Dietary phytochemicals as multitarget strategies against metabolic syndrome: Mechanistic basis and translational outlook

Metabolic syndrome (MetS) is a growing global health problem characterized by central obesity, dyslipidemia, hypertension, and insulin resistance. It poses a major burden, particularly in low- and middle-income countries where lifestyle changes and limited healthcare access accelerate its rise. This review highlights advances from 2014–2024 in understanding MetS, with a focus on the therapeutic promise of natural phytochemicals such as polyphenols, flavonoids, and alkaloids. Evidence was drawn from preclinical, clinical, and population-based studies retrieved from PubMed, Scopus, and Web of Science databases using search terms including combinations of ''metabolic syndrome,'' ''phytochemicals,'' ''polyphenols,'' ''flavonoids,'' ''alkaloids,'' and related metabolic markers, with inclusion criteria focusing on original research articles, systematic reviews, and clinical trials published between 2014 and 2024. Across 152 studies, phytochemicals consistently improved markers of MetS. They lowered triglycerides, raised high-density lipoprotein cholesterol (HDL-C), reduced fasting glucose and homeostatic model assessment for insulin resistance (HOMA-IR), and improved blood pressure regulation. Mechanistic data show polyphenols like resveratrol and epigallocatechin gallate (EGCG) enhance AMP-activated protein kinase (AMPK) signaling and glucose transporter type 4 (GLUT4) activity; flavonoids such as quercetin reduce nuclear factor kappa B (NF-κB)-driven inflammation; and alkaloids like berberine modulate gut microbiota and insulin receptor signaling. These compounds act on overlapping molecular pathways including AMPK, peroxisome proliferator-activated receptor gamma (PPAR-γ), NF-κB, and microbial communities, giving them broad protective potential. Despite promising results, issues of bioavailability, dosage, and inconsistent study designs limit translation. Safety profiles remain favorable, but large-scale, long-term clinical trials are needed. Phytochemicals represent a cost-effective and complementary approach to managing MetS and reducing its cardiovascular and diabetic complications.