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PubMed2025

Alterations in ether lipid metabolism in obesity revealed by systems genomics of multi-omics datasets.

Ratios between two metabolites are sensitive indicators of metabolic changes. Lipidomic profiling studies have revealed that plasma ether lipids, a class of glycero- and glycerophospho-lipids with reported health benefits, are negatively associated with obesity. Here, we utilized lipid ratios as surrogate markers of lipid metabolism to explore the processes underlying the inverse relationship between ether lipid metabolism and obesity. Plasma lipidomics data from two independent human cohorts (n = 10,339 and n = 4,492) were integrated to assess the associations between 82 lipid ratios and obesity-related markers in males and females. Results were externally validated using mouse transcriptomics data from the Hybrid Mouse Diversity Panel (n = 152-227 across 74 strains). Genome-wide association studies using imputed genotypes from a population cohort (n = 4,492) were performed to examine the genetic architecture of the ratios. Findings showed that waist circumference (WC), body mass index, and waist-hip ratio were inversely associated with total plasmalogens relative to total phospholipids in both sexes. Ratios comprising product-substrate pairs positioned either side of enzymes involved in plasmalogen synthesis and degradation showed positive and negative associations with WC, respectively. Branched-chain fatty acids negatively correlated with WC, while omega-6 polyunsaturated fatty acids exhibited differing associations depending on their position within the pathway. Mouse transcriptomics corroborated these results. Genomics data showed strong associations between ratios containing choline-plasmalogens and single-nucleotide polymorphisms in the transmembrane protein 229B (TMEM229B) gene region. This work demonstrates the utility of lipid ratios in understanding lipid metabolism. By applying the ratios to multi-omic datasets, we identified alterations in enzymatic activity and genetic variants likely affecting ether lipid synthesis in obesity that could not have been obtained from lipidomics data alone. Additionally, we characterized a potential role for TMEM229B, offering new perspectives on ether lipid metabolism and regulation.

Humans↗

PubMed2026

Toward large-scale mass spectrometry-based omics for clinical applications.

INTRODUCTION: As healthcare advances toward personalized medicine, mass spectrometry-based research is advancing our understanding of cellular biology and disease states, and translating these findings into clinical applications. This review highlights recent advances in methodology and technology that demonstrate the capabilities of mass spectrometry-based proteomics, lipidomics, and metabolomics in clinical practice. AREAS COVERED: The ability to directly analyze functional molecules with mass spectrometry uncovers crucial clinical information. Each data modality (proteins, lipids, and metabolites) provides essential insight into healthy and disease states. As technology advances, integrating data from different modalities unlocks new possibilities for clinical research. To gain the most from this multi-omic data, unsupervised integration methods can provide detailed insights into complex biological processes. As the field applies this knowledge, healthcare could experience significant leaps in the near future. This review examines recent advancements in mass spectrometry-based proteomics, lipidomics, and metabolomics, focusing on how improvements in sample preparation, automation, and multi-omics data integration are making large-scale clinical studies more accessible. EXPERT OPINION: Recent technical and methodological advancements in mass spectrometry analysis have propelled healthcare toward a tipping point, shifting from traditional RNA- and DNA-based research to downstream analysis of protein, lipid, and metabolite effectors.

Humans↗

PubMed2026

Multi-omics characterization of flavor profile differences in the Longissimus thoracis between Angus and Hereford cattle.

BACKGROUND: Angus and Hereford cattle are premier breeds widely used in genetic improvement and crossbreeding programs to enhance meat quality, yet the flavor differences between them remain poorly understood. RESULTS: In this study, we performed an integrated analysis using headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry (HS-SPME-GC-MS)-based volatile metabolomics, lipidomics, and untargeted metabolomics to characterize the flavor profiles of the Longissimus thoracis (LT) muscle from both breeds and to identify potential precursor substances underlying flavor formation. In total, we identified 76 differential volatile organic compounds (VOCs) among the 493 candidate VOCs. By combing relative odor activity value (ROAV) and sensory attribute annotation, 2,3-butanedione which may contribute to the creamy aroma was revealed as the core differential VOC between the two breeds. This finding was robustly validated across SHAP (Shapley additive explanations) analysis, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment, and flavor annotation. Lipidomic analysis revealed 689 differential lipids primarily belonging to classes such as phosphatidylcholine, triglycerides, and phosphatidylethanolamine. Correlation analysis further linked these lipid profiles to flavor, showing that fatty acids (FAs) including FA(19:0), FA(18:2 + O), FA(14:1), FA(16:1), and FA(14:0) were significantly correlated with 2,3-butanedione. Notably, the unsaturated fatty acids (UFAs) in the Longissimus thoracis (LT) of Hereford cattle exhibited higher double bond content compared to Angus cattle, suggesting a greater potential for rich flavor development. Untargeted metabolomics revealed that nine of the 9474 metabolites were significantly correlated with both 2,3-butanedione and FAs, including norepinephrine, l-beta-aspartyl-l-leucine, and artemetin. CONCLUSIONS: Overall, our research has identified differential flavor compounds and potential precursor substances between Angus cattle and Hereford cattle, providing targeted guidance for breed improvement. © 2026 Society of Chemical Industry.

2,3‐butanedione↗

PubMed2025

Protective effects of liver-derived apolipoprotein A1 against heat stress-induced hypothalamic lipid metabolism and blood-brain barrier integrity.

Heat stress (HS), a prevalent occupational and environmental hazard, has increasingly been recognized as a major contributor to multiple physiological disorders. The hypothalamus, a key regulator of thermoregulation and endocrine signaling, is especially susceptible to metabolic and inflammatory disturbances induced by HS. This study investigates the interplay among lipid metabolism, blood-brain barrier (BBB) integrity, and neuroinflammation in the hypothalamus under HS conditions, with a specific focus on apolipoprotein A1 (APOA1) as a potential protective factor. To achieve this, we integrated proteomic and lipidomic analyses with experimental validation in porcine and murine models. Proteomic analysis identified 266 differentially expressed proteins (DEPs) in the hypothalamus following HS, with significant enrichment in lipid metabolism pathways-especially glycerophospholipid (GP) metabolism-in which APOA1 displayed a marked increase. Lipidomic profiling further revealed HS-induced disruptions in phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) metabolism. Additionally, blood-brain barrier integrity was compromised, as evidenced by increased perivascular IgG extravasation, reduced pericyte coverage, and decreased expression of tight junction proteins ZO-1 and Occludin. HS also triggered pronounced neuroinflammation, characterized by elevated levels of iNOS, GFAP, and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Notably, administration of D-4F, an APOA1 mimetic peptide, alleviated blood-brain barrier damage, reduced neuroinflammation, and preserved synaptic integrity, thereby suggesting a neuroprotective role for APOA1 in HS-induced hypothalamic dysfunction. These findings underscore the critical role of lipid metabolism in maintaining hypothalamic homeostasis under HS conditions and position APOA1 as a key regulator with potential therapeutic implications for mitigating HS-related neuroinflammatory and metabolic disturbances.

Blood-Brain Barrier↗

PubMed2026

Multi-omics dynamic profiling reveals predictive biomarkers for first-line immunochemotherapy in extensive-stage small-cell lung cancer.

BACKGROUND: Extensive-stage small-cell lung cancer (ES-SCLC) is associated with a poor prognosis. Although first-line immunochemotherapy improves clinical outcomes, robust prognostic biomarkers for this treatment modality remain unavailable. The aim of this study was to identify non-invasive, easily accessible, and dynamically monitored biomarkers of ES-SCLC by machine learning integrating serum metabolomics, lipidomics, and proteomics at multiple time points. METHODS: A total of 816 serum samples were collected from ES-SCLC patients receiving first-line immunotherapy combined with chemotherapy or first-line chemotherapy for metabolomics, lipidomics, and proteomics analysis. The immunochemotherapy cohort was randomly divided into training and validation subsets at a 6:4 ratio. Biomarkers were identified using machine learning algorithms, and their prognostic significance was evaluated through receiver operating characteristic (ROC) analysis, Kaplan–Meier survival analysis, and multivariate Cox regression. Potential metabolic pathways and mechanisms were further explored via integrated multi-omic analysis. RESULTS: The immunochemotherapy exhibited a prolonged median progression-free survival (PFS) and higher objective response rate (ORR) compared to the chemotherapy group. A total of 5 serum metabolites (uric acid, L-aspartate-semialdehyde, dimethisterone, xanthine, L-cysteine), 6 lipids (Cer d18:1/26:0, Cer d18:2/25:0, SM d18:1/20:1, SM d17:1/25:1, DG O-18:1_16:0, PS 18:0_24:0), and 3 proteins (ACIN1, ACSL4, PHGDH) were identified and constructed into independent prognostic models. Among patients receiving immunochemotherapy, those categorized as low-risk based on the model demonstrated significantly longer PFS compared with those in the high-risk group. These prognostic signatures also retained predictive value in patients who underwent second-line treatment with anlotinib plus immunochemotherapy. Integrated analysis revealed that glycine, serine, and threonine metabolism was the commonly enriched pathway across all three omics layers. Notably, PHGDH (protein), L-aspartate-semialdehyde and L-cysteine (metabolites), and PS (18:0_24:0) (lipid), key elements in this pathway, were all incorporated in the predictive model. In addition, models of the composition of these substances after one cycle of treatment can still predict the prognosis of patients. CONCLUSION: In this study, we constructed and validated a set of non-invasive, dynamically monitorable prognostic models (containing 5 metabolites, 6 lipids, and 3 proteins) using machine learning by integrating multiple time point data from the serum metabolome, lipid panel, and proteome to accurately distinguish the prognostic risk of patients with ES-SCLC receiving immunochemotherapy. PFS was significantly prolonged in patients in the low-risk group, and this model remains predictive in the subsequent second-line treatment with anlotinib in combination with immunochemotherapy. Glycine-serine-threonine metabolic pathway may be the key mechanism, of which PHGDH, L-aspartate semialdehyde, L-cysteine and PS (18:0_24:0) are the core predictors. This study provides the first multi-omics dynamic prognostic tool for ES-SCLC immunochemotherapy and reveals potential therapeutic targets.

Humans↗

PubMed2026

Subchronic benzo[a]pyrene exposure disrupts APOE4-regulated lipid metabolism to induce Tau hyperphosphorylation and cognitive deficits.

BACKGROUND: Benzo[a]pyrene (B[a]P) is both a carcinogen and a potent neurotoxic pollutant. Despite growing evidence linking B[a]P to neurological dysfunction, the responsible mechanisms have not been elucidated. METHODS: Here, we employed human apolipoprotein E4 (hAPOE4) transgenic mice and APOE knockout (APOE-KO) mice to evaluate the influence of APOE on B[a]P-mediated neurotoxicity. hAPOE4 mice overexpress the human APOE4 isoform, whereas APOE-KO mice lack APOE expression; wild-type C57BL/6 J mice served as controls. Animals received intraperitoneal injections of B[a]P at 0, 2.5, or 6.25 mg/kg on alternate days for 3 months. Spatial memory and learning were examined via Morris Water Maze (MWM). Neuronal morphology, including dendritic branching and spine density in the CA1 region of the hippocampus and dentate gyrus (DG), was assessed using Golgi-Cox staining. Neurofibrillary tangles were detected by silver glycine staining. Tau, phosphorylated Tau (Ser199 and Ser396), and LRP1 were evaluated using Western blot and immunohistochemical analyses. Chromatin immunoprecipitation PCR (ChIP-PCR) was undertaken to examine the regulation of APOE4 expression by the aryl hydrocarbon receptor (AHR). In addition, both untargeted metabolomics and lipidomics analyses were conducted following B[a]P exposure. RESULTS: B[a]P led to pronounced impairments in mouse spatial memory and learning, shown by greater escape latency, less time in the target quadrant, and a decreased number of platform crossings in MWM tests. Structural analyses revealed a significant reduction in dendritic branching within the hippocampal CA1 and DG regions. These neurobehavioral and morphological deficits were most severe in hAPOE4 mice, which displayed greater cognitive impairment and more extensive dendritic loss than B[a]P-treated wild-type mice, indicating that APOE4 amplifies B[a]P-induced neurotoxicity. ChIP assays demonstrated that B[a]P modulates APOE4 transcription through AHR-dependent mechanisms. Additionally, metabolomics and lipidomics analyses revealed widespread B[a]P-induced metabolic remodeling, suggesting that disrupted lipid metabolism and altered neuronal membrane integrity may contribute to the observed neurotoxicity and cognitive dysfunction. CONCLUSION: Collectively, the results indicate that B[a]P-mediated neurotoxicity may be facilitated, at least in part, by APOE4-dependent dysregulation of lipid metabolic pathways.

Animals↗

PubMed2020

Metabolic Dysregulation of the Lysophospholipid/Autotaxin Axis in the Chromosome 9p21 Gene SNP rs10757274.

BACKGROUND: Common chromosome 9p21 single nucleotide polymorphisms (SNPs) increase coronary heart disease risk, independent of traditional lipid risk factors. However, lipids comprise large numbers of structurally related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here, we applied lipidomic and genomic approaches to 3 model systems to characterize lipid metabolic changes in common Chr9p21 SNPs, which confer ≈30% elevated coronary heart disease risk associated with altered expression of ANRIL, a long ncRNA. METHODS: Untargeted and targeted lipidomics was applied to plasma from NPHSII (Northwick Park Heart Study II) homozygotes for AA or GG in rs10757274, followed by correlation and network analysis. To identify candidate genes, transcriptomic data from shRNA downregulation of ANRIL in HEK-293 cells was mined. Transcriptional data from vascular smooth muscle cells differentiated from induced pluripotent stem cells of individuals with/without Chr9p21 risk, nonrisk alleles, and corresponding knockout isogenic lines were next examined. Last, an in-silico analysis of miRNAs was conducted to identify how ANRIL might control lysoPL (lysophosphospholipid)/lysoPA (lysophosphatidic acid) genes. RESULTS: Elevated risk GG correlated with reduced lysoPLs, lysoPA, and ATX (autotaxin). Five other risk SNPs did not show this phenotype. LysoPL-lysoPA interconversion was uncoupled from ATX in GG plasma, suggesting metabolic dysregulation. Significantly altered expression of several lysoPL/lysoPA metabolizing enzymes was found in HEK cells lacking ANRIL. In the vascular smooth muscle cells data set, the presence of risk alleles associated with altered expression of several lysoPL/lysoPA enzymes. Deletion of the risk locus reversed the expression of several lysoPL/lysoPA genes to nonrisk haplotype levels. Genes that were altered across both cell data sets were DGKA, MBOAT2, PLPP1, and LPL. The in-silico analysis identified 4 ANRIL-regulated miRNAs that control lysoPL genes as miR-186-3p, miR-34a-3p, miR-122-5p, and miR-34a-5p. CONCLUSIONS: A Chr9p21 risk SNP associates with complex alterations in immune-bioactive phospholipids and their metabolism. Lipid metabolites and genomic pathways associated with coronary heart disease pathogenesis in Chr9p21 and ANRIL-associated disease are demonstrated.

Chromosomes, Human, Pair 9↗

PubMed2024

Membrane-bound O-acyltransferase 7 (MBOAT7) shapes lysosomal lipid homeostasis and function to control alcohol-associated liver injury.

Recent genome-wide association studies (GWAS) have identified a link between single-nucleotide polymorphisms (SNPs) near the MBOAT7 gene and advanced liver diseases. Specifically, the common MBOAT7 variant (rs641738) associated with reduced MBOAT7 expression is implicated in non-alcoholic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), and liver fibrosis. However, the precise mechanism underlying MBOAT7-driven liver disease progression remains elusive. Previously, we identified MBOAT7-driven acylation of lysophosphatidylinositol lipids as key mechanism suppressing the progression of NAFLD (Gwag et al., 2019). Here, we show that MBOAT7 loss of function promotes ALD via reorganization of lysosomal lipid homeostasis. Circulating levels of MBOAT7 metabolic products are significantly reduced in heavy drinkers compared to healthy controls. Hepatocyte- (Mboat7-HSKO), but not myeloid-specific (Mboat7-MSKO), deletion of Mboat7 exacerbates ethanol-induced liver injury. Lipidomic profiling reveals a reorganization of the hepatic lipidome in Mboat7-HSKO mice, characterized by increased endosomal/lysosomal lipids. Ethanol-exposed Mboat7-HSKO mice exhibit dysregulated autophagic flux and lysosomal biogenesis, associated with impaired transcription factor EB-mediated lysosomal biogenesis and autophagosome accumulation. This study provides mechanistic insights into how MBOAT7 influences ALD progression through dysregulation of lysosomal biogenesis and autophagic flux, highlighting hepatocyte-specific MBOAT7 loss as a key driver of ethanol-induced liver injury.

Animals↗

PubMed2026

Multiomics profiling of plasma reveals lipid-immune dysregulation and exosome remodeling in mpox and mpox-HIV co-infection.

BACKGROUND: Monkeypox virus (MPXV) infects diverse human cell types, and human immunodeficiency virus (HIV) co-infection is common. The immunometabolic consequences of MPXV infection, and how it may be altered by HIV, remain poorly defined. METHODS: We performed quantitative plasma lipidomics and precise metabolomics in a discovery cohort (n = 81) comprising MPXV-monoinfected (MPLWOH), MPXV-HIV-coinfected (MPLWH), and HIV-monoinfected (PLWH) patients and healthy controls, integrating exosome proteomics, cytokine profiling, and transcriptomics of exosome-treated HepG2 and A549 cells for functional interpretation. An independent validation cohort (n = 65) was used to assess cross-cohort reproducibility. FINDINGS: MPXV infection induced broad lipid remodeling, with elevations in phosphatidylserine (PS) and phosphatidylethanolamine (PE) and reductions in phosphatidylcholine (PC), lysophospholipids, cholesteryl ester (CE), and exosomal lecithin-cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL). These lipid alterations were correlated with tissue injury markers and inflammatory cytokines. The MPLWH group exhibited more severe metabolic disruption, including marked sulfatide (SL) depletion, lower cholesterol and high-density lipoprotein cholesterol (HDL-c), and extensive rewiring of lipid-cytokine associations. SL depletion in MPLWH correlated with abundances of COPI-mediated retrograde trafficking proteins in exosomes. Transcriptomic profiling of exosome-treated cells provided functional validation: MPLWOH exosomes induced lipid metabolism and repair-associated epithelial programs, while MPLWH exosomes drove phospholipid remodeling and acute inflammatory and mucosal barrier-stress responses. CONCLUSIONS: MPXV infection reprograms host lipid metabolism and exosome composition, with HIV co-infection amplifying inflammatory, metabolic, and trafficking disruptions. These convergent multi-omics signatures link systemic lipid dysregulation to exosome-mediated immunomodulation and identify potential targets for host-directed interventions. FUNDING: This study was funded by the Major Project of Guangzhou National Laboratory.

Adult↗

PubMed2026

Bridging genotype, phenotype, and clinical insight: the role of multi-omics in cardiovascular disease.

INTRODUCTION: It is increasingly evident that the multifactorial nature of cardiovascular disease requires the combination of different omics approaches for improving our mechanistic understanding, identifying novel drug targets, and developing accurate diagnostic, predictive, and prognostic biomarker panels. AREAS COVERED: We review the current state and the potential of multi-omics in cardiovascular disease, with a specific focus on plasma-, spatial-, and single-cell approaches. We discuss lipidomics as a genotype‑to‑phenotype bridge, the utility of remote longitudinal monitoring via microsampling/dried blood spots, and emerging clinical‑trial integrations of multi-omics approaches. We outline critical gaps in standardization and how to overcome these, pre‑analytical challenges and constraints that are often neglected, and data‑integration methods spanning from canonical correlation analysis to modern machine learning approaches. EXPERT OPINION: Multi‑omics can shape cardiovascular care by identifying drug targets in diseased tissue and by yielding small, usable biomarker panels.

Humans↗

PubMed2025

Physiological and metabolic responses of Zymomonas mobilis to lignocellulosic hydrolysate.

Zymomonas mobilis is a promising biocatalyst for the sustainable conversion of lignocellulosic sugars into biofuels and bioproducts, yet its response to lignocellulosic hydrolysates remains poorly understood. Here, we investigate the physiological response of Z. mobilis to ammonia fiber expansion (AFEX)-pretreated switchgrass hydrolysate using a systems-level approach integrating LC-MS/MS-based lipidomics and shotgun proteomics. Growth on hydrolysate induced substantial shifts in fatty acid and membrane phospholipid composition, alongside broad proteomic remodeling. Notably, Z. mobilis exhibited a stress response characterized by the upregulation of heat shock proteins and efflux transporters and the downregulation of cell motility proteins. Unexpectedly, hydrolysate exposure also led to a robust upregulation of the Entner-Doudoroff pathway, the ethanol fermentation pathway, and other central carbon metabolism enzymes, indicating a substantial cellular investment potentially driven by additional nutrient availability in hydrolysate. These findings provide new insights into the metabolic adaptations of Z. mobilis to lignocellulosic hydrolysates, informing strategies to enhance its biofuel production capabilities.IMPORTANCEBiomass pretreatment processes release fermentable sugars from lignocellulosic biomass, but they also generate inhibitors that can impact microbial metabolism. This study provides a systems-level evaluation of how Zymomonas mobilis responds to hydrolysate stress, revealing distinct physiological and lipid membrane remodeling responses. While some stress responses overlap with those induced by ethanol and isobutanol toxicity, both valuable biofuels, hydrolysate exposure elicits unique metabolic shifts. These findings offer valuable insights for engineering Z. mobilis strains with improved tolerance and performance for efficient bioconversion of lignocellulosic hydrolysates into biofuels and bioproducts.

Zymomonas↗

PubMed2025

A comprehensive analysis of supermere, exomere, and extracellular vesicle isolation and cargo in colorectal cancer.

Biofluids contain a heterogeneous mixture of extracellular vesicles and non-vesicular nanoparticles (including exomeres and supermeres) that transport a diverse array of proteins, RNA, and lipids. Our previous efforts to characterize the contents of these carriers in colorectal cancer relied on 2D culture systems requiring large-scale setups and time-consuming ultracentrifugation-based isolation. To streamline this process, we have combined 3D hollow-fiber bioreactor production and fast-protein liquid chromatography-based size-exclusion chromatography. Here, we compare the impact of culture methods and purification strategies on small extracellular vesicle, exomere, and supermere cargo. Proteomic analyses show consistently distinct profiles for extracellular vesicles, exomeres, and supermeres regardless of culture conditions or isolation method. In contrast, these two variables influence small RNAs, their base modifications, and lipidomic profiles. We present an online tool to query these and future secretome datasets (https://superomics.shinyapps.io/browse).

Humans↗

PubMed2026

Omics in hereditary optic neuropathies: A systematic review of clinical studies with an integrated point of view.

Hereditary optic neuropathies are characterized by bilateral visual loss due to the degeneration of retinal ganglion cells, resulting in optic nerve degeneration and atrophy. Although the genetic origin of the main isolated and syndromic hereditary optic neuropathies has been characterized, the clinical phenotypes exhibit significant and poorly understood variability in both penetrance and expressivity. Additionally, the genetic and environmental factors that influence the onset of these optic neuropathies remain poorly understood, with limited biomarkers to predict disease progression or as readouts for therapeutic trials. Data-driven omics strategies allow deep phenotyping to improve our understanding of pathophysiological mechanisms and to search for new biomarkers and therapeutic targets. We explore whether the omics strategies applied to patients with hereditary optic neuropathies have provided such new insights. MEDLINE, Web of Science and EMBASE databases were screened for studies with terms relating to hereditary optic neuropathies, transcriptomics, epigenomics, proteomics, metabolomics and lipidomics in clinical studies exploring patients' samples. Out of 1244 references identified, 22 articles were included after double-masked data curation. These articles focused only on the 3 main forms of hereditary optic neuropathies, namely, OPA1-related dominant optic atrophy (n = 4), Leber hereditary optic neuropathy (n = 13), and Wolfram syndrome (n = 5). While the methodological designs and results of these studies were highly heterogeneous, they revealed molecular alterations that we have attempted to discuss at the integrated multi-omics level. This data integration highlighted several common pathophysiological mechanisms such as energetic impairment, endoplasmic reticulum stress, proteotoxic and oxidative stresses, lipid remodeling and altered amino acid and purine metabolisms, while suggesting potential new biomarkers and therapeutic targets. These findings underscore the potential of integrated multi-omics approaches to deepen our understanding of the phenotypic complexity of hereditary optic neuropathies and to support the development of innovative diagnostic and therapeutic strategies.

Humans↗

PubMed2026

Comparative Multiomics Analysis of Cerebral Organoid-Derived Exosomes during Organoid Maturation.

Cerebral organoids derived from human pluripotent stem cells recapitulate key features of early brain development and provide a physiologically relevant model for neurogenesis. Exosomes secreted by these organoids carry bioactive cargo and offer a noninvasive means to monitor maturation and intercellular communication. We performed comprehensive multiomics profiling of exosomes collected from cerebral organoids at defined developmental stages to evaluate their utility as biomarkers of neuronal differentiation. Metabolomic analysis revealed a progressive decline in amino acids, including glutamic acid, consistent with increased metabolic demand during neurogenesis. Lipidomic and neurosteroid profiling showed dynamic increases in phosphatidylethanolamine and pregnenolone, reflecting synaptic membrane formation and signaling. Transcriptomic and proteomic analyses identified stage-specific neurodevelopmental signatures, with key markers mirroring those of parent organoids. Collectively, cerebral organoid-derived exosomes faithfully reflect organoid maturation and provide a robust platform for tracking in vitro brain development.

Humans↗

PubMed2026

Plasma lipid species, immune cell traits, and gastric cancer risk: A Mendelian randomization study.

Plasma lipid composition has been linked to multiple cancers, yet its causal contribution to gastric cancer and the potential intermediary role of immune cells remain unclear. We aimed to clarify these relationships and identify specific lipid and immune cell traits that either protect against or promote gastric cancer. We performed a 2-sample, 2-step Mendelian randomization analysis using summary statistics from large genome-wide association studies of gastric cancer (1423 cases, 3,14,193 controls), plasma lipidomics (179 molecular species), and 731 immune cell phenotypes. Independent, genome-wide significant single-nucleotide variants served as instrumental variables. First, we estimated the causal effects of each plasma lipid on gastric cancer. Then, we explored the potential intermediary role of lipid-associated immune cell traits using a 2-step Mendelian randomization framework. Two lipids - phosphatidylethanolamine (18:0 0:0) and phosphatidylcholine (O-18:0 16:1) - were causally associated with a lower risk of gastric cancer. Three immune cell traits (CD8br and CD8dim %leukocyte, IgD on IgD+ CD38- and CD3 on CD28- CD8br) similarly showed protective effects. In contrast, phosphatidylcholine (O-16:1 18:2), triacylglycerol (49:1), triacylglycerol (56:3), and triacylglycerol (56:4) increased gastric cancer risk, as did immune traits such as TD DN (CD4-CD8-)AC, CD19 on memory B cell, CD28 on CD39+ activated Treg, CD45 on CD4+, CD127 on CD28+DN(CD4-CD8-) and CCR2 on CD14+CD16+ monocyte. Exploratory mediation analyses found no statistically significant evidence that immune cell traits mediated the effects of plasma lipids on gastric cancer risk. Specific phosphatidylethanolamines and phosphatidylcholines confer protection against gastric cancer, whereas several triacylglycerols increase risk. However, exploratory mediation analyses provided no statistically significant evidence that immune cell traits mediated these associations.

Humans↗

PubMed2026

Molecular Signature of Prediabetes With High-Risk of Diabetes Revealed by Deep Plasma Proteome.

AIMS: Prediabetes is biologically heterogeneous, but molecular subtypes linked to diabetes progression remain poorly defined. We aimed to identify plasma proteome-based subtypes of impaired fasting glucose (IFG), characterise their molecular features and assess their association with future diabetes risk. MATERIALS AND METHODS: We quantified 2584 plasma proteins using liquid chromatography-mass spectrometry in 538 IFG participants from a prospective discovery cohort (Nutrition and Health of Aging Population in China, NHAPC). Proteomic subtypes were defined by consensus clustering, linked to longitudinal changes in insulin sensitivity and incident type 2 diabetes mellitus (T2DM), which were further validated in an independent Shanghai Brain Aging Study (SBAS) cohort. RESULTS: Two reproducible IFG molecular subtypes based on plasma proteomics were identified. The high-risk subtype showed higher incident diabetes and a greater 6-year decline in insulin sensitivity and was characterised by enrichment of glycolysis/gluconeogenesis, insulin signalling and neutrophil degranulation, together with a dyslipidemic lipidomic profile indicating co-dysregulation of glucose and lipid homeostasis. The low-risk subtype demonstrated a higher complement cascade and high-density lipoprotein particle remodelling signature. In the high-risk subtype, key proteins and lipids showed stronger associations with longitudinal declines in insulin sensitivity, including PPBP, PGK1 and ALDOA, as well as PE-P 18:0/20:3 and PE-P 18:1/20:3. CONCLUSIONS: Proteome-based molecular subtyping stratifies IFG individuals with similar fasting glucose levels but distinct biology and future diabetes risk, supporting earlier and more targeted prevention.

Humans↗

PubMed2026

A lipid-immune network signature defines susceptibility to asparaginase-associated pancreatitis.

BACKGROUNDAsparaginase is essential for curing acute lymphoblastic leukemia (ALL), but its use is limited by asparaginase-associated pancreatitis (AAP), a severe and unpredictable toxicity lacking validated prospective biomarkers. We sought to define early systemic molecular features of susceptibility to AAP.METHODSWe performed longitudinal lipidomic and proteomic profiling in two independent pediatric ALL cohorts (n = 161; 79 AAP cases, 82 controls) using paired blood samples collected before asparaginase exposure and at the end of induction therapy (including a single dose of asparaginase), thereby capturing pre-injury biology rather than consequences of pancreatitis. We applied differential abundance and network-based analyses and integrated lipid-cytokine associations using proteomics.RESULTSAcross cohorts, we identified a reproducible lysophosphatidylcholine-centered (LPC-centered) signature characterized by attenuated induction therapy-associated LPC responses and disruption of LPC coregulation at the network level. Proteomic profiling revealed enrichment of cytokine signaling pathways, and integrative analyses demonstrated altered lipid-cytokine coupling, including a flip in association direction for LPC species and IL-18 between cases and controls. Although IL-18/LPC ratios did not differ globally, elevated postinduction IL-18/LPC ratios identified AAP risk within a protocol-defined very high-risk ALL subgroup (AUC = 0.81).CONCLUSIONThese findings support a systems-level model in which failure of coordinated lipid-immune responses under therapeutic stress confers vulnerability to AAP, providing a framework for validation and mitigation strategies.TRIAL REGISTRATIONNCT00400946; NCT01574274; NCT03020030 (parent trials).FUNDINGServier Pharmaceuticals (IIT-95014-027-USA); SDRC (P30DK116074); Stanford SPARK; Fonds de Recherche du Québec - Santé; Fondation Charles-Bruneau; Leukemia & Lymphoma Society of Canada.

Adolescent↗

PubMed2026

Integrative Multidimensional Profiling of Individuals Recovered from Mild COVID-19 Reveals Immune-Metabolic-Oxidative Network Interactions.

The COVID-19 pandemic underscored the need to better characterize immune and molecular responses following SARS-CoV-2 infection and vaccination. Beyond antibody and cellular immunity, COVID-19 involves oxidative stress and DNA damage, affecting repair mechanisms and metabolic adaptation linked to immune resilience. Here, we present a multidimensional analysis of 20 individuals who recovered from mild COVID-19, integrating clinical features with humoral and cellular immune responses, T cell and myeloid phenotypes, oxidative stress, DNA damage, and metabolomic and lipidomic profiles. Although most individual parameters fell within physiological ranges, network modeling revealed structured associations spanning multiple biological domains. A central finding was a coherent cluster organized around vaccine dose number, linking anti-Spike antibody titers, oxidative stress, bioenergetic signatures, and granulocyte activation. Higher vaccination was associated with stronger humoral responses, lower oxidative stress, and a more balanced myeloid-metabolic profile, suggesting a potential protective role extending beyond antibody induction. Additional associations linked symptom patterns to T cell differentiation states, anti-nucleocapsid responses to systemic inflammation, and anaerobic signatures to DNA damage markers, revealing interconnections between immunometabolism, clinical expression, and genomic stress. Despite the small sample size, these findings offer a preliminary systems-level perspective on mild COVID-19 recovery and illustrate the value of integrative exploratory frameworks in infectious disease research, laying the groundwork for validation in larger longitudinal cohorts.

Humans↗