{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T09:12:19Z","timestamp":1788858739935,"version":"build-2803163510"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004775","name":"Natural Science Foundation of Gansu Province","doi-asserted-by":"publisher","award":["21JR7RA446"],"award-info":[{"award-number":["21JR7RA446"]}],"id":[{"id":"10.13039\/501100004775","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The central amygdala (CeA) is closely associated with the development of alcohol dependence by mediating negative affective and stress responses during alcohol withdrawal. Chronic alcohol disrupts CeA neuroimmune balance and lipid metabolism, accelerating alcohol use disorder (AUD), but the regulatory mechanisms remain unclear. This exploratory study aimed to identify CeA key genes associated with AUD and investigate their potential involvement in mediating these dysregulations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Based on the GSE31708 dataset, differential gene analysis, protein-protein interaction (PPI) network, random forest, and LASSO regression were used to screen hub genes. Adult male Long-Evans rats were trained to consume alcohol over 8 weeks; open field test (OFT) and elevated plus maze (EPM) assessed withdrawal-induced anxiety, and RT-qPCR validated candidate genes. CIBERSORT analyzed immune cell composition, co-expression networks delineated molecular interactions, and Mendelian randomization (MR) explored potential genetic associations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Hub gene\n                      <jats:italic>Cbr4<\/jats:italic>\n                      was found to be significantly upregulated in the CeA of AUD subjects. Preliminary\n                      <jats:italic>in vivo<\/jats:italic>\n                      validation revealed increased\n                      <jats:italic>Cbr4<\/jats:italic>\n                      expression in alcohol-withdrawn rats, and a negative correlation was observed between\n                      <jats:italic>Cbr4<\/jats:italic>\n                      expression and anxiety-like behavioral parameters. Mendelian randomization analyses suggest that\n                      <jats:italic>Ephx2<\/jats:italic>\n                      -a pivotal molecule in the co-expression network-has a genetic association with\n                      <jats:italic>Cbr4<\/jats:italic>\n                      (OR = 1.32, 95% CI = 1.15\u20131.51,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.031). Immune infiltration analysis indicated reduced regulatory T cell (Treg) levels in AUD subjects, with\n                      <jats:italic>Cbr4<\/jats:italic>\n                      expression showing a negative correlation with Treg abundance. Multiple Treg subtypes appeared to be associated with a protective effect against AUD (OR = 0.9744\u20130.9797,\n                      <jats:italic>p<\/jats:italic>\n                      = 0.036\u20130.043).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our findings suggest that\n                      <jats:italic>Cbr4<\/jats:italic>\n                      in the CeA may play a role in the pathological processes of AUD. It may contribute to AUD development through two potential mechanisms: a possible genetic interaction with\n                      <jats:italic>Ephx2<\/jats:italic>\n                      , and a negative association with Treg abundance, which may be associated with dysregulation of CeA neuroimmune homeostasis. These preliminary observations provide a basis for further investigation into\n                      <jats:italic>Cbr4<\/jats:italic>\n                      as an exploratory molecular indicator for AUD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1829878","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T06:10:44Z","timestamp":1782886244000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative bioinformatics and in vivo validation suggest a potential role of Cbr4 in alcohol use disorder through modulation of lipid metabolism and treg cell function in the central amygdala"],"prefix":"10.3389","volume":"17","author":[{"given":"Yao","family":"Ge","sequence":"first","affiliation":[{"name":"Department of Pathology, School of Basic Medical Sciences, Lanzhou University","place":["Lanzhou, Gansu, China"]},{"name":"The First School of Clinical Medicine, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihan","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Basic Medical Sciences, Lanzhou University","place":["Lanzhou, Gansu, China"]},{"name":"The Second Clinical Medical School, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Basic Medical Sciences, Lanzhou University","place":["Lanzhou, Gansu, China"]},{"name":"The First School of Clinical Medicine, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenxia","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Basic Medical Sciences, Lanzhou University","place":["Lanzhou, Gansu, China"]},{"name":"The First School of Clinical Medicine, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Basic Medical Sciences, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caiyu","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Basic Medical Sciences, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyu","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Qingyuan Hospital, Guangzhou Medical University","place":["Qingyuan, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Hospital of Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Hospital of Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Basic Medical Sciences, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rao","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiheng","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Basic Medical Sciences, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/bs.irn.2024.07.003","article-title":"Pharmacological activators of ALDH2: a new strategy for the treatment of alcohol use disorders","volume":"178","author":"Adasme-Reyes","year":"2024","journal-title":"Int. Rev. Neurobiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"90","DOI":"10.34172\/bshj.24","article-title":"The effects of alcohol on recovery from musculoskeletal trauma and injuries","volume":"1","author":"Bazargan-Hejazi","year":"2024","journal-title":"Biosoc. Health Journal"},{"key":"B3","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1708\/2925.29415","article-title":"Diagnosis of alcohol use disorder from a psychological point of view","volume":"53","author":"Coriale","year":"2018","journal-title":"Riv. Di Psichiatr."},{"key":"B4","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1111\/acer.14979","article-title":"A critical review of recent knowledge of alcohol\u2019s effects on the immunological response in different tissues","volume":"47","author":"Crotty","year":"2023","journal-title":"Alcohol, Clin. and Exp. Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"2611","DOI":"10.1038\/s41380-024-02514-8","article-title":"Chemogenetic inhibition of central amygdala CRF-Expressing neurons decreases alcohol intake but not trauma-related behaviors in a rat model of post-traumatic stress and alcohol use disorder","volume":"29","author":"Cruz","year":"2024","journal-title":"Mol. Psychiatry"},{"key":"B6","doi-asserted-by":"publisher","first-page":"103049","DOI":"10.1016\/j.jbc.2023.103049","article-title":"Disruption of Ephx2 in cardiomyocytes but not endothelial cells improves functional recovery after ischemia-reperfusion in isolated mouse hearts","volume":"299","author":"Edin","year":"2023","journal-title":"J. Biol. Chem."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1016\/j.bbrc.2008.11.003","article-title":"Human carbonyl reductase 4 is a mitochondrial NADPH-Dependent quinone reductase","volume":"377","author":"Endo","year":"2008","journal-title":"Biochem. Biophysical Res. Commun."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1435","DOI":"10.1111\/j.1530-0277.2011.01479.x","article-title":"Ethanol inhibits lipid raft-mediated TCR signaling and IL-2 expression: potential mechanism of alcohol-induced immune suppression","volume":"35","author":"Ghare","year":"2011","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"01276-X","DOI":"10.1016\/j.biopsych.2026.05.004","article-title":"Continuous theta-burst stimulation improves long-term outcomes in alcohol use disorder by modulating a craving-related dynamic network","author":"Huang","year":"2026","journal-title":"Biol. Psychiatry"},{"key":"B10","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1080\/13543776.2022.2054329","article-title":"Soluble epoxide hydrolase inhibitors: an overview and patent review from the last decade","volume":"32","author":"Iyer","year":"2022","journal-title":"Expert Opin. Ther. Pat."},{"key":"B11","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1194\/jlr.R119000547","article-title":"Alcohol effects on hepatic lipid metabolism","volume":"61","author":"Jeon","year":"2020","journal-title":"J. Lipid Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"S146","DOI":"10.1016\/j.bbi.2011.02.018","article-title":"Cytokine involvement in stress may depend on corticotrophin releasing factor to sensitize ethanol withdrawal anxiety","author":"Knapp","year":"2011","journal-title":"Brain, Behav. Immun."},{"key":"B13","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1176\/appi.ajp.20230488","article-title":"Overview of alcohol use disorder","volume":"180","author":"Kranzler","year":"2023","journal-title":"Am. J. Psychiatry"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4103\/cjp.cjp_80_21","article-title":"Epoxyeicosatrienoic acids and soluble epoxide hydrolase in physiology and diseases of the central nervous system","volume":"65","author":"Kuo","year":"2022","journal-title":"Chin. J. Physiology"},{"key":"B15","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1038\/s41386-022-01482-3","article-title":"Rostromedial tegmental nucleus nociceptin\/orphanin FQ (N\/OFQ) signaling regulates anxiety- and depression-like behaviors in alcohol withdrawn rats","volume":"48","author":"Li","year":"2023","journal-title":"Neuropsychopharmacol. Official Publ. Am. Coll. Neuropsychopharmacol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.biochi.2024.03.015","article-title":"Inhibition of soluble epoxide hydrolase as a therapeutic approach for blood-brain barrier dysfunction","volume":"223","author":"Li","year":"2024","journal-title":"Biochimie"},{"key":"B17","doi-asserted-by":"publisher","first-page":"109","DOI":"10.4103\/aja.aja_34_20","article-title":"Clinical significance of EPHX2 deregulation in prostate cancer","volume":"23","author":"Liu","year":"2021","journal-title":"Asian J. Androl."},{"key":"B18","doi-asserted-by":"publisher","first-page":"639","DOI":"10.2174\/138920010794233530","article-title":"Human carbonyl reductases","volume":"11","author":"Mal\u00e1tkov\u00e1","year":"2010","journal-title":"Curr. Drug Metab."},{"key":"B19","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1007\/s11481-016-9709-2","article-title":"Modulation of binge-like ethanol consumption by IL-10 signaling in the basolateral amygdala","volume":"12","author":"Marshall","year":"2017","journal-title":"J. Neuroimmune Pharmacol. Official J. Soc. NeuroImmune Pharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"888345","DOI":"10.3389\/fnmol.2022.888345","article-title":"Subregional differences in alcohol modulation of central amygdala neurocircuitry","volume":"15","author":"Melkumyan","year":"2022","journal-title":"Front. Mol. Neurosci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"100194","DOI":"10.1016\/j.addicn.2024.100194","article-title":"Central amygdala neuroimmune signaling in alcohol use disorder","volume":"14","author":"Melkumyan","year":"2025","journal-title":"Addict. Neurosci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1038\/s41586-019-1700-7","article-title":"Alcohol metabolism contributes to brain histone acetylation","volume":"574","author":"Mews","year":"2019","journal-title":"Nature"},{"key":"B23","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1038\/s41398-025-03337-z","article-title":"Central amygdala astrocyte plasticity underlies GABAergic dysregulation in ethanol dependence","volume":"15","author":"Nentwig","year":"2025","journal-title":"Transl. Psychiatry"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1016\/j.jceh.2022.05.004","article-title":"Pathogenesis of alcohol-associated liver disease","volume":"12","author":"Osna","year":"2022","journal-title":"J. Clin. Exp. Hepatology"},{"key":"B25","doi-asserted-by":"publisher","first-page":"101952","DOI":"10.1016\/j.pneurobio.2020.101952","article-title":"IL-10 normalizes aberrant amygdala GABA transmission and reverses anxiety-like behavior and dependence-induced escalation of alcohol intake","volume":"199","author":"Patel","year":"2021","journal-title":"Prog. Neurobiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1142614","DOI":"10.3389\/fimmu.2023.1142614","article-title":"Impact of chronic alcohol exposure on conventional and regulatory murine T cell subsets","volume":"14","author":"Paterson","year":"2023","journal-title":"Front. Immunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2269","DOI":"10.1016\/s0140-6736(25)01496-5","article-title":"Alcohol use disorders","volume":"406","author":"Rehm","year":"2025","journal-title":"Lancet"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2356","DOI":"10.1523\/jneurosci.1578-21.2022","article-title":"A distinct metabolically defined central nucleus circuit bidirectionally controls anxiety-related behaviors","volume":"42","author":"Ren","year":"2022","journal-title":"J. Neurosci. Official J. Soc. Neurosci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1038\/s41386-023-01582-8","article-title":"LPA1 receptors in the lateral habenula regulate negative affective states associated with alcohol withdrawal","volume":"48","author":"Ren","year":"2023","journal-title":"Neuropsychopharmacol. Official Publ. Am. Coll. Neuropsychopharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"a039339","DOI":"10.1101\/cshperspect.a039339","article-title":"The role of the central amygdala in alcohol dependence","volume":"11","author":"Roberto","year":"2021","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"3252","DOI":"10.2174\/1381612827666210203142539","article-title":"Targeting epigenetic mechanisms to treat alcohol use disorders (AUD)","volume":"27","author":"Rodriguez","year":"2021","journal-title":"Curr. Pharm. Des."},{"key":"B32","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1111\/jnc.15530","article-title":"Lipidome changes in alcohol-related brain damage","volume":"160","author":"Smith","year":"2022","journal-title":"J. Neurochem."},{"key":"B33","doi-asserted-by":"publisher","first-page":"107367","DOI":"10.1016\/j.nbd.2026.107367","article-title":"Thalamostriatal circuit as a therapeutic target of alcohol use disorder","volume":"223","author":"Song","year":"2026","journal-title":"Neurobiol. Dis."},{"key":"B34","doi-asserted-by":"publisher","first-page":"106115","DOI":"10.1016\/j.bbi.2025.106115","article-title":"Purinergic and extracellular vesicle signaling in alcohol-induced blood-brain barrier breakdown and neuroimmune activation","volume":"130","author":"Togre","year":"2025","journal-title":"Brain, Behav. Immun."},{"key":"B35","doi-asserted-by":"publisher","first-page":"105952","DOI":"10.1016\/j.neuint.2025.105952","article-title":"Dysregulation of immune system markers, gut microbiota and short-chain fatty acid production following prenatal alcohol exposure: a developmental perspective","volume":"185","author":"Vella","year":"2025","journal-title":"Neurochem. Int."},{"key":"B36","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1016\/j.cld.2024.06.009","article-title":"Diagnosis of alcohol use disorder and alcohol-associated liver disease","volume":"28","author":"Witkiewitz","year":"2024","journal-title":"Clin. Liver Dis."},{"key":"B37","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1136\/jnnp-2023-331142","article-title":"Systematic druggable genome-wide Mendelian randomisation identifies therapeutic targets for Alzheimer\u2019s disease","volume":"94","author":"Wm","year":"2023","journal-title":"J. Neurology, Neurosurgery, Psychiatry"},{"key":"B38","doi-asserted-by":"publisher","first-page":"4502","DOI":"10.3390\/ijms27104502","article-title":"Searching for new pharmacological treatments of alcohol use disorder (AUD): focus on GLP-1 receptor agonists","volume":"27","author":"Zawilska","year":"2026","journal-title":"Int. J. Mol. Sci."}],"updated-by":[{"DOI":"10.3389\/fgene.2026.1975571","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000}}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1829878\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T08:57:37Z","timestamp":1788857857000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2026.1829878\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":38,"alternative-id":["10.3389\/fgene.2026.1829878"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2026.1829878","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,1]]},"article-number":"1829878"}}