95% CI, 0.40–0.92) [65]. Several studies published on the correlation between H. pylori and MetS. In Japan, the group with H. pylori infection (HR, 4.20; 95% CI, 1.60–11.10) had a higher risk of GC compared to the non-infected group [66]. Additionally, an elevated fasting blood glucose (HR, 3.00; 95% CI, 1.50–6.40) increased the risk for GC [66]. In a multicenter study in South Korea involving 15,195 individuals, 43.2% tested positive for H. pylori [67]. Compared to individuals negative for H. pylori, those positive for H. pylori showed higher levels of BMI, WC, TC, and LDL-C, while HDL-C levels were lower [67]. The prevalence of MetS was 27.2% in H. pylori-positive individuals and 21.0% in those negative for H. pylori (p<0.05), and H. pylori antibody positivity was associated with the occurrence of MetS (OR, 1.19; 95% CI, 1.09–1.31) [67]. The impact of H. pylori on MetS and lipid has been investigated with a focus on sex differences [68]. Analysis found associations between H. pylori infection and TC (OR, 1.01; 95% CI, 1.00–1.01) in males and HDL-C (OR, 0.98; 95% CI, 0.97–1.00) in females [68]. In both H. pylori-positive male and female groups, the prevalence of MetS was higher, though not statistically significant. This suggests H. pylori may influence lipid profiles related to MetS, with its effect varying by sex.

However, these studies have limitations in definitively proving causality between H. pylori infection and lipid profiles. Taking this into consideration, several studies analyzing changes in MetS-related factors after eradication therapy have also been published. A study conducted in Iran reported reductions in TC, LDL-C, fasting plasma glucose, hemoglobin A1c, and WC after eradication therapy [69]. In Japan, a study reported that LDL-C levels did not significantly change after H. pylori eradication, but HDL-C levels increased significantly post-eradication [70]. Consequently, the LDL-C/HDL-C ratio, considered a predictive parameter for assessing the severity of myocardial infarction or atherosclerosis, significantly decreased after eradication [70]. A meta-analysis reported that HDL-C and TG levels increased after eradication therapy [71]. Specifically, in an analysis focusing on four randomized controlled trials, the increase in HDL-C was significant, but not for TG [71]. Previous studies had the drawback of relatively short follow-up periods after eradication therapy. However, a recent domestic study analyzed metabolic parameters for more than 1 year after eradication therapy [72]. The study revealed that in females, HDL-C levels increased, while LDL-C levels decreased after eradication therapy [72]. In other words, the association between MetS and H. Pylori infection may further support the link between MetS and GC.

Recent strides in endoscopic resection notwithstanding, surgical resection remains the cornerstone of GC treatment. Postoperative outcomes, particularly concerning MetS, have been a focal point in numerous studies within the realm of GC patients. Among cancer survivors, especially those with GC, the risk of developing MetS (OR, 0.42; 95% CI, 0.20–0.86) was lower [73]. This intriguing association may be attributed to the common therapeutic approach of gastrectomy, a procedure often undertaken for curative purposes, potentially contributing to the observed reduced risk of MetS in GC survivors.

An in-depth analysis using data from the Fujian Prospective Investigation of Cancer explored the influence of preoperative MetS on the long-term prognosis after GC surgery [74]. During a 15-year follow-up involving 3,012 individuals, 1,331 experienced GC-related mortality. Those with preoperative MetS had a significantly shorter median survival time of 31.3 months compared to those without MetS. The concurrent presence of MetS before surgery was linked to a 2.3-fold increase in the risk of GC mortality (p<0.001) [74].

In a retrospective analysis forecasting postoperative survival outcomes in GC, considering presurgical MetS, a cohort of 2,779 patients was scrutinized, encompassing both smokers and never-smokers. Intriguingly, presurgical MetS complications were significantly associated with heightened GC-specific mortality in smokers, manifesting as a 2.73-fold higher risk, while no such association was observed in never-smokers [75]. These findings underscore the intricate interplay between MetS and postoperative outcomes in GC patients, shedding light on potential nuances influenced by therapeutic interventions and individual lifestyle factors such as smoking.

The intricate relationship between MetS and GC involves various interconnected factors. Overall, considering these intricate connections is crucial for comprehensive risk assessment and effective prevention strategies in the context of GC. However, most studies have been retrospective, making it somewhat challenging in establishing a causal relationship. Investigating the mechanisms that underlie the association between MetS and GC requires crucial future prospective research.