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Objective <p>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.</p> Methods <p>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.</p> Results <p>MR identified four causal genes (GSR, PGAP6, FZD6, FGD4). FZD6 was upregulated in BA tissues (Wilcoxon <i>p</i> = 0.00021) and correlated with immune dysregulation, including central memory CD4 T cells (<i>r</i> = 0.66, **<i>p</i> &lt; 0.01) and T follicular helper cells (<i>r</i> = 0.36, *<i>p</i> &lt; 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&#xa0;kcal/mol) and gomisin N (− 9.5&#xa0;kcal/mol) as high-affinity FZD6 ligands.</p> Conclusion <p>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.</p>

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Dual Functions and Therapeutic Potential of FZD6 in Biliary Atresia

  • 期刊论文

  • 发表日期：

    2025年7月6日

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

摘要

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.