Metabolic syndrome (MetS), also known as X Syndrome, is a multifactorial cluster of pathologic conditions significantly increasing the risk of developing cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and other pathological conditions, including cancer (Bellastella et al., 2018). According to 1999 World Health Organization (WHO) definition, primary components of MetS are insulin resistance and central obesity, together with dyslipidemia, hypertension and increased fasting glucose levels (Rochlani et al., 2017). Different organizations established MetS diagnostic criteria over time with slight variations. Among them, the most widely used criteria are the ones described by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and the International Diabetes Federation (IDF) (Huang, 2009). The 2005 NCEP ATP III criteria define MetS as the presence of three or more of the following parameters (Alberti et al., 2009; Grundy et al., 2004):•

Abdominal Obesity: Waist circumference >102 cm in men and >88 cm in women

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Hypertriglyceridemia: Triglycerides (TGs) ≥150 mg/dL;

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Low HDL Cholesterol (HDL-C): <40 mg/dL in men and <50 mg/dL in women

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Hypertension: Blood pressure ≥130/85 mmHg

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Impaired fasting glucose (≥100 mg/dL) or diagnosed T2DM

Alternatively, the 2006 IDF criteria require central obesity as a mandatory criterion (with ethnic-specific waist circumference cutoffs), paired with any two of the other clinical parameters mentioned above (Alberti et al., 2009). Further criteria for diagnosis of MetS are shown in Table 1.

Starting from these assumptions, MetS cannot be considered as a single disease but as a constellation of pathological conditions, whose genesis results in the complex interplay of genetic, environmental and lifestyle factors.

MetS is a global public health issue with a significant and increasing prevalence due to rising rates of obesity and sedentary lifestyles. Globally, the prevalence of MetS reflects the growing impact of urbanization, sedentary lifestyles, and dietary transitions, highlighting the need for coordinated public health efforts to address this critical issue (Jha et al., 2023). In the United States, the prevalence of MetS has been reported to range between 33 % and 39 %, with higher rates observed in older populations (Hirode & Wong, 2020). Recent data from the National Health and Nutrition Examination Survey (NHANES) highlight an increasing trend in MetS prevalence, particularly among adults over 50 years of age, where it exceeds 50 % in some cohorts (Hirode & Wong, 2020). Ethnic variations also exist, with higher prevalence noted in Hispanic and South Asian populations compared to non-Hispanic whites and African Americans (Okosun et al., 2014). The increasing MetS is alarming due to its association with heightened risks of CVD, T2DM, cancer and overall mortality. Public health strategies focusing on lifestyle modifications, early diagnosis, and comprehensive management are essential to mitigate the burden of MetS on healthcare systems worldwide.

Although the relationship between MetS and GI cancers have been extensively investigated in several studies, a focused literature report on the impact of MetS components on GI cancer risk needs a particular attention. In this light, the object of the present systematic review is how MetS might contribute specifically to GI cancer onset, highlighting the novel interesting anti-tumoral therapeutic potential of conventional pharmacological agents currently used to mitigate MetS signs. Specifically, pre-clinical evidence of their therapeutic potential and of their integration in novel compelling therapeutic strategies will be discussed to bring to the attention of the scientific community novel combinatory treatments possibly improving conventional chemotherapy response of GI cancer patients affected by MetS.