Intermittent Fasting in Metabolic Syndrome: Clinical Evidence, Molecular Mechanisms, and Future Perspectives

The objective for this narrative review was to synthesize and critically assess the clinical evidence, molecular mechanisms, and future directions of intermittent fasting (IF) for managing metabolic syndrome (MetS). Metabolic syndrome is a complex cardiometabolic disorder associated with abnormal dietary patterns, epigenetic regulation, and gene activity, and characterized by central adiposity, insulin resistance, hypertension, and dyslipidemia. Intermittent fasting regimens, including time-restricted eating, alternate-day fasting, and the 5:2 fasting regimen, are promising nutritional interventions. Nonetheless, large, randomized trials have reported mixed clinical outcomes, and critical uncertainties persist regarding clinical effectiveness, molecular mechanisms, and whether benefits arise from fasting timing or weight-loss-driven energy restriction. A comprehensive literature search was conducted in major databases through July 2026. Articles, including those reporting on randomized controlled trials, systematic reviews, meta-analyses, and relevant preclinical mechanistic investigations in MetS, were selected and their data synthesized. Findings show that certain IF regimens produce modest improvements in body weight, waist circumference, and selected cardiometabolic risk markers; however, effects on glycemic control, lipid profiles, and liver-related end points are heterogeneous across trials. Observed clinical responses vary by fasting protocol, participant phenotype, and adherence, and high-quality human mechanistic data remain limited. Mechanistic insights, largely derived from preclinical models, highlight circadian rhythm synchronization and nutrient-sensing network modulation as key biological pathways. Important unresolved controversies cover protocol optimization, long-term adherence, and inter-individual metabolic variability. Intermittent fasting may serve as a feasible nonpharmacological adjunct intervention for MetS and related conditions, yet existing evidence is inconsistent. Translation toward precision lifestyle medicine requires resolution of ongoing controversies, improved evaluation of evidence quality, development of personalized fasting protocols, and rigorous assessment of long-term safety and sustainability across diverse patient populations.