Wu Cichun, Cheng Da, Mo Juan, Zhou Nianqi, Peng Shifang, Fu Lei
Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, China.
Mamm Genome. 2025 Jun 16. doi: 10.1007/s00335-025-10146-8.
Cholestasis, characterized by impaired bile flow, leads to significant hepatic dysfunction and poses a clinical challenge. This study investigated cellular communication networks and molecular mechanisms underlying cholestasis using advanced single-cell and transcriptomic sequencing. Data from the GEO database, including single-cell sequencing (GSE237622) and transcriptome datasets (GSE206364, GSE183754), were analyzed to identify biomarkers and therapeutic targets. Lasso regression highlighted IL32, CRIP2, ANXA2, and VWF as key genes, supported by immune infiltration, functional enrichment, and drug repurposing analysis via the Connectivity Map (CMap) database. Expression of these genes was validated in liver tissue from 13 cholestatic liver disease (CLD) patients and 10 controls. Single-cell sequencing identified 534 cell-type-specific markers, with significant upregulation of IL32, CRIP2, ANXA2, and VWF in CLD patients, particularly in endothelial cells near liver sinusoids and periportal areas. Their expression correlated with serum ALT and AST levels, reflecting disease severity. Drug repurposing analysis identified dexamethasone, fenofibrate, promazine, and SB-590,885 as potential therapies. This study identifies IL32, CRIP2, ANXA2, and VWF as pivotal biomarkers and therapeutic targets for cholestasis, offering new avenues for targeted interventions.
胆汁淤积以胆汁流动受损为特征，会导致严重的肝功能障碍并带来临床挑战。本研究使用先进的单细胞和转录组测序技术，调查了胆汁淤积背后的细胞通讯网络和分子机制。分析了来自基因表达综合数据库（GEO）的数据，包括单细胞测序（GSE237622）和转录组数据集（GSE206364、GSE183754），以识别生物标志物和治疗靶点。套索回归突出显示白细胞介素32（IL32）、富含半胱氨酸的分泌性蛋白2（CRIP2）、膜联蛋白A2（ANXA2）和血管性血友病因子（VWF）为关键基因，通过连通性图谱（CMap）数据库进行的免疫浸润、功能富集和药物再利用分析也支持这一结果。在13例胆汁淤积性肝病（CLD）患者和10例对照的肝组织中验证了这些基因的表达。单细胞测序确定了534个细胞类型特异性标志物，在CLD患者中IL32、CRIP2、ANXA2和VWF显著上调，尤其是在肝血窦附近和门静脉周围区域的内皮细胞中。它们的表达与血清谷丙转氨酶（ALT）和谷草转氨酶（AST）水平相关，反映了疾病的严重程度。药物再利用分析确定地塞米松、非诺贝特、异丙嗪和SB - 590,885为潜在治疗药物。本研究确定IL32、CRIP2、ANXA2和VWF为胆汁淤积的关键生物标志物和治疗靶点，为靶向干预提供了新途径。
