{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T16:25:34Z","timestamp":1775147134668,"version":"3.50.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2019YFE0115300"],"award-info":[{"award-number":["2019YFE0115300"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Exposure to sevoflurane in neonatal rats disrupts energy metabolism during brain development, which is associated with anesthetic-induced neurodevelopmental toxicity. Hepatic fatty acid metabolism plays a critical role in response to brain energy supply. However, how sevoflurane exposure affect hepatic fatty acid metabolism remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We employed multiple analytical methods in neonatal rats following sevoflurane exposure to: (1) Analyze alterations in hepatic fatty acid metabolism-related gene expression and immune cell infiltration; (2) Decipher associated metabolic pathways, including cholesterol metabolism and the expression changes of Dhcr24; (3) Conduct enrichment analyses (GO, KEGG, GSEA, GSVA) and functional investigations via Friends analysis; (4) Construct mRNA-miRNA-lncRNA regulatory networks; (5) Identify key genedrug small molecule interactions based on IC50 differences and (6) Verify the expression of key genes involved in fatty acid metabolism and the activation of immune cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Significant alterations were observed: (1) Identification of 15 key fatty acid metabolism-related differentially expressed genes (DEGs and RT-PCR); (2) Significant enrichment of 40 GO terms and 5 KEGG pathways; (3) GSEA\/GSVA revealed 130 up-regulated and 62 down-regulated GO gene sets, along with 5 up-regulated and 2 down-regulated KEGG pathways; (4) Friends analysis highlighted Dhcr24 as a critical player in cholesterol metabolism; (5) Network analysis identified pivotal mRNA and lncRNA nodes within the regulatory networks; (6) Screening yielded 43 key gene-drug combinations with significant IC50 differences; and (7) Immunofluorescence confirmed the activation expression of relevant immune cells. Bioinformatics analysis pinpointed diagnostic biomarkers for both hepatic fatty acid metabolism perturbations and immune cell infiltration following exposure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings demonstrate that neonatal sevoflurane exposure profoundly affects hepatic fatty acid metabolism and immune cell infiltration, involving specific key genes (including Dhcr24), perturbed pathways, and regulatory networks. The identified biomarkers and potential therapeutic targets provide a crucial foundation for developing more specific countermeasures against sevoflurane-induced neurodevelopmental toxicity, potentially via targeting the liver-brain metabolic axis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnmol.2025.1369365","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T05:33:37Z","timestamp":1756964017000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Identifying biomarkers of hepatic fatty acid metabolism disorder in sevoflurane-induced brain developmental injury by bioinformatics analysis"],"prefix":"10.3389","volume":"18","author":[{"given":"Haozheng","family":"Yuan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuying","family":"Lv","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengyu","family":"Jia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kailing","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haodong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinlin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengbo","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1093\/bioinformatics\/btu842","article-title":"J-circos: an interactive circos plotter","volume":"31","author":"An","year":"2015","journal-title":"Bioinformatics"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3390\/neurosci5020016","article-title":"In the brain, it is not all about sugar","volume":"5","author":"Antunes","year":"2024","journal-title":"NeuroSci"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1016\/j.clinthera.2021.01.024","article-title":"Anesthesia and the developing brain: a review of sevoflurane-induced neurotoxicity in pediatric populations","volume":"43","author":"Apai","year":"2021","journal-title":"Clin. Ther."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s40478-022-01338-3","article-title":"The role of dhcr24 in the pathogenesis of ad: re-cognition of the relationship between cholesterol and ad pathogenesis","volume":"10","author":"Bai","year":"2022","journal-title":"Acta Neuropathol. Commun."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1017551","DOI":"10.3389\/fgene.2022.1017551","article-title":"Construction and validation of a prognostic marker and risk model for hcc ultrasound therapy combined with wgcna identification","volume":"13","author":"Bi","year":"2022","journal-title":"Front. Genet."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s41065-021-00177-x","article-title":"Identification of metabolism genes related to hepatocarcinogenesis and progression in type 2 diabetes mellitus via co-expression networks analysis","volume":"158","author":"Bi","year":"2021","journal-title":"Hereditas"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"2985","DOI":"10.21037\/jgo-21-664","article-title":"Screening of a novel autophagy-related prognostic signature and therapeutic targets in hepatocellular carcinoma","volume":"12","author":"Chen","year":"2021","journal-title":"J. Gastrointest. Oncol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"5439","DOI":"10.3390\/cancers14215439","article-title":"Identification of myeov-associated gene network as a potential therapeutic target in pancreatic cancer","volume":"14","author":"Chen","year":"2022","journal-title":"Cancer"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s12967-020-02689-y","article-title":"Three hematologic\/immune system-specific expressed genes are considered as the potential biomarkers for the diagnosis of early rheumatoid arthritis through bioinformatics analysis","volume":"19","author":"Cheng","year":"2021","journal-title":"J. Transl. Med."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"3321","DOI":"10.1096\/fj.12-208751","article-title":"The nuclear receptor rev-erbalpha is required for the daily balance of carbohydrate and lipid metabolism","volume":"26","author":"Delezie","year":"2012","journal-title":"FASEB J."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.taap.2017.12.013","article-title":"Stage-specific metabolic features of differentiating neurons: implications for toxicant sensitivity","volume":"354","author":"Delp","year":"2018","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1097\/ACO.0000000000001183","article-title":"Cerebral metabolic derangements following traumatic brain injury","volume":"35","author":"Demers-Marcil","year":"2022","journal-title":"Curr. Opin. Anaesthesiol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1258\/002367703766453038","article-title":"Effects of repetitive sevoflurane anaesthesia on immune response, select biochemical parameters and organ histology in mice","volume":"37","author":"Elena","year":"2003","journal-title":"Lab. Anim."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1016\/j.molcel.2016.05.029","article-title":"Interplay between metabolism and epigenetics: a nuclear adaptation to environmental changes","volume":"62","author":"Etchegaray","year":"2016","journal-title":"Mol. Cell"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.brainres.2014.07.050","article-title":"Interactions of innate and adaptive immunity in brain development and function","volume":"1617","author":"Filiano","year":"2015","journal-title":"Brain Res."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"3671","DOI":"10.1021\/acschemneuro.9b00248","article-title":"Cholesterol biosynthesis and uptake in developing neurons","volume":"10","author":"Genaro-Mattos","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"3844","DOI":"10.1093\/bioinformatics\/btac409","article-title":"Ggtranscript: an r package for the visualization and interpretation of transcript isoforms using ggplot2","volume":"38","author":"Gustavsson","year":"2022","journal-title":"Bioinformatics"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"jeb242968","DOI":"10.1242\/jeb.242968","article-title":"Microrna-mediated inhibition of ampk coordinates tissue-specific downregulation of skeletal muscle metabolism in hypoxic naked mole-rats","volume":"224","author":"Hadj-Moussa","year":"2021","journal-title":"J. Exp. Biol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"909932","DOI":"10.3389\/fimmu.2022.909932","article-title":"Infiltration of lpar5(+) macrophages in osteosarcoma tumor microenvironment predicts better outcomes","volume":"13","author":"He","year":"2022","journal-title":"Front. Immunol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.psyneuen.2017.04.001","article-title":"Role of environmental stressors in determining the developmental outcome of neonatal anesthesia","volume":"81","author":"Ju","year":"2017","journal-title":"Psychoneuroendocrinology"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1515\/tnsci-2019-0043","article-title":"Interactions of aromatase and seladin-1: a neurosteroidogenic and gender perspective","volume":"10","author":"Kelicen-Ugur","year":"2019","journal-title":"Transl. Neurosci."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"61","DOI":"10.3233\/BPL-160035","article-title":"The role of lipid metabolism for neural stem cell regulation","volume":"3","author":"Knobloch","year":"2017","journal-title":"Brain Plast."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1088943","DOI":"10.3389\/fgene.2022.1088943","article-title":"Differentially expressed gene profiles and associated cerna network in atg7-deficient lens epithelial cells under oxidative stress","volume":"13","author":"Li","year":"2022","journal-title":"Front. Genet."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"109501","DOI":"10.1016\/j.abb.2022.109501","article-title":"Mir-582-5p targets skp1 and regulates nf-kappab signaling-mediated inflammation","volume":"734","author":"Li","year":"2023","journal-title":"Arch. Biochem. Biophys."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"996625","DOI":"10.3389\/fgene.2022.996625","article-title":"Prognostic significance and immune landscape of a fatty acid metabolism-related gene signature in colon adenocarcinoma","volume":"13","author":"Liu","year":"2022","journal-title":"Front. Genet."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1093\/toxsci\/kfv150","article-title":"Potential adverse effects of prolonged sevoflurane exposure on developing monkey brain: from abnormal lipid metabolism to neuronal damage","volume":"147","author":"Liu","year":"2015","journal-title":"Toxicol. Sci."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"e149222","DOI":"10.1128\/jvi.01492-22","article-title":"Augmentation of 3beta-hydroxysteroid-delta24 reductase (dhcr24) expression induced by bovine viral diarrhea virus infection facilitates viral replication via promoting cholesterol synthesis","volume":"96","author":"Ma","year":"2022","journal-title":"J. Virol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"5856","DOI":"10.1007\/s12035-022-02945-w","article-title":"Dhcr24 knockdown induces tau hyperphosphorylation at thr181, ser199, ser262, and ser396 sites via activation of the lipid raft-dependent ras\/mek\/erk signaling pathway in c8d1a astrocytes","volume":"59","author":"Mai","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"2527","DOI":"10.1007\/s11064-015-1600-7","article-title":"Metabolic alterations in developing brain after injury: knowns and unknowns","volume":"40","author":"Mckenna","year":"2015","journal-title":"Neurochem. Res."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1802444369","DOI":"10.1177\/1178635317747281","article-title":"Some lipid droplets are more equal than others: different metabolic lipid droplet pools in hepatic stellate cells","volume":"10","author":"Molenaar","year":"2017","journal-title":"Lipid Insights"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"28747","DOI":"10.1038\/s41598-024-79150-3","article-title":"Sevoflurane exposure in early life: mitochondrial dysfunction and neurotoxicity in immature rat brains without long-term memory loss","volume":"14","author":"Qiu","year":"2024","journal-title":"Sci. Rep."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.nut.2018.06.003","article-title":"A comparison of two different software packages for analysis of body composition using computed tomography images","volume":"57","author":"Rollins","year":"2019","journal-title":"Nutrition"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s42255-018-0014-7","article-title":"Coupling Krebs cycle metabolites to signalling in immunity and cancer","volume":"1","author":"Ryan","year":"2019","journal-title":"Nat. Metab."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1090324","DOI":"10.3389\/fendo.2022.1090324","article-title":"Glycosylation-related molecular subtypes and risk score of hepatocellular carcinoma: novel insights to clinical decision-making","volume":"13","author":"Shi","year":"2022","journal-title":"Front. Endocrinol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"3795","DOI":"10.1038\/s41380-019-0640-9","article-title":"A variant near dhcr24 associates with microstructural properties of white matter and peripheral lipid metabolism in adolescents","volume":"26","author":"Sliz","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1461","DOI":"10.1152\/physrev.00038.2023","article-title":"Neuronal glucose sensing mechanisms and circuits in the control of insulin and glucagon secretion","volume":"104","author":"Thorens","year":"2024","journal-title":"Physiol. Rev."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.canlet.2013.08.016","article-title":"Helicobacter pylori-induced gastric inflammation and gastric cancer","volume":"345","author":"Wang","year":"2014","journal-title":"Cancer Lett."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"e32555","DOI":"10.1097\/MD.0000000000032555","article-title":"The mechanism of bai he gu jin tang against non-small cell lung cancer revealed by network pharmacology and molecular docking","volume":"101","author":"Xie","year":"2022","journal-title":"Medicine (Baltimore)"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"589370","DOI":"10.3389\/fgene.2020.589370","article-title":"Wfs1 and related molecules as key candidate genes in the hippocampus of depression","volume":"11","author":"Yang","year":"2020","journal-title":"Front. Genet."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s12967-022-03845-2","article-title":"Computed tomography-detected extramural venous invasion-related gene signature: a potential negative biomarker of immune checkpoint inhibitor treatment in patients with gastric cancer","volume":"21","author":"Yang","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1016\/j.bja.2021.08.028","article-title":"Testosterone attenuates sevoflurane-induced tau phosphorylation and cognitive impairment in neonatal male mice","volume":"127","author":"Yang","year":"2021","journal-title":"Br. J. Anaesth."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"7621","DOI":"10.3390\/ijms25147621","article-title":"Metabolic crosstalk between liver and brain: from diseases to mechanisms","volume":"25","author":"Yang","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1147545","DOI":"10.1155\/2022\/1147545","article-title":"Hybrid metabolic activity-related prognostic model and its effect on tumor in renal cell carcinoma","volume":"2022","author":"Yu","year":"2022","journal-title":"J. Healthc. Eng."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"15286","DOI":"10.3390\/ijms232315286","article-title":"Identification of novel hub genes associated with psoriasis using integrated bioinformatics analysis","volume":"23","author":"Yue","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"480","DOI":"10.2174\/1573409918666220930102601","article-title":"Exploring the mechanism of the baishao luoshi formula against poststroke spasticity by network pharmacology and experimental validation","volume":"18","author":"Zeng","year":"2022","journal-title":"Curr. Comput. Aided Drug Des."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s40246-022-00445-5","article-title":"Circulating mir-320a-3p and mir-483-5p level associated with pharmacokinetic-pharmacodynamic profiles of rivaroxaban","volume":"16","author":"Zhang","year":"2022","journal-title":"Hum. Genomics"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1186\/s12864-020-6599-8","article-title":"Identification and characterization of circrnas in the skin during wool follicle development in aohan fine wool sheep","volume":"21","author":"Zhao","year":"2020","journal-title":"BMC Genomics"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1034208","DOI":"10.3389\/fmolb.2022.1034208","article-title":"Comprehensive analyses of one-carbon metabolism related genes and their association with prognosis, tumor microenvironment, chemotherapy resistance and immunotherapy in lung adenocarcinoma","volume":"9","author":"Zhou","year":"2022","journal-title":"Front. Mol. Biosci."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1186\/s12894-022-01132-2","article-title":"Circrna\/mirna\/mrna axis participates in the progression of partial bladder outlet obstruction","volume":"22","author":"Zhu","year":"2022","journal-title":"BMC Urol."}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2025.1369365\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T05:33:39Z","timestamp":1756964019000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2025.1369365\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,4]]},"references-count":49,"alternative-id":["10.3389\/fnmol.2025.1369365"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2025.1369365","relation":{},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,4]]},"article-number":"1369365"}}