Dual Functions and Therapeutic Potential of FZD6 in Biliary Atresia.

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.