PubMed

Talanta. 2025 Mar 1;291:127847. doi: 10.1016/j.talanta.2025.127847. Online ahead of print.ABSTRACTLipidomics, a subfield of metabolomics, provides comprehensive analysis of lipids in biological systems and is essential for biomedical research, driven by advances in analytical technologies. Lipids are crucial biomolecules in cellular functions and have been increasingly recognized for their role in physiological and pathological processes. This study focuses on advanced strategies for the development, validation, and implementation of untargeted lipidomics methods in human plasma and extracellular vesicles (EVs) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Method validation demonstrated excellent accuracy (precision and trueness) (81-120 % of nominal value), precision with inter-day repeatability below 20 %, limits of quantification ranging from 0.25 to 25 μM, and recovery rates exceeding 80 % for most lipid classes, as well as matrix effects. Plasma samples were used as a proof-of-concept study, and the method was ultimately applied to human macrophage-derived EVs. Lipid extraction utilized four liquid-liquid extraction methods to ensure broad lipid class coverage, high recovery, and repeatability. Additionally, we demonstrated that a sonication-assisted homogenization step effectively facilitates lipid extraction from EVs. Through untargeted lipidomics, our study identifies and quantifies a diverse range of lipid species in human plasma (225 lipids analytes) and macrophage-derived EVs (124 lipids analytes) within different classes. Overall, we present sophisticated approaches that combine pre-analytical lipid extraction techniques with high-resolution LC-MS/MS to enhance lipidomics research. This approach enhances the characterization of lipid profiles and their biological implications, paving the way for applications in personalized medicine and the discovery of novel lipid biomarkers associated with EVs biogenesis.PMID:40056647 | DOI:10.1016/j.talanta.2025.127847

Phytomedicine. 2025 Feb 25;140:156582. doi: 10.1016/j.phymed.2025.156582. Online ahead of print.ABSTRACTBACKGROUND: The clinical application of cyclosporine A (CsA) is limited due to nephrotoxicity. Lipid metabolism disorders play important roles in renal injury, but their role in CsA nephrotoxicity is not yet clear. Huangqi (Astragalus mongholicus Bunge) and Danshen (Salvia miltiorrhiza Bunge) (HD) play roles in ameliorating the nephrotoxicity of CsA, but their mechanisms still need to be fully clarified.OBJECTIVE: This study innovatively aimed to analyse the coexpression of renal proteins and serum metabolites for the identification of key pathways and targets. This study provides novel insight into the mechanism by which HD ameliorates CsA-induced nephrotoxicity.METHODS: We utilized HD to intervene in both in vivo and in vitro nephrotoxicity models induced by CsA. For the in vivo experiments, we constructed a coexpression network of renal proteins and serum metabolites, which was used to screen for key pathways. To validate these findings, we knocked down key proteins in vivo. For the in vitro studies, we employed MTT, Transwell, flow cytometry, and immunofluorescence assays to monitor the epithelial-mesenchymal transition (EMT) of HK-2 cells. Additionally, we used electron microscopy and Seahorse assays to examine the effects of HD on mitochondrial structure and function. Furthermore, we overexpressed Ppara to further confirm the mechanism by which HD improves renal function.RESULTS: HD can improve renal pathological damage and function; regulate blood lipids, inflammation and oxidative stress indicators; and reduce apoptosis in renal tissues. Joint protein and metabolomics analyses revealed that two lipid metabolism-related pathways (the PPAR signalling pathway and linoleic acid metabolism pathway) were coenriched, involving six differential proteins (Cyp2e1, Cyp4a10, Gk, Lpl, Ppara, and Pck1) and two differentially abundant metabolites (alpha-Dimorphecolic acid and 12,13-EpOME). Western blot was used to verify differentially expressed proteins. HD improved mitochondrial damage and lipid accumulation, as demonstrated by transmission electron microscopy (TEM) analysis and Oil Red O staining. Knockdown of the key protein Ppara affected the expression of ACOX1 and exacerbated RF. In vitro verification demonstrated that HD significantly inhibited CsA-induced EMT in HK-2 cells and improved mitochondrial structure and function. Ppara overexpression promoted HD-mediated regulation of mitochondrial function, reduced apoptosis, and improved HK-2 RF.CONCLUSION: HD can ameliorate CsA nephrotoxicity through renal protein-serum metabolism coexpression, the PPAR signalling pathway, and linoleic acid metabolism. HD-induced upregulation of Ppara to regulate lipid metabolism, improve mitochondrial function and reduce apoptosis are important mechanisms. The Ppara/ACOX1/TGF-β1 axis may play an important role in this process. These findings offer potential targets for the future development of therapeutic strategies and novel drugs.PMID:40056636 | DOI:10.1016/j.phymed.2025.156582

Environ Sci Pollut Res Int. 2025 Mar 8. doi: 10.1007/s11356-025-36197-7. Online ahead of print.ABSTRACTExposome represents one of the most pressing issues in the environmental science research field. However, a comprehensive summary of worldwide human exposome research is lacking. We aimed to explore the bibliometric characteristics of scientific publications on the human exposome. A bibliometric analysis of human exposome publications from 2005 to December 2024 was conducted using the Web of Science in accordance with PRISMA guidelines. Trends/hotspots were investigated with keyword frequency, co-occurrence, and thematic map. Sex disparities in terms of publications and citations were examined. From 2005 to 2024, 931 publications were published in 363 journals and written by 4529 authors from 72 countries. The number of publications tripled during the last 5 years. Publications written by females (51% as first authors and 34% as last authors) were cited fewer times (13,674) than publications written by males (22,361). Human exposome studies mainly focused on air pollution, metabolomics, chemicals (e.g., per- and polyfluoroalkyl substances (PFAS), endocrine-disrupting chemicals, pesticides), early-life exposure, biomarkers, microbiome, omics, cancer, and reproductive disorders. Social and built environment factors, occupational exposure, multi-exposure, digital exposure (e.g., screen use), climate change, and late-life exposure received less attention. Our results uncovered high-impact countries, institutions, journals, references, authors, and key human exposome research trends/hotspots. The use of digital exposome technologies (e.g., sensors, and wearables) and data science (e.g., artificial intelligence) has blossomed to overcome challenges and could provide valuable knowledge toward precision prevention. Exposome risk scores represent a promising research avenue.PMID:40056347 | DOI:10.1007/s11356-025-36197-7

Environ Microbiol. 2025 Mar;27(3):e70073. doi: 10.1111/1462-2920.70073.ABSTRACTWe examined the effects of symbiont identity and heat stress on the host metabolome and proteome in the cnidarian-dinoflagellate symbiosis. Exaiptasia diaphana ('Aiptasia') was inoculated with its homologous (i.e., native) symbiont Breviolum minutum or a heterologous (i.e., non-native) symbiont (Symbiodinium microadriaticum; Durusdinium trenchii) and thermally stressed. Integrated metabolome and proteome analyses characterised host thermal responses between symbioses, with clear evidence of enhanced nutritional deprivation and cellular stress in hosts harbouring heterologous symbionts following temperature stress. Host metabolomes were partially distinct at the control temperature; however, thermal stress caused metabolomes of anemones containing the two heterologous symbionts to become more alike and more distinct from those containing B. minutum. While these patterns could be partly explained by innate symbiont-specific differences, they may also reflect differences in symbiont density, as under control conditions D. trenchii attained 60% and S. microadriaticum 15% of the density attained by B. minutum, and at elevated temperature only D. trenchii-colonised anemones bleached (60% loss). Our findings add to a growing literature that highlights the physiological limits of partner switching as a means of adaptation to global warming. However, we also provide tentative evidence for improved metabolic functioning with a heterologous symbiont (D. trenchii) after sustained symbiosis.PMID:40056008 | DOI:10.1111/1462-2920.70073

Kardiologiia. 2025 Feb 28;65(2):3-16. doi: 10.18087/cardio.2025.2.n2879.ABSTRACTArtificial intelligence (AI) has an enormous potential for improving the quality of medical care, diagnostic methods, and treatments. AI allows taking scientific research to a fundamentally new level. The article addresses the most important areas of using AI in cardiology. AI can be used to accelerate making clinical decisions, remote patient monitoring, tomographic image analysis, patient phenotyping, including metabolomic analysis, to assess the risk of complications and many other areas.PMID:40055902 | DOI:10.18087/cardio.2025.2.n2879

J Am Heart Assoc. 2025 Mar 7:e039201. doi: 10.1161/JAHA.124.039201. Online ahead of print.ABSTRACTBACKGROUND: The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Almost all patients with Fontan operation develop liver fibrosis at a young age, known as Fontan-associated liver disease (FALD). The pathogenesis and mechanisms underlying FALD remain little understood, and there are no effective therapies. We aimed to present a comprehensive multiomic analysis of human FALD, revealing the fundamental biology and pathogenesis of FALD.METHODS AND RESULTS: We recently generated a single-cell transcriptomic and epigenomic atlas of human FALD using single-nucleus multiomic RNA sequencing and assay for transposase-accessible chromatin using sequencing, which uncovered substantial metabolic reprogramming. Here, we applied liquid chromatography-mass spectrometry-based untargeted metabolomics to unveil the metabolomic landscape of human FALD, using liver samples/biopsies from age- and sex-matched donors and patients with FALD (n=12 per group). Results were integrated with liver single-nucleus multiomic RNA sequencing and assay for transposase-accessible chromatin using sequencing and serum metabolomics data to present a comprehensive multiomic atlas of FALD.We discovered significant metabolic abnormalities in livers of adolescent patients with Fontan circulation, particularly amino acid metabolism, peroxisomal fatty acid oxidation, cytochrome P450 system, glycolysis, tricarboxylic acid cycle, ketone body metabolism, and bile acid metabolism. Integrated analyses with liver single-nucleus multiomic RNA sequencing and assay for transposase-accessible chromatin using sequencing results unveiled potential underlying mechanisms of these metabolic changes. Comparison with serum metabolomics data indicate that liver metabolic reprogramming contributes to circulatory metabolomic changes in FALD. Furthermore, comparison with metabolomics data of human metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatohepatitis highlighted dysregulated amino acid metabolism as a common metabolic abnormality.CONCLUSIONS: Our comprehensive multiomic analyses reveal new insights into the fundamental biology and pathogenesis mechanisms of human FALD.PMID:40055870 | DOI:10.1161/JAHA.124.039201

Cell Biosci. 2025 Mar 7;15(1):32. doi: 10.1186/s13578-025-01370-5.ABSTRACTOBJECTIVES: Drug-induced liver injury (DILI) can be improved by modulating gut microbiota. We aimed to investigate a probiotic mixture comprising Bifidobacterium Longum, Streptococcus thermophilus, and Lactobacillus delbrueckii subspecies bulgaricus (BSL) in mitigating acetaminophen induced liver injury (AILI), and to elucidate the underlying mechanisms.METHODS: Gut bacterial communities were analyzed in fecal samples from patients with DILI and healthy controls. Mice were pretreated with BSL or PBS for 10 days, then subjected to a single dose of acetaminophen (300 mg/kg) gavage and euthanized 24 h later. Transcriptome sequencing, microbiome, and metabolome sequencing were performed on mouse samples, respectively.RESULTS: Gut bacterial dysbiosis existed in DILI patients, with a decrease in Gram-positive bacteria and an increase in Gram-negative bacteria. A similar situation occurred in AILI mice. Pretreatment of BSL significantly improved APAP-induced disorders of gut bacteria and alleviated hepatic inflammation and necrosis. Transcriptome sequencing showed that BSL inhibited the hepatic damage pathways, such as Hippo and TGF-β signaling pathway. Metabolomic profiling revealed an obvious increase in oligopeptides containing branched-chain amino acids (BCAAs) in AILI mice, whereas these metabolites were significantly negatively correlated with the abundance of BSL, but positively with key genes of Hippo pathway. In vitro experiments showed that leucine exerted a dose-related exacerbation pattern on APAP-mediated hepatocellular injury. Mice supplemented with leucine resulted in the further overexpression of Yes-associated protein, an increase in oxidative stress, and a worsening of AILI.PMID:40055814 | DOI:10.1186/s13578-025-01370-5

Breast Cancer Res. 2025 Mar 7;27(1):32. doi: 10.1186/s13058-025-01991-1.ABSTRACTBACKGROUND: Lipid metabolic reprogramming is increasingly recognized as a hallmark of endocrine resistance in estrogen receptor-positive (ER+) breast cancer. In this study, we investigated alterations in lipid metabolism in ER + breast cancer cell lines with acquired resistance to common endocrine therapies and evaluated the efficacy of a clinically relevant fatty acid synthase (FASN) inhibitor.METHODS: ER + breast cancer cell lines resistant to Tamoxifen (TamR), Fulvestrant (FulvR), and long-term estrogen withdrawal (EWD) were derived. Global gene expression and lipidomic profiling were performed to compare parental and endocrine resistant cells. Lipid storage was assessed using Oil Red O (ORO) staining. The FASN inhibitor TVB-2640 was tested for its impact on lipid storage and cell growth. 13C2-acetate tracing was used to evaluate FASN activity and the efficacy of TVB-2640.RESULTS: Endocrine resistant cells showed significant enrichment in lipid metabolism pathways and distinct lipidomic profiles, characterized by elevated triglyceride levels and enhanced cytoplasmic lipid droplets. 13C2-acetate tracing revealed increased FASN activity in endocrine resistant cells, which was effectively reduced by TVB-2640. While TVB-2640 reduced lipid storage in most but not all cell lines, this did not correlate with decreased cell growth. Polyunsaturated fatty acids (PUFAs) containing 6 or more double bonds were elevated in endocrine resistant cells and remained unaffected or increased with TVB-2640.CONCLUSION: Endocrine resistant breast cancer cells undergo a metabolic shift toward increased triglyceride storage and PUFAs with high degrees of desaturation. While TVB-2640 reduced lipid storage in most conditions, it had limited effects on the growth of endocrine resistant breast cancer cells. Targeting specific lipid metabolic dependencies, particularly pathways that produce PUFAs, represents a potential therapeutic strategy in endocrine resistant breast cancer.PMID:40055794 | DOI:10.1186/s13058-025-01991-1

J Exp Clin Cancer Res. 2025 Mar 8;44(1):88. doi: 10.1186/s13046-025-03352-4.ABSTRACTBACKGROUND: The αvβ6- and αvβ8-integrins, two cell-adhesion receptors upregulated in many solid tumors, can promote the activation of transforming growth factor-β (TGFβ), a potent immunosuppressive cytokine, by interacting with the RGD sequence of the latency-associated peptide (LAP)/TGFβ complex. We have previously described a chromogranin A-derived peptide, called "peptide 5a", which recognizes the RGD-binding site of both αvβ6 and αvβ8 with high affinity and selectivity, and efficiently accumulates in αvβ6- or αvβ8-positive tumors. This study aims to demonstrate that peptide 5a can inhibit TGFβ activation in tumors and suppress tumor growth.METHODS: Peptide 5a was chemically coupled to human serum albumin (HSA) to prolong its plasma half-life. The integrin recognition properties of this conjugate (called 5a-HSA) and its capability to block TGFβ activation by αvβ6+ and/or αvβ8+ cancer cells or by regulatory T cells (Tregs) were tested in vitro. The in vivo anti-tumor effects of 5a-HSA, alone and in combination with S-NGR-TNF (a vessel-targeted derivative of tumor necrosis factor-a), were investigated in various murine tumor models, including pancreatic ductal adenocarcinoma, fibrosarcoma, prostate cancer, and mammary adenocarcinoma.RESULTS: In vitro assays showed that peptide 5a coupled to HSA maintains its capability of recognizing αvβ6 and αvβ8 with high affinity and selectivity and inhibits TGFβ activation mediated by αvβ6+ and/or αvβ8+ cancer cells, as well as by αvβ8+ Tregs. In vivo studies showed that systemic administration of 5a-HSA to tumor-bearing mice can reduce TGFβ signaling in neoplastic tissues and promote CD8-dependent anti-tumor responses. Combination therapy studies showed that 5a-HSA can enhance the anti-tumor activity of S-NGR-TNF, leading to tumor eradication.CONCLUSION: Peptide 5a is an efficient tumor-homing inhibitor of αvβ6- and αvβ8-integrin that after coupling to HSA, can be used as a drug to block integrin-dependent TGFβ activation in tumors and promote immunotherapeutic responses.PMID:40055773 | DOI:10.1186/s13046-025-03352-4

BMC Med. 2025 Mar 8;23(1):143. doi: 10.1186/s12916-025-03980-9.NO ABSTRACTPMID:40055695 | DOI:10.1186/s12916-025-03980-9

BMC Plant Biol. 2025 Mar 8;25(1):301. doi: 10.1186/s12870-025-06293-4.ABSTRACTBACKGROUND: Polyploids in citrus are generally used to improve crop varieties. Changshan Huyou (Citrus changshan-huyou) is a native citrus species in China that is highly adaptable and has pharmaceutical value. However, the influence in Changshan Huyou following polyploidization remains unclear. Here we evaluated the adult tetraploid scions of Changshan Huyou with contemporary diploid scions as the control in the phenotypic variations, metabolic alterations of fruits and associated transcriptomic changes.RESULT: The tetraploid scions had rounder and thicker leaves, larger floral organs and fruits, and satisfactory viability of pollen grains and ovules. The tetraploid fruits accumulated lower levels of soluble solids but similar levels of organic acids. Metabolic profiling of three tissues of fruits revealed that most of 2064 differentially accumulated metabolites (DAMs), including flavonoids, lignans, and coumarins, were downregulated. In contrast, the upregulated DAMs mainly included alkaloids (clausine K and 2-(1-pentenyl)quinoline), amino acids (L-asparagine and L-ornithine), and terpenoids (deacetylnomilin and evodol) in tetraploid peels, as well as, flavonoids (neohesperidin and quercetin-5-O-β-D-glucoside) and organic acids (2-methylsuccinic acid and dimethylmalonic acid) in juice sacs. The upregulated genes were associated with phenylpropanoid biosynthesis, secondary metabolite biosynthesis, and the biosynthesis of various alkaloid pathways. Pearson Correlation Analysis showed that the upregulated genes encoding PEROXIDASE and CYTOCHROME P450 (CYP450) were closely related to the higher accumulation of amino acids and alkaloids in tetraploid peels, and up-regulated neohesperidin and quercetin glucoside were positively associated with FERULATE-5-HYDROXYLASE (F5H), CYP450 81Q32, FLAVONOID 3'-MONOOXYGENASE (F3'H), 4-COUMARATE-CoA LIGASE 1 (4CL1), and UDP-GLUCOSE FLAVONOID 3-O-GLUCOSYLTRANSFERASE (UFOG), as well as, some transcription factors in tetraploid juice sacs.CONCLUSION: The tetraploid Changshan Huyou investigated here may be used in triploids breeding to produce seedless citrus, and for fruit processing on pharmaceutical purpose due to the alteration of metabolites following polyploidization.PMID:40055582 | DOI:10.1186/s12870-025-06293-4

Nat Neurosci. 2025 Mar 7. doi: 10.1038/s41593-025-01926-1. Online ahead of print.NO ABSTRACTPMID:40055545 | DOI:10.1038/s41593-025-01926-1

NPJ Precis Oncol. 2025 Mar 7;9(1):64. doi: 10.1038/s41698-025-00833-9.ABSTRACTBrain metastasis from breast cancer (BMBC) contributes significantly to mortality, yet its mechanisms remain unclear. This study investigates the activation of GPX3+ astrocytes by circulating tumor cell (CTC)-derived exosomes in the metastatic process. Using a mouse model of BMBC, we performed single-cell RNA sequencing (scRNA-seq) and metabolomics to explore the role of GPX3+ astrocytes in the brain microenvironment. We found that CTCs activate these astrocytes, promoting IL-1β production and Th17 cell differentiation, crucial for the formation of the metastatic niche. Conditional knockout of GPX3 reduced brain metastasis and extended survival, highlighting its importance in metastasis. Our findings uncover a novel mechanism by which CTCs activate GPX3+ astrocytes to drive breast cancer brain metastasis, suggesting new therapeutic targets for intervention.PMID:40055530 | DOI:10.1038/s41698-025-00833-9

Sci Rep. 2025 Mar 8;15(1):8069. doi: 10.1038/s41598-025-92550-3.ABSTRACTSmall extracellular vesicles (EVs) are a subtype of nano-sized extracellular vesicles that mediate intercellular communication. EVs can be found in different body fluids, including milk. Monocytes internalize porcine milk EVs and modulate immune functions in vitro by decreasing their phagocytosis and chemotaxis while increasing their oxidative burst. This study aimed to assess the impact of porcine milk EVs on the porcine peripheral blood mononuclear cells (PBMC) proteome. Porcine PBMC were incubated with porcine milk EVs or medium as a control. Extracted proteins were then analyzed using nano-LC-MS/MS. A total of 1584 proteins were identified. The supervised multivariate statistical analysis, sparse variant partial least squares - discriminant analysis (sPLS-DA) for paired data identified discriminant proteins (DP) that contributed to a clear separation between the porcine milk EVs treated cells and control groups. A total of 384 DP from both components were selected. Gene Ontology (GO) enrichment analysis with ProteINSIDE provided the evidence that the DP with a higher abundance in porcine milk EVs, like TLR2, APOE, CD36, MFGE8, were mainly involved in innate immunity and the process of EVs uptake processes. These results provide a proteomics background to the immunomodulatory activity of porcine milk EVs and to the potential mechanisms used by immune cells to internalize them.PMID:40055486 | DOI:10.1038/s41598-025-92550-3

Sci Rep. 2025 Mar 7;15(1):8010. doi: 10.1038/s41598-025-91317-0.ABSTRACTSalix variegata, a typical dioecious plant with high reproductive and adaptive ability, has important ecological and ornamental value. To understand the potential mechanisms and metabolite dynamics of male and female flowers development, the first comparative analysis of the transcriptome and metabolome of S. variegata was applied. As a result, 12,245 differentially expressed genes (DEGs) and 4,145 differently expressed metabolites (DEMs) were identified. Transcriptomic analysis showed that the male and female flowers development processes were related to phenylpropanoid and flavonoid biosynthesis. According to the metabolic profile, the main amino acids, flavonoids, phenylpropanoids, and their derivatives were accumulated during the development of male and female flowers of the S. variegata. Combined transcriptomic and metabolomic analyses indicated that the AUX/IAA, bHLH, MIKC, MYB, NAC, ERF and RLK transcription factors (TFs) and their associated key DEGs may mediate the metabolism of phenylpropanoids and flavonoids, which in turn regulate the development of male and female flowers in S. variegata. These results provide important insights to elucidate the development of male and female flowers of S. variegata at the molecular level. Our results will contribute to understanding the molecular and genetic mechanisms of male and female flower development in typical dioecious plants.PMID:40055394 | DOI:10.1038/s41598-025-91317-0

Nat Commun. 2025 Mar 7;16(1):2278. doi: 10.1038/s41467-025-57583-2.ABSTRACTDisrupted pH homeostasis can precipitate cell death and represents a viable therapeutic target in oncological interventions. Here, we utilize mass spectrometry-based drug analysis, transcriptomic screens, and lipid metabolomics to explore the metabolic mechanisms underlying pH-dependent cell death. We reveal CYP51A1, a gene involved in cholesterol synthesis, as a key suppressor of alkalization-induced cell death in pancreatic cancer cells. Inducing intracellular alkalization by the small molecule JTC801 leads to a decrease in endoplasmic reticulum cholesterol levels, subsequently activating SREBF2, a transcription factor responsible for controlling the expression of genes involved in cholesterol biosynthesis. Specifically, SREBF2-driven upregulation of CYP51A1 prevents cholesterol accumulation within lysosomes, leading to TMEM175-dependent lysosomal proton efflux, ultimately resulting in the inhibition of cell death. In animal models, including xenografts, syngeneic orthotopic, and patient-derived models, the genetic or pharmacological inhibition of CYP51A1 enhances the effectiveness of JTC801 in suppressing pancreatic tumors. These findings demonstrate a role of the CYP51A1-dependent lysosomal pathway in inhibiting alkalization-induced cell death and highlight its potential as a targetable vulnerability in pancreatic cancer.PMID:40055353 | DOI:10.1038/s41467-025-57583-2

Nat Commun. 2025 Mar 7;16(1):2297. doi: 10.1038/s41467-025-57540-z.ABSTRACTAtherosclerosis is the underlying cause of myocardial infarction and ischemic stroke. It is a lipid-triggered and cytokine/chemokine-driven arterial inflammatory condition. We identify D-dopachrome tautomerase/macrophage migration-inhibitory factor-2 (MIF-2), a paralog of the cytokine MIF, as an atypical chemokine promoting both atherosclerosis and hepatic lipid accumulation. In hyperlipidemic Apoe-/- mice, Mif-2-deficiency and pharmacological MIF-2-blockade protect against lesion formation and vascular inflammation in early and advanced atherogenesis. MIF-2 promotes leukocyte migration, endothelial arrest, and foam-cell formation, and we identify CXCR4 as a receptor for MIF-2. Mif-2-deficiency in Apoe-/- mice leads to decreased plasma lipid levels and suppressed hepatic lipid accumulation, characterized by reductions in lipogenesis-related pathways, tri-/diacylglycerides, and cholesterol-esters, as revealed by hepatic transcriptomics/lipidomics. Hepatocyte cultures and FLIM-FRET-microscopy suggest that MIF-2 activates SREBP-driven lipogenic genes, mechanistically involving MIF-2-inducible CD74/CXCR4 complexes and PI3K/AKT but not AMPK signaling. MIF-2 is upregulated in unstable carotid plaques from atherosclerotic patients and its plasma concentration correlates with disease severity in patients with coronary artery disease. These findings establish MIF-2 as an atypical chemokine linking vascular inflammation to metabolic dysfunction in atherosclerosis.PMID:40055309 | DOI:10.1038/s41467-025-57540-z

Nat Commun. 2025 Mar 7;16(1):2298. doi: 10.1038/s41467-025-57422-4.ABSTRACTNon-targeted metabolomics holds great promise for advancing precision medicine and biomarker discovery. However, identifying compounds from tandem mass spectra remains a challenging task due to the incomplete nature of spectral reference libraries. Augmenting these libraries with simulated mass spectra can provide the necessary references to resolve unmatched spectra, but generating high-quality data is difficult. In this study, we present FIORA, an open-source graph neural network designed to simulate tandem mass spectra. Our main contribution lies in utilizing the molecular neighborhood of bonds to learn breaking patterns and derive fragment ion probabilities. FIORA not only surpasses state-of-the-art fragmentation algorithms, ICEBERG and CFM-ID, in prediction quality, but also facilitates the prediction of additional features, such as retention time and collision cross section. Utilizing GPU acceleration, FIORA enables rapid validation of putative compound annotations and large-scale expansion of spectral reference libraries with high-quality predictions.PMID:40055306 | DOI:10.1038/s41467-025-57422-4

Am J Physiol Cell Physiol. 2025 Mar 7. doi: 10.1152/ajpcell.00875.2024. Online ahead of print.ABSTRACTThe deficiency of fructose-1,6-bisphosphatase 1 (FBP1), a key enzyme of gluconeogenesis, causes fatty liver. However, its underlying mechanism and physiological significance are not fully understood. Here we demonstrate that carbohydrate response element-binding protein (ChREBP) mediates lipid metabolic remodeling and promotes progressive triglycerides accumulation against metabolic injury in adult FBP1-deficient liver. Inducible liver-specific deletion of Fbp1 gene caused progressive hepatomegaly and hepatic steatosis, with a marked increase in hepatic de novo lipogenesis (DNL) as well as a decrease in plasma beta-hydroxybutyrate levels. Notably, FBP1 deficiency resulted in a persistent activation of ChREBP and its target genes involved in glycolysis, lipogenesis, and fatty acid oxidation, even under fasting condition. Furthermore, liver-specific ChREBP disruption could markedly restore the phenotypes of enhanced DNL and triglyceride accumulation in FBP1-deficient liver, but exacerbated its hepatomegaly and liver injury, which was associated with remarkable energy deficit, impaired mTOR activation, and increased oxidative stress. Furthermore, metabolomics analysis revealed a robust elevation of phosphoenolpyruvate, phosphoglycerates, phospholipids, and ceramides caused by ChREBP deletion in FBP1-deficient liver. Put together, these results suggest that overactivation of ChREBP pathway mediates liver metabolic remodeling in the absence of FBP1, which contributes to the pathogenesis of progressive hepatic steatosis and provides a protection against liver injury. Thus our findings point to a beneficial role of ChREBP in metabolic remodeling in the context of excessive gluconeogenic intermediates.PMID:40055186 | DOI:10.1152/ajpcell.00875.2024

Eur J Pharmacol. 2025 Mar 5:177445. doi: 10.1016/j.ejphar.2025.177445. Online ahead of print.ABSTRACTThe prevention and treatment of scars has always posed a challenge in the medical field. Researchers have reached the consensus that safe, effective and affordable treatments are needed. Here, by conducting non-targeted metabolomics and RNA sequencing experiments, we revealed that a significant number of metabolites and genes related to glucose and lipid metabolism underwent changes during scar formation, with peroxisome proliferator-activated receptor-γ (PPAR-γ) exerting a profound influence. Considering that rosiglitazone is a selective orally active PPAR-γ receptor agonist, scar models were induced in rats, and rosiglitazone was administered at different dosages. We characterized rosiglitazone as a crucial mediator in a rat scar model in vivo and in vitro in two models of transforming growth factor β1(TGF-β1) stimulated fibroblasts (NIH 3T3 and 3T3 L1). Functionally, activation of PPAR-γ with rosiglitazone effectively impedes fibrosis and mitigates scar formation. Rosiglitazone also inhibits some inflammatory factors, and downregulates triglyceride, lactic acid, glycogen and lactic dehydrogenase levels in rat scars. Conversely, rosiglitazone increases adenosine triphosphate (ATP) production and increases free fatty acid levels and the activity of acetyl-CoA carboxylase, fatty acid synthetase, succinate dehydrogenase. Collectively, these findings shed light on the underlying mechanisms and suggest that the use of rosiglitazone could be a promising therapeutic approach to alleviate fibrosis and reduce scar formation.PMID:40054722 | DOI:10.1016/j.ejphar.2025.177445