Search Results (542)

Background: Childhood is a key period for the development of body composition and physical activity habits that may influence health throughout life. Although physical activity has been widely associated with adiposity indicators, the role of enjoyment of physical activity as a motivational and affective component remains less explored. Therefore, the aim of this study was to analyze the relationship between several anthropometric indicators and both the level of physical activity and enjoyment of physical activity in schoolchildren. Methods: An observational, analytical, cross-sectional study was conducted with 386 schoolchildren (176 boys and 210 girls) with a mean age of 11.15 ± 0.66 years. Anthropometric indicators included body mass index, waist circumference, hip circumference, waist-to-hip ratio, and triceps and subscapular skinfold thickness. Physical activity level was assessed using the Physical Activity Questionnaire for Children (PAQ-C), and enjoyment of physical activity was evaluated using the Physical Activity Enjoyment Scale (PACES). Multiple linear regression analyses were performed, adjusting for age and sex. Results: Higher levels of physical activity were significantly associated with lower body mass index (B = −1.592; p < 0.001), waist circumference (B = −8.010; p < 0.001), hip circumference (B = −8.227; p < 0.001), waist-to-hip ratio (B = −0.008; p < 0.001), triceps skinfold thickness (B = −0.910; p = 0.002), and subscapular skinfold thickness (p < 0.05). Greater enjoyment of physical activity was significantly associated with lower body mass index (B = −1.778; p < 0.001), reduced waist circumference (B = −8.944; p < 0.001), hip circumference (B = −9.185; p < 0.001), waist-to-hip ratio (B = −0.008; p < 0.001), and triceps skinfold thickness (B = −1.100; p = 0.001). Greater enjoyment was also associated with lower anthropometric indicators of central adiposity (waist circumference and waist-to-hip ratio), whereas no significant association was observed with subscapular skinfold thickness (p = 0.066). Conclusions: Physical activity level and enjoyment of physical activity were associated with multiple anthropometric indicators in children, although physical activity showed more consistent associations, whereas enjoyment demonstrated a more selective pattern depending on the specific adiposity measure. These findings highlight the importance of considering both behavioral and affective dimensions of physical activity when promoting healthy morphofunctional development during childhood. Full article

Background: Obesity represents a major public health challenge worldwide and contributes substantially to the burden of type 2 diabetes and hypertension. While body mass index (BMI) is widely used in clinical practice, indices reflecting central adiposity may provide additional prognostic value. This study aimed to assess the prevalence of general and central obesity in an adult population across different age groups from Stara Zagora, Bulgaria, and to examine their associations with cardiometabolic outcomes and lifestyle factors. Methods: A quasi-representative cross-sectional study was conducted among 3512 adults (mean age 53.7 ± 14.9 years). Anthropometric indices, including BMI, waist circumference, waist-to-hip ratio, and waist-to-height ratio were measured. Cardiometabolic outcomes included diabetes, hypertension, and their combined presence. Multicollinearity was assessed using the Variance Inflation Factor (VIF), and the discriminatory ability of indices was evaluated using Receiver Operating Characteristic (ROC) analysis and DeLong’s test. Results: The prevalence of overweight/obesity (BMI ≥25) was 68.4%, while central obesity (WHtR ≥0.5) affected 66.9% of participants. BMI demonstrated the highest discriminatory ability in this dataset for hypertension (AUC = 0.852) and diabetes (AUC = 0.796), significantly outperforming WC and WHR (p < 0.05). However, 24.4% of individuals with normal BMI exhibited high-risk central adiposity. Significant sex-specific differences were observed: short sleep duration (<6 h) was a strong predictor of obesity in women (aOR = 2.98), whereas smoking showed stronger associations in men. Age-stratified analyses revealed that while BMI stabilizes in the oldest age group (75–89 years), WHtR continues to increase, reflecting age-related redistribution of visceral fat. A strong protective effect of physical activity was observed, supported by quasi-complete separation in active subgroups. Conclusions: General and central obesity represent a substantial health burden in this urban population. While BMI remains a robust screening tool, the integration of WHtR enhances the identification of “hidden” cardiometabolic risk particularly in older adults and individuals with normal BMI. Given the quasi-representative nature of the sample, these findings are primarily generalizable to similar urban populations and may inform targeted regional public health strategies. Full article

Background/Objectives: Candidates with cardiometabolic risk are considered for living kidney donation more frequently because of the global organ shortage. The 2017 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines introduced individualized risk assessment based on composite donor profiles rather than categorical exclusion, but the long-term implications of accepting donors with potential risk factors require careful evaluation. This review synthesizes current evidence on outcomes of living kidney donors with obesity, prediabetes, hypertension, and smoking. Methods: A literature search was conducted in PubMed/MEDLINE for studies published between 1 January 2000 and 28 February 2026, including cohort studies, registry analyses, meta-analyses, and clinical guidelines evaluating living kidney donors with obesity, smoking, prediabetes, or hypertension. Priority was given to large cohorts with long-term follow-up. Over 70 publications were included in the final synthesis. Findings were synthesized narratively by risk factors and outcomes. Results: Obesity was associated with an 86% increased end-stage kidney disease (ESKD) risk and 32% increased 20-year mortality. Central adiposity measures outperformed body mass index (BMI) for predicting estimated glomerular filtration rate (eGFR) decline. Post-donation weight gain increased the risk for developing hypertension and diabetes. Smoking conferred a 7.5-fold chronic kidney disease (CKD) risk, with impaired compensatory renal adaptation after donation. Prediabetic donors showed comparable outcomes to normoglycemic donors, with 57.8% reverting to normoglycemia at 10 years. Pre-donation hypertension increased 15-year ESKD risk 3-fold, but absolute risk remained low. At 15 years post-donation, over 50% of the donors developed hypertension. Glucagon-like peptide-1 (GLP-1) receptor agonists reduce diabetes progression by 73–94% in at-risk populations, but prospective studies in donors are lacking. Conclusions: Each risk factor carries quantifiable risks for individualized stratification. These risk factors usually coexist and interact. Refinement of risk prediction models, strategies for metabolic optimization and prospective evaluation of emerging pharmacologic therapies are key priorities. Full article

Background: The Middle East and North Africa (MENA) region faces a high cardiovascular disease (CVD) burden alongside endemic serum 25(OH)D (vitamin D) deficiency. This systematic review examines the relationship between vitamin D deficiency and CVD risk factors in MENA populations. Methods: PubMed, Cochrane Library, and Scopus were searched from inception to 18 October 2024, for observational studies in the MENA region examining vitamin D deficiency and cardiovascular risk factors in adults. Independent data extraction was conducted. Study quality was appraised using the Joanna Briggs Institute tool and the Newcastle–Ottawa Scale, with risk of bias visualized using Robvis. Weighted mean differences in cholesterol, body mass index (BMI), and HbA1c between those with and without vitamin D deficiency were computed with random-effects meta-analysis. The protocol was registered in PROSPERO (ID: CRD42025615188) and funded by the Royal College of Surgeons in Ireland—Medical University of Bahrain. Results: Seventeen studies from nine MENA countries were included, predominantly cross-sectional, involving community-based and disease-specific cohorts. Vitamin D deficiency was highly prevalent and consistently associated with higher adiposity and central obesity. Several studies reported significant links between deficiency and poor glycemic control, particularly in obese and prediabetic groups. Meta-analysis demonstrated significantly higher total cholesterol (MD = 0.32; 95% CI = 0.11 to 0.52, p < 0.001), BMI (MD = 1.81; 95% CI = 0.68 to 2.94, p < 0.001), and HbA1c levels (MD = 0.31; 95% CI = 0.06 to 0.57, p = 0.02) in vitamin D deficient individuals, with notable heterogeneity. Conclusions: Vitamin D deficiency is highly prevalent in the MENA region and consistently associated with adiposity-related risk factors. Despite heterogeneity, findings underscore the need for public health strategies and further research to clarify causal pathways and population-specific interventions. Full article

Background/Objectives: Elevated central adiposity (ECA) in childhood is associated with early cardiometabolic risk and hemodynamic alterations. However, evidence in Spanish schoolchildren regarding the relationship between eating behavior traits and central adiposity is limited, particularly across developmental stages. This study aimed to examine the association between Children’s Eating Behaviour Questionnaire (CEBQ) subscales and ECA, and to explore potential differences by age group. Methods: A cross-sectional study was conducted in 496 rural schoolchildren aged 6–15 years. ECA was defined using the waist-to-height ratio (WHtR) and sex-specific cut-offs validated for the Spanish pediatric population. Eating behavior was assessed with the CEBQ (Z-scores), and diet quality was measured using the KIDMED index. Multivariable logistic regression models were adjusted for sex, KIDMED score, and maternal education. Analyses were subsequently stratified by age (6–9 and 10–15 years). Results: The prevalence of ECA was 45.90%. In fully adjusted models, higher Food Responsiveness (FR) was associated with increased odds of ECA, while Satiety Responsiveness (SR) acted as a protective factor; sex also showed an independent association. After stratification, sex remained the only significant predictor in children aged 6–9 years. Among those aged 10–15 years, FR was significantly associated with ECA (p = 0.008), while Slowness in Eating (SE) showed a borderline positive association in the adjusted model (p = 0.049) and was therefore interpreted cautiously. SR and Emotional Undereating (EU) showed protective trends near significance (p = 0.081 and p = 0.082, respectively). Conclusions: The association between eating behavior traits and ECA varies by age. In older children, FR showed a robust association with ECA, whereas no behavioral predictors were observed in younger children. The protective role of SR in the global model and the emergence of behavioral predictors in older participants highlight the importance of targeted interventions during late childhood. Full article

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a systemic metabolic disorder characterized by impaired metabolic flexibility involving the liver, skeletal muscle, and adipose tissue. Although weight loss has traditionally been emphasized in its management, emerging evidence suggests that exercise exerts therapeutic effects beyond body weight reduction. This narrative review aims to examine exercise as a metabolic therapy for MASLD by integrating mechanistic insights and clinical evidence. Exercise improves hepatic steatosis, insulin resistance, mitochondrial function, and inflammatory signaling through interconnected pathways, including activation of AMPK-related signaling, enhanced fatty acid oxidation, and muscle–liver crosstalk mediated by myokines. Importantly, these benefits can occur independently of weight loss, supporting a shift from weight-centered to metabolism-focused treatment strategies. Both aerobic and resistance exercise demonstrate efficacy, with combined approaches providing complementary benefits. In conclusion, exercise should be considered a central therapeutic strategy for MASLD by restoring metabolic flexibility rather than solely promoting weight reduction. Future research should focus on optimizing individualized and sustainable exercise prescriptions to enhance long-term clinical outcomes. Full article

Background/Objectives: Vitamin D plays an important role in glucose metabolism, lipid regulation, and inflammatory processes, and has been implicated in cardiometabolic health. However, its associations with specific metabolic biomarkers remain inconsistent, particularly in older adults. This study aimed to examine whether vitamin D deficiency is differentially associated with multiple metabolic biomarkers in a nationally representative sample of older adults. Methods: This cross-sectional study used data from the 2024 Korea National Health and Nutrition Examination Survey, including 1806 adults aged ≥65 years. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D levels < 20 ng/mL. Metabolic biomarkers included fasting glucose, glycated hemoglobin (HbA1c), triglycerides, C-reactive protein (CRP), high-density lipoprotein cholesterol (HDL-C), waist circumference, and body mass index (BMI). Complex sample linear regression analyses were performed with sequential adjustment for sociodemographic factors, health behaviors, and comorbidities. Results: In unadjusted analyses, vitamin D deficiency was associated with adverse metabolic profiles, including higher fasting glucose, HbA1c, triglycerides, waist circumference, and CRP levels, and lower HDL-C levels. After adjustment for sociodemographic factors, health behaviors, and comorbidities, significant associations remained for HbA1c (β = 0.10, p = 0.034), triglycerides (β = 0.10, p = 0.003), and waist circumference (β = 1.21, p = 0.040). No significant associations were observed for fasting glucose, HDL-C, CRP, or BMI. Conclusions: Vitamin D deficiency was independently associated with poorer long-term glycemic status, hypertriglyceridemia, and central adiposity in older adults, but not with other metabolic markers after adjustment. These findings suggest that the metabolic correlates of vitamin D deficiency may be domain-specific rather than generalized. Longitudinal and interventional studies are needed to clarify causality and underlying mechanisms. Full article

Background/Objectives: Down syndrome (DS), the most common chromosomal disorder, is associated with obesity and related metabolic complications. Although physical activity (PA) improves health outcomes in individuals with DS, global research trends in this field have not been systematically synthesized, and evidence regarding the effects of aerobic training (AT) on obesity-related parameters in individuals with DS remains inconsistent. This study incorporated a dual bibliometric and meta-analytical approach. Methods: First, the bibliometric analysis included 321 original research articles published between 2001 and 2024, retrieved from Scopus, Web of Science, and PubMed. Second, a meta-analysis of 15 randomized controlled trials (n = 477) was conducted to examine the effects of AT on obesity-related parameters, including body weight (BW), body mass index (BMI), fat mass (FM), waist circumference (WC), and waist-to-hip ratio (WHR) in individuals with DS. Results: Keyword co-occurrence and collaboration network analyses revealed a notable increase in research output since 2018, with “adolescent,” “obesity,” and “intellectual disability” the most co-occurring keywords associated with DS and PA. “Obesity” emerged as the most prominently growing keyword associated with DS and PA. A meta-analysis concluded that AT reduced FM (standardized mean differences [SMD] = −0.44; p < 0.001) and WC (SMD = −0.39; p < 0.01), while subtle changes in BW, BMI, and WHR were found. These findings suggest that AT improves body composition, particularly reducing central adiposity, even without changes in traditional weight-based metrics. Conclusions: Our findings demonstrate that AT can be an effective non-pharmacological strategy for improving body composition in individuals with DS and obesity and highlight the urgent need to shift clinical and research paradigms toward multidimensional, individualized health strategies that support PA and healthy body composition throughout the lifespan. Full article

Leucine-rich repeat kinase 2 (LRRK2) is a multidomain serine/threonine kinase and a major genetic contributor to Parkinson’s disease (PD). Although LRRK2 has been extensively studied in neurodegeneration, emerging evidence indicates that it also plays a critical role in systemic metabolism. LRRK2 regulates glucose homeostasis through modulation of insulin signaling, vesicle trafficking, mitochondrial function, and inflammatory responses. Studies using LRRK2 knockout and knock-in models, including the pathogenic G2019S mutation, have revealed abnormalities in insulin sensitivity, adipose tissue inflammation, hepatic glucose production, and skeletal muscle metabolism. Mechanistically, LRRK2 phosphorylates Rab GTPases, thereby controlling insulin receptor trafficking and GLUT4 translocation. In addition, LRRK2 influences mitochondrial dynamics and reactive oxygen species production, linking metabolic stress to inflammatory signaling. Importantly, LRRK2 also regulates innate immune pathways, including TLR4–NFκB signaling and inflammasome activation, thereby connecting peripheral metabolic dysfunction to neuroinflammation. Here, we propose an integrated metabolic–neuroinflammatory crosstalk model in which LRRK2 functions as a molecular coordinator linking peripheral metabolic dysfunction to central neurodegeneration. In this framework, systemic metabolic stress—characterized by insulin resistance, chronic inflammation, advanced glycation end product (AGE) accumulation, and blood–brain barrier disruption—drives microglial activation and neurodegenerative processes. Understanding this systemic axis may provide new therapeutic opportunities targeting both metabolic dysfunction and neurodegeneration in PD. Full article

Background/Objectives: Cardiovascular disease is the leading cause of adult deaths globally and has recently been reported to be on the rise in younger adult women. The present study examined the impact of physical and lifestyle predictors of vascular health in 125 apparently healthy premenopausal East Asian volunteers. Methods: Vascular health outcomes included carotid–femoral pulse wave velocity (cfPWV), central augmentation index (cAIx), and mean arterial pressure (MAP). Body composition/anthropometric predictors included total adiposity, visceral adipose tissue (VAT) and skeletal muscle mass (SMM), as well as body mass index (BMI) and waist circumference (WC). Lifestyle predictors included the International Physical Activity Questionnaire (IPAQ) and dietary recall. Multivariate linear regression was used to identify independent predictors of combined vascular health and individual vascular outcome variables. The analysis for independent vascular outcomes was repeated after age stratification (<35 years versus $\ge$35 years). Results: VAT showed a significant multivariate effect on combined vascular health outcomes (p = 0.002) and independently contributed to cfPWV (p = 0.013). WC positively predicted cAIx (p = 0.010) while SMM was inversely related to cAIx (p = 0.024). BMI positively predicted MAP (p = 0.039) in the multivariate analysis. After age adjustment however, only BMI emerged as a significant independent predictor of both cfPWV (p = 0.040) and MAP (p = 0.024). Furthermore, WC remained positively associated with cAIx (p = 0.042) while SMM remained inversely related to cAIx (p = 0.038). After age stratification, IPAQ was inversely related to cfPWV while BMI was positively associated with MAP (p = 0.035) in women < 35 years only. However, in older women, total adiposity (p = 0.040) and total cholesterol (p = 0.011) were both positively, while SMM (p = 0.046) was negatively associated with cAIx. Conclusions: With the exception of age, VAT was the single best predictor of general vascular health in East Asian women. Independent of age, however, BMI, WC, and SMM significantly contributed to independent vascular outcome measures and in combination with age, substantially add to the prediction of vascular risk. Furthermore, stratifying younger versus older premenopausal women resulted in different associations with independent vascular outcome measures demonstrating that across a large age range of premenopausal women, it is important to consider age in the evaluation of vascular health. Full article

Introduction: Childhood and adolescent obesity is a growing global health challenge associated with early metabolic and cardiovascular complications. This study aims to compare questionnaire-assessed physical activity patterns and lifestyle characteristics among children and adolescents with obesity and normal-weight peers and to explore their associations with clinical measurements and cardiometabolic risk. Assessing resting metabolic rate (RMR) by indirect calorimetry may provide additional insight into metabolic status beyond conventional anthropometric indicators. Methods: This prospective cross-sectional study included 58 children and adolescents aged 5–18 years with obesity and 30 normal-weight controls evaluated in Sfânta Maria Emergency Children’s Hospital Iași, Romania. Clinical data included anthropometric measurements and available biochemical parameters. RMR was assessed through indirect calorimetry (Fitmate Pro, Cosmed, Rome, Italy). Parents completed a structured lifestyle questionnaire adapted from validated international instruments, collecting information on physical activity, sedentary behavior, and wearable device use. Data analysis was conducted using SPSS 22.0, applying descriptive statistics and Pearson correlation analysis. Results: Children with obesity reported higher body mass index (BMI) (30.48 ± 5.31 kg/m²), higher RMR values, lower physical activity levels and greater sedentary time than controls. RMR correlated positively with BMI, central adiposity, blood pressure, waist-to-height, hepatic steatosis and exercise tolerance. Although electronic devices for monitoring physical activity were more frequently used in the obesity group, this was not associated with higher activity levels. Conclusions: Children and adolescents with obesity exhibited a clustered cardiometabolic risk profile and reduced physical activity. RMR measured by indirect calorimetry may contribute to a more comprehensive metabolic assessment in pediatric obesity. Full article

Background: Μetabolic syndrome (MetS)—comprises central adiposity, elevated blood pressure, dyslipidaemia, and dysglycaemia, increasing the risk of type 2 diabetes and cardiovascular disease. Exercise training improves cardiorespiratory fitness and several MetS components, but real-world effectiveness is limited by poor adherence, restricted supervision, and insufficient personalisation. Objective: This scoping review mapped the clinical intervention evidence on technology-enhanced exercise and structured physical activity relevant to MetS, while distinguishing direct MetS evidence from translational evidence. Methods: In accordance with PRISMA-ScR, we searched PubMed and extended the search to Scopus and Web of Science; a supplementary IEEE Xplore search and a post hoc Embase check were also conducted. Eligible studies were interventions using web-based delivery, wearables, telemonitoring/mobile health (mHealth), artificial intelligence (AI) coaching, virtual reality (VR)/exergaming, or continuous glucose monitoring (CGM) alongside exercise training or structured physical activity. Results: Nineteen studies met the eligibility criteria. The evidence base was weighted toward wearable/app-based feedback and telemonitoring/mHealth/web-based approaches, with fewer studies on VR/exergaming, CGM-enabled exercise, and AI coaching. Most studies were randomised or cluster-randomised, but interventions were usually short term. Across categories, technology most consistently supported adherence, self-monitoring, accountability, remote supervision, and, in selected cases, physiology-informed personalisation. Direct MetS evidence was strongest for wearables with structured feedback, telemonitoring, mHealth, and web-based delivery, whereas AI coaching and CGM were supported by adjacent translational evidence. Conclusions: Technology-enhanced exercise and structured physical activity show promising but heterogeneous and still preliminary potential for MetS management. Key limitations include short follow-up, uneven representation across categories, inconsistent reporting of exercise dose/intensity fidelity and adverse events, and limited equity and implementation outcomes. Full article

Glucose transporter type 4 (GLUT4), encoded by the SLC2A4 gene, is the final effector of insulin-stimulated glucose uptake in insulin-sensitive tissues: skeletal muscle, adipose tissue, and cardiac muscle. Its dynamic localization, retained intracellularly under basal conditions and extensively translocated to the plasma membrane upon stimulation, makes it a master regulator of glycemic homeostasis. While the canonical insulin pathway (PI3K/Akt/TBC1D4) is the most potent and specific mechanism in the postprandial state, its dysfunction is centrally associated with insulin resistance and type 2 diabetes mellitus (T2DM). Crucially, robust alternative signaling networks function completely independently of insulin to regulate GLUT4 synthesis and translocation. Prominent among these are contraction-mediated pathways in skeletal muscle, which employ calcium signaling (via CaMKII), mechanical/metabolic stress sensors (via p38 MAPK γ/δ), and AMP-activated protein kinase (AMPK). This review critically integrates current knowledge, linking the molecular architecture and post-translational modifications of GLUT4 to the complex, tissue-specific signaling networks that govern its vesicular trafficking. We emphasize the hierarchy, redundancy, and interdependence of these pathways, highlighting differences between acute translocation and chronic transcriptional adaptations. Finally, we discuss how deciphering insulin-independent mechanisms offers promising therapeutic opportunities, particularly in identifying pharmacological targets that mimic the metabolic benefits of physical exercise. Full article

Background: Metabolic syndrome is associated with early impairments in cellular bioenergetics that are not fully captured by conventional body composition measures. Molecular hydrogen, produced endogenously through gut microbial fermentation and measurable in breath, has been implicated in redox and mitochondrial regulation. Whether breath hydrogen relates to preservation of intracellular, metabolically active tissue in metabolic syndrome remains unclear. Objectives: To examine the association between breath hydrogen concentration and an integrated cellular bioenergetic phenotype derived from intracellular body composition indices in sedentary adults with metabolic syndrome. Methods: Twenty-eight sedentary, middle-aged adults (51.2 ± 7.9 years, 19 females) with metabolic syndrome underwent fasting breath hydrogen assessment and multifrequency bioelectrical impedance analysis. A composite cellular bioenergetic phenotype was derived using principal component analysis of body cell mass, intracellular water, total body potassium, and glycogen. Associations between breath hydrogen and the composite phenotype were evaluated using Spearman correlation with bootstrapped confidence intervals, Theil-Sen regression, and Bayesian linear regression adjusted for age, sex, and waist circumference. Sensitivity analyses included fat-free mass. Results: A single principal component explained 98.6% of the variance across intracellular variables, indicating a highly coherent cellular bioenergetic phenotype. Breath hydrogen concentration was positively associated with this phenotype (ρ = 0.43, p = 0.021; BCa 95% CI 0.07–0.70). Theil-Sen regression confirmed a robust positive association (β = 0.017 per ppm hydrogen; 95% CI 0.002–0.046). Bayesian models showed posterior distributions centered on positive effect sizes, independent of central adiposity. In contrast, the association with fat-free mass alone was borderline. Conclusions: Breath hydrogen concentration reflects an integrated intracellular bioenergetic phenotype in sedentary adults with metabolic syndrome, tracking cellular quality rather than lean mass quantity. Breath hydrogen may serve as a non-invasive biomarker of cellular bioenergetic integrity and a potential tool for phenotype-guided metabolic interventions. Full article

Cystathionine β-synthase (CBS) deficiency causes classical homocystinuria with severe hyperhomocysteinemia (HHcy) that is inadequately controlled by current therapies. We tested whether liver-targeted CBS gene therapy provides durable biochemical and phenotypic rescue. Using a Cre-inducible adult mouse model of whole-body CBS loss, a single intravenous dose of AAV-DJ-hCBS (3 × 10¹² or 3 × 10¹³ vg/kg) was administered, and the animals were followed for 12 months. Vector biodistribution showed ~100-fold hepatic enrichment over the kidney and spleen. Both doses rapidly normalized plasma homocysteine (<8 µM), maintaining correction throughout the study while preventing alopecia, weight loss, and loss of adiposity. Liver histology showed resolution of inflammation, and only 2 of 19 mice developed anti-hCBS antibodies. Liver proteomics (3998 proteins quantified) revealed CBS deficiency-associated suppression of tRNA aminoacylation and dysregulation of lipid and carbon metabolism with an HNF4A transcriptional signature, all normalized by therapy. Liver metabolomics demonstrated accumulation of S-adenosylmethionine and S-adenosylhomocysteine and disruption of phosphatidylcholine synthesis, also corrected by treatment. Plasma metabolomics revealed systemic disturbances fully normalized by hepatic CBS restoration. These findings identify the liver as the central metabolic control point in CBS deficiency and support liver-targeted gene therapy as a durable corrective strategy. Full article