Abstract 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.
Abstract Context Protein (PRO) intake supports exercise adaptation and recovery, but its effects on gut microbiota (GM) in physically active individuals remain inconsistent across doses, PRO sources, and exercise conditions. Objective To systematically evaluate and meta-analyze the effects of PRO intake on GM in physically active individuals. Data Sources The PubMed, EBSCOhost, the Cochrane Library, and Web of Science databases were searched through June 2026. Reference lists of relevant studies and reviews were also examined. Data Extraction Two reviewers independently screened records and extracted study, participant, intervention, and outcome data. Eligible studies quantified PRO intake, included an exercise or physical-activity component, and reported extractable GM outcomes. Risk of bias and evidence certainty were assessed using the Cochrane Risk of Bias 2.0 tool and Grading of Recommendations, Assessment, Development and Evaluation approach, respectively. Data Analysis Random-effects meta-analyses using Hedges’ g, subgroup analyses, and meta-regression were performed. Eighteen studies (n = 819 participants) were included. Protein intake significantly increased the Shannon and Chao1 indices but not the Simpson index or observed operational taxonomic units (OTUs). A significant U-shaped association was observed between PRO dose and the α-diversity effect size, with the fitted curve reaching its lowest point at 1.5-2.0 g kg−1 d−1. Protein intake significantly decreased populations of Actinobacteria, Bifidobacterium, and Firmicutes, and the Firmicutes to Bacteroidetes ratio, and increased Bacteroidetes numbers. Subgroup findings suggested that age, body mass index, intervention duration, PRO dose, and exercise modality and intensity moderated the effects on Shannon diversity and Bifidobacterium abundance. Conclusions Protein intake appears to improve gut microbial diversity in physically active individuals but may also induce notable shifts in beneficial taxa, particularly reductions in Bifidobacterium. Future studies should prioritize individualized microbiome-informed strategies, evaluate long-term safety, and clarify the ecological impact of different PRO sources to optimize exercise nutrition interventions. Systematic Review Registration PROSPERO registration No. CRD420261288197.
Abstract Breast cancer (BC) is a prevalent and heterogeneous neoplasm whose therapeutic resistance remains a major challenge. Ferroptosis, an iron-dependent form of regulated cell death that is characterized by lipid peroxidation, has emerged as a key mechanism linking iron metabolism, oxidative stress, and tumor aggressiveness. The objective for this narrative review was to summarize the principal mechanisms regulating ferroptosis in BC and discuss its potential as a therapeutic target. A literature review was conducted to investigate the mechanisms involved in ferroptosis in BC, with emphasis on iron metabolism, oxidative stress, lipid peroxidation, antioxidant defense systems, and differences in ferroptosis sensitivity among BC subtypes. The literature indicates intracellular iron accumulation increases reactive oxygen species generation and enhances the susceptibility of cancer cells to ferroptosis. This process is mainly controlled by the glutathione peroxidase 4–glutathione and ferroptosis suppressor protein 1–coenzyme Q10 antioxidant systems, which neutralize lipid peroxides and preserve membrane integrity. Dysregulation of these pathways contributes to redox imbalance and disease progression. Among BC subtypes, triple-negative tumors show greater sensitivity to ferroptosis due to heightened oxidative activity and reduced expression of protective enzymes, whereas luminal and Human epidermal growth factor receptor 2–positive tumors exhibit increased resistance. Controlled induction of ferroptosis may help eliminate drug-resistant cells and enhance treatment efficacy, reinforcing its relevance as a central axis connecting metabolism, oxidative stress, and programmed cell death.
Abstract Context Evaluating the effects of low-fat diets (LFDs) on nontraditional blood lipid measures provides a more comprehensive assessment of their impact on lipid metabolism. Objectives This systematic review and meta-analysis aimed to evaluate the effects of LFDs (≤30% energy from fat) compared with high-fat diets (HFDs; >30% energy from fat) on non–high-density lipoprotein cholesterol (non-HDL-C), apolipoproteins, and lipoprotein ratios. Data source We systematically searched PubMed, Scopus, and Web of Science from inception to June 2, 2024, and then updated the search through August 8, 2025, without language restrictions. Data extraction and synthesis Randomized controlled trials (RCTs) that examined the effects of LFDs compared with HFDs on nontraditional lipid measures among adults were selected. Independent reviewers extracted data and assessed the risk of bias and the certainty of evidence. Random-effects meta-analyses were used to estimate weighted mean differences (WMDs) and 95% CIs for each outcome. Reporting adhered to the PRISMA guidelines. Results Ninety-two trials were included in this meta-analysis. Compared to HFDs, LFDs significantly reduced non-HDL-C (WMD = −8.00 mg/dL, 95% CI, −13.1 to −2.89; I2 = 77.8%; high-quality evidence), apolipoprotein (Apo) A1 (WMD = −2.51 mg/dL, 95% CI , −3.92, to −1.10; I2 = 66.1%; low-quality evidence), HDL-C2 (WMD = −0.72 mg/dL, 95% CI , −1.20, to −0.23; I2 = 0%; moderate-quality evidence), and HDL-C3 (WMD = −1.32 mg/dL, 95% CI , −2.29, to −0.36; I2 = 36.7%; moderate-quality evidence). No significant effects were observed on ApoB, ApoB100, ApoB in LDL-C, ApoC3, and the ApoB/ApoA1 ratio (low- to very low-quality evidence). LFDs led to a slight but significant increase in the total cholesterol/HDL-C and triglycerides/HDL-C ratios (moderate-quality evidence). Moderate-quality evidence indicated no effect of LFDs on lipoprotein (a) (LP[a]). Conclusions Although LFDs significantly reduce non-HDL-C, the evidence for their effects on ApoB, ApoA1, HDL-C/ApoA, and ApoB/ApoA1 remains inconclusive. This meta-analysis indicates that LFDs can be an effective dietary strategy to reduce non–HDL-C, without strong evidence of adverse effects on lipoprotein ratios. Systematic review registration PROSPERO registration no. CRD42023420978.
Abstract Severe obesity (SO), defined as a BMI ≥40 kg m−2 or ≥35 kg m−2 with comorbidities, is a complex chronic condition that poses major challenges to clinical management. Current evidence on the pathophysiological and environmental factors influencing outpatient care for people with SO (PSO) is synthesized and analyzed in this review. A literature search covering the past 10 years was conducted, including scientific articles and guidelines from scientific societies addressing these factors. The evidence suggests that conventional outpatient approaches are often insufficient for PSO, because they fail to address the complex biological, behavioral, and environmental mechanisms sustaining SO. Clinically meaningful weight loss often requires reductions of more than 10%, 15%, or even 20%; long-term success rates remain low among individuals treated with nonpharmacological or nonsurgical approaches alone. Genetic predisposition plays a central role, including rare monogenic and syndromic forms associated with early-onset obesity and poorer response to nontargeted therapies, as well as polygenic obesity. Dysfunctions in the leptin-melanocortin pathway also may impair appetite regulation and modify sensory, endocrine, and neural responses related to food intake. People with SO may also present with hedonic hunger and emotional or uncontrolled eating, in addition to higher rates of eating disorders, depression, and anxiety, which contribute to weight regain. The increasing prevalence of SO reinforces the need for a comprehensive, individualized, and multidisciplinary approach that incorporates pathophysiological and environmental determinants into care. Improving outcomes in SO depends not only on expanding therapeutic options but also on better training healthcare teams to recognize the multifactorial mechanisms underlying treatment resistance and weight regain. A structured, person-centered outpatient framework is proposed that integrates biological, psychosocial, and environmental determinants of SO, along with practical clinical tools to support individualized management and improve long-term care.
