Cancer patients receiving doxorubicin (DOX) chemotherapy are at high risk of developing cardiac alterations, but the mechanisms remain elusive. Both breast cancer and DOX therapy are associated with dyslipidemia. We aimed to investigate whether changes in high-density lipoprotein (HDL) particles subclass distribution and functionalities are associated with DOX-induced cardiac alterations in breast cancer patients and tumor-bearing mice. HDL particles subclasses were assessed using the Lipoprint® system in breast cancer patients (n = 34) and tumor-bearing mice at baseline and after receiving DOX chemotherapy. HDL particles antioxidative properties were assessed by measuring paraoxonase-1 (PON1) activity. The ability of isolated HDL particles to protect against DOX-induced cytotoxicity was assessed in H9c2 cells. In breast cancer patients, DOX therapy reduced intermediate HDL particles subclasses, an effect that positively correlated with cardiac alterations. In mice, breast cancer shifted HDL particles subclasses distribution from intermediate to large HDL particles while DOX therapy increased small HDL particles. Both breast cancer and DOX therapy were associated with reduced PON1 activity. The decrease in intermediate HDL particles correlated with poorer cardiac function and lower PON1 activity. Interestingly, HDL particles isolated from tumor-bearing mice or from micereceiving DOX failed to protect H9c2 cells against DOX-induced cytotoxicity compared to HDL particles of healthy mice. In our study, a shift in HDL particles subclasses and functionalities correlated with cardiac alterations in cancer patients and mice treated with DOX. Consequently, our data warrant further research to explore whether targeting HDL particles may represent a therapeutic strategy to limit DOX-induced cardiotoxicity in breast cancer patients.

Purpose: To investigate associations between lipid oxidation biomarkers (oxylipins), antioxidant micronutrients, lipoprotein particles, and apolipoproteins in multiple sclerosis (MS). Methods: Blood and neurological assessments were collected from 30 healthy controls, 68 relapsing remitting MS subjects, and 37 progressive MS subjects. Hydroxy (H) and hydroperoxy lipid peroxidation products of the polyunsaturated fatty acids (PUFAs) arachidonic (20:4, ω-6), linoleic (octadecadienoic acid or ODE, 18:2, ω-6), eicosapentaenoic (20:5, ω-3), and α-linolenic (18:3, ω-3) acids were measured using liquid chromatography-mass spectrometry. Antioxidant micronutrients, including β-cryptoxanthin and lutein/zeaxanthin, were quantified by high-performance liquid chromatography. Lipoprotein and metabolite profiles were obtained using nuclear magnetic resonance spectroscopy. Regression models were adjusted for age, sex, body mass index, and disease status. Results: The 9-hydroxy octadecadienoic acid to 13-hydroxy octadecadienoic acid ratio (9-HODE/13-HODE ratio), which reflects autoxidative versus enzymatic oxidation, was associated with MS status (p = 0.002) and disability on the Expanded Disability Status Scale (p = 0.004). Lutein/zeaxanthin (p = 0.023) and β-cryptoxanthin (p = 0.028) were negatively associated with the 9-HODE/13-HODE ratio. Apolipoprotein-CII, a marker of liver-X-receptor (LXR) signaling, was associated with 9-HODE/13-HODE ratio and other oxylipins. Octadecadienoic fatty acid-derived oxylipins were negatively associated with LC3A, a mitophagy marker, and positively correlated with 7-ketocholesterol, a cholesterol autoxidation product. Conclusions: Autoxidation of PUFAs is associated with greater disability in MS. Higher β-cryptoxanthin and lutein/zeaxanthin were associated with reduced auto-oxidation. Lipid peroxidation shows associations with LXR signaling, mitophagy, inflammation, and cholesterol autoxidation.

Sonic hedgehog (Shh) morphogens are lipidated proteins that firmly attach to the outer plasma membrane (PM) of the cells that produce them. The process by which Shh is solubilized requires the transmembrane protein Dispatched1 (Disp), the soluble glycoprotein Scube2, the proteolytic removal of lipidated peptide termini, and the use of soluble lipoproteins (LPPs) as Shh transporters. However, their molecular interplay remains controversial. Here, we demonstrate that A Disintegrin and Metalloproteinase 10, Scube2, and Disp act synergistically to remove Shh from the PM and transfer it to LPP acceptors. We also demonstrate physical Scube2 interactions with LPPs and that these interactions increase Shh release. Finally, we demonstrate that Scube2 strongly binds to heparan sulfate (HS) on cell surfaces. These findings reveal Scube2's previously unknown role in binding low-abundance, soluble LPP carriers for Shh and recruiting these carriers to HS-rich Shh release sites at the PM to enhance morphogen release.

Ageing increases the risk of obesity and related metabolic diseases, emphasizing the need to understand how dietary interventions influence metabolism and metabolic health in older populations. This study aimed to investigate the impact of time‐restricted feeding (TRF) on energy balance, adipose tissue metabolism and overall metabolic health in aged female mice with high‐fat diet (HFD)‐induced obesity. A 10‐week TRF regimen was implemented in aged female mice following 12 weeks of HFD exposure. Mice were either maintained on HFD ad libitum (HFD‐AL) or subjected to TRF with HFD access restricted to a 10 h daily feeding window (HFD‐TRF). Glucose and insulin tolerance tests, meal pattern and indirect calorimetry were measured during the regimen. We showed that TRF partially reversed HFD‐induced weight gain and fat mass accumulation. In white adipose tissue TRF reduced average adipocyte size and increased the heterogeneity in adipocyte size distribution. TRF also led to increased VO2 and VCO2, along with a decreased respiratory efficiency ratio (RER) compared to the HFD‐AL group, particularly during the light phase. Meal pattern analysis showed increased meal frequency during the feeding window in HFD‐TRF mice relative to HFD‐AL. Additionally TRF lowered fasting blood glucose and reduced liver lipid accumulation. At the molecular level TRF induced significant metabolic adaptations in adipose tissue, including upregulation of genes involved in adipogenesis and lipid cycling, as well as depot‐specific alterations in mitochondrial oxidation and circadian rhythm gene expression. In conclusion TRF promotes beneficial metabolic adaptations and may serve as an effective dietary strategy to improve metabolic health in aged females.Key pointsTime‐restricted feeding (TRF) reduced body weight and fat mass, lowered blood glucose and decreased lipid accumulation in the liver.TRF also changed energy fuel utilization, increased metabolic activity of adipose tissue and altered the size and function of fat cells.Altered meal timing can trigger beneficial metabolic changes and suggests that TRF may help protect against obesity‐related diseases during ageing.

BackgroundType 2 diabetes mellitus (T2DM) increases the risk of cardiovascular disease (CVD), largely by alterations in the blood lipids and the metabolism of circulating lipoproteins (LPs). We studied whether the presence of additional risk factors, such as hypertension, or CVD itself, is associated with further alterations in the LP profiles in individuals with T2DM.MethodsWe performed LP profiling using 1H NMR spectroscopy and quantified 65 parameters in 393 healthy controls (HC) and in 390 T2DM patients with and without cardiovascular comorbidities. Univariate and multivariate analyses were used to assess alterations in LPs in diabetic patients.ResultsTriglycerides in all major LP classes, as well as particle numbers of very low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL) were increased in T2DM compared to HC. In contrast, particle numbers of low-density lipoproteins (LDL) and high-density lipoproteins (HDL) were reduced, suggesting slower lipolytic conversion of IDL to LDL and impaired clearance of triglyceride-enriched HDL. Univariate and multivariate analyses converged in identifying distinct LP profiles associated with T2DM, while differences between patients with and without hypertension or CVD were minor, indicating that T2DM is the primary factor driving LP dysregulation. T2DM, with or without cardiovascular comorbidities, also causes differential disruption of the correlation structure among LPs.ConclusionsT2DM is associated with major alterations in LP metabolism independent of hypertension or CVD. Thus, early lipid management in T2DM is important to mitigate CVD risk. Further research is needed to elucidate how T2DM progresses to CVD in relation to atherogenic LPs.Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s12933-025-03039-2.

To mitigate the harmful effects of oxidative stress, the body has evolved a range of defense mechanisms, with antioxidants playing a central role. Aronia melanocarpa exhibits strong antioxidant and anti-inflammatory effects due to its rich content of bioactive compounds, especially phenolic compounds. Paraoxonase 1 (PON1) is a liver-synthesized enzyme that circulates in the bloodstream by binding to high-density lipoprotein particles and exerts antioxidant effects by hydrolyzing lipid peroxides. Through this mechanism, it plays a critical role in mitigating oxidative damage implicated in various pathological conditions, including atherosclerosis, diabetes, and cancer, thereby representing a promising therapeutic target. In the present study, the potential effects of phenolic compounds naturally present in Aronia fruit on biological targets associated with the PON1 gene were investigated using in silico approaches. The potential targets of each phenolic compound were identified through bioinformatics platforms. The genes obtained were functionally classified through GO and enrichment analyses, with results visualized using the SR Plot. PON1 protein-interacting genes were identified using the STRING database. The pharmacokinetic properties selected phenolic compounds were evaluated using the ADMETLab platform, which identified naringenin and trans-ferulic acid as the most promising candidate compounds. The molecular interactions of the identified phenolic compounds with the proteins encoded by PON1 related hub genes were analyzed through molecular docking using the CB-Dock2. Results indicate that catechin, isorhamnetin, naringenin, quercetin, and rutin may modulate the PON1 signaling pathway, contributing to reduced oxidative stress and improved lipid metabolism. These findings suggest their potential pharmacological agent candidates.

The APOE4 variant was the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Individuals with APOE4 have an increased risk of developing the disease at an early age of onset. Similarly, APOE4 carriers are predisposed to high cholesterol levels and tend to have an increased risk of cardiovascular disease (CVD). The global allele frequency of APOE4 was 13.7%, underlining its widespread impact on global human health. Conversely, the relatively rare APOE2 allele was a genetic protective factor against AD and CVD. However, the mechanisms underlying this association remain to be elucidated. The apolipoprotein E (APOE) protein coats lipoprotein particles and mediates lipid transport and metabolism in the peripheral circulation and central nervous system (CNS). Although initial studies causally linked APOE lipoprotein particles (APOE particles) with lipid homeostasis, our understanding of the physiological and pathological effects of APOE particles has extended to amyloid-β (Aβ) accumulation, tau hyperphosphorylation and spread, as well as neuroinflammation in AD initiation and progression. Moreover, the most examined functions of APOE particles are reverse cholesterol transport, anti-inflammatory, anti-oxidation, and improvement of endothelial dysfunction in atherosclerotic CVD. This review outlines what is known about the structure and functions of APOE particles, emphasizing their involvement in AD and CVD pathogenesis, while also considering the crosstalk between the peripheral circulation and CNS. In addition, we discuss how these APOE particles act as therapeutic targets.

Long-chain fatty acids in the blood are prevented from unfettered movement into nonfenestrated tissues or the arterial wall. During fasting, nonesterified FAs are released from adipose tissue into the circulation and bind to albumin, forming a complex >65 kDa, with limited ability to efficiently cross endothelial cell (EC) barriers without a specific receptor. For this reason, nonhepatic tissue distribution of circulating FA parallels EC expression of the FA-binding protein CD36. The deletion of CD36 in ECs reduces nonesterified FA uptake by the heart, muscle, and brown adipose tissue. The other major transport system for FAs is via lipoproteins. Circulating FAs are contained within TRLs (triglyceride-rich lipoproteins), chylomicrons during the postprandial period, and VLDL (very low-density lipoprotein) both postprandially and during fasting. LPL (lipoprotein lipase) on capillary ECs releases FAs from TRLs and likely allows their passage into tissues, in part, via a CD36-independent process. ECs can also internalize lipoprotein particles, followed by the transendothelial movement of lipids. In this review, we will discuss the pathways of EC uptake of FAs from circulation, how this process affects both EC and tissue biology, and the importance of these processes for systemic metabolism and vascular health. We will conclude with speculations on methods to modulate EC FA uptake and their implications for human health.

Efficient fatty acid (FA) re-esterification is essential for lipid homeostasis in adipocytes, yet the mechanisms coordinating Coenzyme A (CoA) availability at the endoplasmic reticulum (ER)-a major site of lipid synthesis-remain unclear. Here, we identify TMEM120A as an ER-resident CoA-binding protein that regulates intracellular FA metabolism. TMEM120A interacts with the ER-localized acyl-CoA synthetase ACSL1 and ACSL3 to promote long-chain acyl-CoA synthesis and channeling into the ER, thereby facilitating FA re-esterification and lipid cycling during lipolysis. By relieving acyl-CoA-mediated feedback inhibition of lipolysis, TMEM120A enhances lipid turnover while protecting against ER stress and lipotoxicity. Adipocyte-specific deletion of Tmem120a in mice impairs lipolysis-induced energy expenditure and exacerbates inflammation and metabolic dysfunction under high-fat diet conditions. These findings establish TMEM120A as a critical regulator of ER CoA handling and lipid flux, revealing a previously unrecognized mechanism that links intracellular CoA dynamics to systemic energy balance and metabolic health.

BackgroundSmall dense low-density lipoprotein (sdLDL) is recognized as a reliable predictor of atherosclerotic vascular diseases and is also associated with the severity of diabetes. Vascular status directly affects tissue perfusion, indicating that sdLDL could serve as a potential marker for tissue perfusion in diabetic feet. However, an alternative possibility exists. In patients with diabetes, discrepancies can occur between vascular status and actual tissue perfusion due to complications related to diabetes such as neuropathy and hematologic changes in red blood cells. In such instances, sdLDL may not consistently correlate with tissue perfusion. Tissue perfusion is a crucial element in managing diabetic foot conditions. Despite acknowledging its importance, no studies to date have explored the relationship between sdLDL levels and tissue perfusion in diabetic feet. This prospective study seeks to explore this correlation.MethodsFifty patients with diabetes were enrolled in the study. Tissue perfusion was assessed by measuring the foot’s transcutaneous oxygen pressure (TcPO2). SdLDL levels were determined based on the mean low-density lipoprotein (LDL) particle size, proportion of sdLDL as a percentage of total LDL, and LDL subfraction score. Correlations between TcPO2 and each variable were evaluated through scatter plots, and correlation coefficients (R) with corresponding P values were calculated. Statistical analyses were conducted for all participants and further stratified into two subgroups based on a TcPO2 threshold of ≥ 40 mmHg and < 40 mmHg.ResultsIn the overall analysis (n = 50), no statistically significant relationships were detected between TcPO2 and sdLDL size, sdLDL percentage, or LDL subfraction score. Nevertheless, in the TcPO2 ≥ 40 mmHg subgroup (n = 29), a statistically significant positive correlation was found between mean LDL particle size and TcPO2 (R = 0.414, P = 0.026). In contrast, statistically significant negative correlations emerged between sdLDL percentage and TcPO2 (R = −0.415, P = 0.025), as well as between LDL subfraction score and TcPO2 (R = −0.419, P = 0.024).ConclusionThis study identified a significant correlation between sdLDL levels and tissue perfusion in diabetic feet with TcPO2 ≥ 40 mmHg, but no significant correlation in those with TcPO2 < 40 mmHg.

Relevance. Familial hypercholesterolemia (FH) is a monogenic hereditary disorder characterized by impaired lipid metabolism. The prevalence of FH in the general population averages 0.32% (95% CI: 0.26-0.39%). The disease can have both autosomal dominant and autosomal recessive inheritance patterns. Eight FH phenotypes associated with mutations in the LDLRAP1, PCSK9, APOA2, APOB, GHR, GSBS, EPHX2, and LDLR genes are known, which can lead to early manifestation of the pathology. The aim of this review is to comprehensively analyze current literature data on the molecular genetics, biological, and psychological aspects of FH. Analysis of signaling pathways in FH revealed three clusters of genes and their encoded proteins responsible for the following processes: assembly, remodeling, and clearance of plasma lipoproteins (genes: LDLR, LDLRAP1, VLDLR, NPC1L1, APOC1, LPA, CETP, MTTP, APOB, PCSK9); cholesterol metabolism (gene: PPP1R17);regulation of plasma lipoprotein particle levels (gene: ANGPTL3). The proteins PCSK9, APOB, and MTTP were identified as key elements (central hubs) of these metabolic networks. The PPP1R17 protein is involved in the mechanisms of long-term depression, a form of synaptic plasticity. Furthermore, the literature describes an association of FH with five other genes: ABCG5, ABCG8, STAP1, CYP7A1, LIPA, and PNPLA5. Conclusion. Thus, for the early diagnosis and effective management of patients with FH, it is necessary to consider not only the expanded spectrum of associated genes and proteins but also the psychological state of patients, particularly their levels of anxiety, depression, and stress.

Peripheral nerve injuries represent a significant clinical challenge due to their limited regenerative capacity. Although immediate repair is ideal, delayed intervention is often unavoidable. Understanding the mechanisms underlying both conditions is essential for optimizing functional recovery. Thus, this study aimed to uncover key pathways in nerve regeneration through the first transcriptomic analysis of regenerating nerves within a conduit, also comparing immediate and delayed nerve repair over time in a rat model. Immediately after injury, or following a delay of three months, microsurgical intervention with a chitosan tube was performed to repair an 8-mm median nerve gap, and regenerated nerves inside the conduit were collected at 14- and 21-days for morphometric analysis, and at 7-, 14-, and 21-days post-repair for RNA sequencing. Morphometric analysis based on absolute values showed a significant reduction in Schwann cell and axonal areas at 14-days, along with a decreased number of blood vessels and an overall smaller section area at 21-days in the delayed group. However, when normalized to the total section area to assess the relative proportions occupied by Schwann cells, axons, and vessels, no significant differences were observed between immediate and delayed groups at 21-days. To correlate morphometric data with transcriptomic profiles, RNA sequencing was conducted. Approximately 25,000 genes were differentially expressed in regenerating nerves compared to healthy controls, mainly related to inflammatory response, phagocytosis, cell signalling, and response to lipoprotein particles. Only 137 genes differed between delayed and immediate repair. Gene ontology analysis showed that the most enriched pathways were involved in angiogenesis, especially at 7-days, in accordance with the higher density of vessel area observed at 14-days. Overall, the comparison between the experimental groups indicated that immediate repair initiated a more rapid regenerative response, while delayed repair followed a slower, but ultimately convergent, trajectory highlighting that regeneration is postponed and partially impaired. Indeed, it is noteworthy that the nerve calibre was hindered in the delayed compared to the immediate repair. These findings underscore the importance of early intervention, but also suggest that, over time, delayed repair might achieve similar regenerative outcomes, especially if novel therapies will be developed to further enhance recovery.

Myocardial infarction (MI) is one of the most serious cardiovascular diseases in the world. Nevertheless, the majority of diagnostic procedures conducted subsequent to the illness do not provide any means to prevent several risks associated with MI. Blood and urine tests are frequently employed in clinical examinations to detect cardiovascular diseases at an early stage. Mendelian randomization (MR) is commonly employed to explore disease-trait relationships and uncover therapeutic targets. Our goal was to explore the genetic links between 35 blood and urine biomarkers and MI. Blood and urine biomarker MR correlations with MI risk were studied. In version R10, the UK Biobank and Finnish databases included blood and urine marker data and MI data (26,060 cases and 343,079 controls). We performed bidirectional 2-sample MR with 4 methods: inverse variance weighted, MR-Egger, weighted median, and weighted mode. Final causal associations were determined by inverse variance weighted. Sensitivity analyses (heterogeneity, pleiotropy) were conducted. MR-PRESSO and PhenoScanner were used to exclude invalid instruments. We used multivariate MR to filter the most important genes without including other positive genes. To identify positive gene pathways and gene networks that cause MI, we employed GeneMANIA for gene prediction. The findings revealed a positive genetic association between the 8 blood and urine biomarker levels and an elevated risk of MI. There are apolipoprotein B (APOB), glycated hemoglobin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, sex hormone-binding globulin, triglycerides, and urate. Moreover, APOB, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol selectively affect MI through the rejection of other positive gene stems. Finally, APOB and numerous genes strongly impact MI development. APOB collaborates with related genes to regulate plasma lipoprotein particle levels, sterol homeostasis, organization, lipid homeostasis, and remodeling in MI. Our research further reveals the causal relationship between MI and blood/urine biomarkers, providing a new perspective for the prevention, diagnosis, and treatment of MI. Blood and urine marker tests can subsequently be conducted based on these results to detect MI and study the underlying mechanisms linking these metabolites to MI.

BackgroundHypercholesterolemia remains a key risk factor for atherosclerotic cardiovascular disease (CVD). The clearance of low-density lipoprotein (LDL) particles from plasma, primarily mediated by LDL receptor (LDLR) activity, is an established target of lipid-lowering therapies. Enhancing reverse cholesterol transport via high-density lipoprotein and modulating cholesterol efflux from macrophages further complements atherogenic risk reduction. Enhancing LDLR expression and supporting effective cholesterol efflux via ATP binding cassette subfamily A member 1 (ABCA1) are therefore essential therapeutic targets for CVD prevention. Recent studies implicate autophagy in lipid and cholesterol metabolism. This study examines the influence of autophagy on LDLR and ABCA1 expression in hepatocytes after treatment with the AKT inhibitors MK-2206 and triciribine.MethodsAutophagy was disrupted pharmacologically using SBI-0206965 and genetically via short-interfering RNA (siRNA) targeting autophagy-related genes ATG5 and ATG7 in HepG2. Stable knockout (KO) HAP1 cell lines for ATG5 and ATG7 were generated by CRISPR to ensure complete abrogation of autophagy. The possible effect of SREBP2 silencing on MK-2206-induced LDLR expression was assessed in HepG2 cells. Quantitative analyses included measurement of ABCA1, LDLR and MAP1LC3B (LC3B) expression at protein and mRNA levels, in addition to ULK1 and SQSTM1 (p62) mRNA levels.ResultsMK-2206 administration increased hepatic LDLR and the autophagy marker LC3B. Triciribine did not show evidence of autophagy induction, and neither AKT inhibitors modified ABCA1 expression. Inhibition of autophagy, either by SBI-0206965 or by siRNA targeting ATG5 and ATG7, reduced the MK-2206-mediated LDLR upregulation by approximately 50% in HepG2. In KO-ATG5/ATG7 HAP1 cells, the MK-2206-induced LDLR expression decreased by 70% compared to wild-type cells, and ABCA1 expression was abolished.ConclusionBoth pharmacological and genetic impairment of autophagy attenuate the LDLR-inducing effects of MK-2206, supporting a role for autophagy in the regulation of cholesterol metabolism. The substantial reduction of ABCA1 expression in autophagy-deficient cells further indicates that autophagy is involved in cholesterol efflux regulation.

Protective ApoE variants support neuronal function by effluxing oxidized phospholipids.

The role of age and sex in paraoxonase 1 activity in patients with Alzheimer's dementia.

Lipoprotein(a) as a multisystem disease risk factor: Clinical implications and the Dawn of RNA-based therapeutics.

Introduction Sarcopenia is increasingly linked to metabolic dysregulation, including dyslipidemia. The LDL-C/ApoB ratio (LAR), reflecting cholesterol content per atherogenic lipoprotein particle, may serve as a novel biomarker for sarcopenia risk. This study aimed to investigate the association between LAR and sarcopenia using data from the National Health and Nutrition Examination Survey (NHANES). Material and methods Data from NHANES cycles 2011-2016 were analyzed between July 2024 and February 2025. Sarcopenia was defined using dual-energy X-ray absorptiometry (DXA)-derived appendicular lean mass (ALM) standardized to body mass index (BMI). Multivariable logistic regression, restricted cubic spline (RCS) regression analysis, subgroup analysis, and interaction tests were applied to evaluate the relationship between LAR and sarcopenia, adjusting for covariates. Results A negative correlation between LAR and sarcopenia was observed in 3,235 participants included in the study (OR: 0.399, 95% CI: 0.224-0.712, P = 0.007), which was further confirmed to be non-linear via RCS regression analysis (Pnon-linear = 0.037), with one significant inflection point identified, and participants with LAR ≥ 1.268 demonstrated a significantly reduced risk of sarcopenia. Subgroup analyses and interaction tests indicated that the association between LAR and sarcopenia remained consistent across different subgroups and was not modified by other covariates. Conclusions Elevated LAR is significantly associated with lower sarcopenia risk, suggesting its potential role as a biomarker for muscle health. Further studies are needed to elucidate underlying mechanisms and validate these findings prospectively.

Down syndrome (DS) is associated with elevated rates of insulin resistance and chronic metabolic disease, yet its detailed metabolic and lipidomic profiles, particularly in pediatric populations, remain poorly defined. To characterize plasma lipid profiles in children and young adults with DS and overweight or obesity, to determine degree of lipid heterogeneity and if the observed dyslipidemia is independent of obesity severity. An extended objective is to search for metabolite features that may differentiate DS from weight‑matched controls. Plasma samples from 12 African‑American participants with DS (age 11-21 years, all overweight or obese) and 513 age‑matched overweight or obese controls were profiled by Nightingale1H‑NMR spectroscopy (249 metabolites). Because all participants with DS in our cohort were overweight or obese, we restricted the control group to individuals with comparable weight status to minimize confounding by adiposity. Metabolites were log₂‑transformed and standardized to z-scores. Partial least‑squares discriminant analysis (two components) was followed by k‑means clustering (k = 2). Cluster distributions were compared by χ² test, and metabolite differences between clusters, stratified by obesity class, were assessed using Welch's t‑tests and Benjamini-Hochberg false‑discovery correction. Nine of twelve DS samples (75%) clustered into a dyslipidemic profile (cluster 1), compared to 209 of 513 controls (41%), demonstrating a significant enrichment (p = 0.033). Among controls, cluster assignment showed no association with obesity class. Across all obesity strata, 92 metabolites consistently differed between clusters. Cluster 1 exhibited a distinct lipidomic pattern marked by triglyceride enrichment across the lipoprotein spectrum [from extra-extra-large very-low-density lipoprotein (XXL-VLDL) to high-density lipoprotein (HDL)], elevated remnant cholesterol, increased intermediate-density lipoprotein (IDL) and HDL particle concentrations, and cholesterol-ester-poor, triglyceride-rich HDL particles. Additionally, this cluster showed elevated levels of saturated and monounsaturated fatty acids, alongside a relative depletion of Ω-6 polyunsaturated fatty acids. Together, these features recapitulate a lipid profile associated with insulin resistance and pro-inflammatory metabolic dysfunction. A lipidomic profile characterized by high triglyceride and low cholesterol ester content is highly prevalent among children with DS and overweight or obesity, and present in approximately 40% of overweight or obese controls, irrespective of obesity severity. This insulin-resistant phenotype, independent of adiposity, likely reflects intrinsic alterations in lipid metabolism. The use of the Nightingale1H‑NMR offers a scalable and clinically accessible platform for detecting this metabolic signature, offering promise for early risk stratification and precision management of metabolic dysfunction in DS.

Chronic obstructive pulmonary disease (COPD) pathogenesis involves the cross-links between inflammation, oxidative stress, and metabolic dysregulation leading to irreversible airflow limitation. The metabolic vulnerability index (MVX) integrates inflammation and metabolic malnutrition related metabolic biomarkers that may reflect these underlying mechanisms. This study aimed to assess the associations of MVX score with risk of incident COPD and lung function in the UK Biobank. The sex-specific MVI score was developed as a composite biomarker, which integrates six nuclear magnetic resonance (NMR)-based plasma biomarkers, including glycoprotein acetyls (GlycA), small high-density lipoprotein particles (sHDL), citrate, and the branched-chain amino acids (isoleucine, leucine, and valine). Multivariable Cox or linear regression model was used to assess the association of MVX score with risk of COPD and lung function level, respectively. A total of 240,873 participants were included. The results showed that per 1-SD increase in MVX score was associated with a 19% increased risk of COPD (HR: 1.19, 95% CI: 1.16, 1.21). Furthermore, compared to low MVX score group (Q1), high MVX score group (Q4) was associated with 55% increased risk of COPD (HR: 1.55, 95% CI: 1.45, 1.66). Furthermore, per 1-SD increase in MVX score was associated with decreased lung function level, including FVC (β: -67.55, 95% CI: -71.36, -63.74) and FEV1 (β: -52.24, 95% CI: -55.34, -49.14). Compared to low MVX score group (Q1), high MVX score group (Q4) was also associated with lower FVC (β: -174.78, 95% CI: -185.47, -164.10) and FEV1 (β: -135.72, 95% CI: -144.42, -127.02) levels. Furthermore, we observed the significant dose-response relationship between MVX score and COPD risk and lung function level. Our study demonstrates that higher MVX score, reflecting inflammation and metabolic malnutrition, is significantly associated with increased COPD risk and impaired lung function. These findings suggest that MVX score may help identify high-risk individuals for early intervention.