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.

Authors

Yao Ge, Yihan Yuan, Min Li, Zhenxia Huang, Chenli Zhang, Caiyu Yu, Jinyu Xu, Siao Zhang, Hongwei Guo, Xu Zhang, Rao Fu, Zhiheng Ren

Published in

Frontiers in genetics. Volume 17. Pages 1829878. Epub Jul 01, 2026.

Abstract

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.
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.
Hub gene Cbr4 was found to be significantly upregulated in the CeA of AUD subjects. Preliminary in vivo validation revealed increased Cbr4 expression in alcohol-withdrawn rats, and a negative correlation was observed between Cbr4 expression and anxiety-like behavioral parameters. Mendelian randomization analyses suggest that Ephx2 -a pivotal molecule in the co-expression network-has a genetic association with Cbr4 (OR = 1.32, 95% CI = 1.15-1.51, p = 0.031). Immune infiltration analysis indicated reduced regulatory T cell (Treg) levels in AUD subjects, with Cbr4 expression showing a negative correlation with Treg abundance. Multiple Treg subtypes appeared to be associated with a protective effect against AUD (OR = 0.9744-0.9797, p = 0.036-0.043).
Our findings suggest that Cbr4 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 Ephx2, 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 Cbr4 as an exploratory molecular indicator for AUD.

PMID:
42460148
Bibliographic data and abstract were imported from PubMed on 16 Jul 2026.

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