FZD6在胆道闭锁中的双重功能及治疗潜力

Dual Functions and Therapeutic Potential of FZD6 in Biliary Atresia.

作者信息

Wang Xinying, Lai Hongkun, Tan Ledong, Wen Ying, Tong Yanlu, Huang Lin, Liao Jiachi, Xu Yingyi, Li Le, Fu Ming, Lin Zefeng

机构信息

Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510000, China.

Department of Thoracic Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510000, China.

出版信息

Dig Dis Sci. 2025 Jul 6. doi: 10.1007/s10620-025-09154-0.

DOI:10.1007/s10620-025-09154-0

PMID:40618286

Abstract

OBJECTIVE

Biliary atresia (BA), a severe neonatal cholangiopathy, lacks pharmacological therapies. This study aimed to identify causal genes and therapeutic targets through multi-omics analyses, emphasizing FZD6's role in immune-pathological mechanisms.

METHODS

Mendelian randomization (MR) and GWAS prioritized BA-associated genes. Co-localization, ceRNA network construction, transcriptomic profiling (GSE46960: 64 BA vs 17 controls), and immune infiltration (ssGSEA/CIBERSORT) were conducted. Immunohistochemistry validated FZD6 expression. Molecular docking (CB-Dock2) screened FZD6-targeting drugs.

RESULTS

MR identified four causal genes (GSR, PGAP6, FZD6, FGD4). FZD6 was upregulated in BA tissues (Wilcoxon p = 0.00021) and correlated with immune dysregulation, including central memory CD4 T cells (r = 0.66, **p < 0.01) and T follicular helper cells (r = 0.36, *p < 0.05). Machine learning identified CD56dim NK cells and mast cells as key immune drivers. Immunohistochemistry confirmed FZD6 overexpression in BA bile ducts. Molecular docking identified dexamethasone (- 9.8 kcal/mol) and gomisin N (- 9.5 kcal/mol) as high-affinity FZD6 ligands.

CONCLUSION

This study establishes FZD6 as a novel therapeutic target in BA, linking its dysregulation to immune-mediated bile duct injury. Multi-omics integration advances BA pathogenesis understanding, while drug candidates offer translational potential.

摘要

目的

胆道闭锁（BA）是一种严重的新生儿胆管病，缺乏药物治疗方法。本研究旨在通过多组学分析确定因果基因和治疗靶点，重点强调FZD6在免疫病理机制中的作用。

方法

孟德尔随机化（MR）和全基因组关联研究（GWAS）对与BA相关的基因进行了优先级排序。进行了共定位、ceRNA网络构建、转录组分析（GSE46960：64例BA患者与17例对照）和免疫浸润分析（单样本基因集富集分析/ CIBERSORT）。免疫组织化学验证了FZD6的表达。分子对接（CB-Dock2）筛选了靶向FZD6的药物。

结果

MR确定了四个因果基因（GSR、PGAP6、FZD6、FGD4）。FZD6在BA组织中上调（Wilcoxon检验p = 0.00021），并与免疫失调相关，包括中央记忆CD4 T细胞（r = 0.66，**p < 0.01）和滤泡辅助性T细胞（r = 0.36，*p < 0.05）。机器学习确定CD56dim自然杀伤细胞和肥大细胞是关键的免疫驱动因素。免疫组织化学证实FZD6在BA胆管中过表达。分子对接确定地塞米松（-9.8 kcal/mol）和五味子素N（-9.5 kcal/mol）是高亲和力的FZD6配体。