Another ciliopathy? Uncovering the ciliary basis of biliary atresia

Biliary atresia (BA) is a rare but severe neonatal cholangiopathy characterized by progressive fibro-inflammatory obstruction of the bile ducts, ultimately leading to liver failure and the need for liver transplants. Despite intensive researches, the etiology of BA remains poorly understood. Recent discoveries implicate primary cilia-solitary, microtubule-based organelles that regulate developmental signaling pathways-as central to the pathogenesis of both syndromic and non-syndromic BA.

We systematically reviewed genetic, histological, organoid-based, and animal model studies that investigate the role of primary cilia in BA. Evidence was synthesized across genome-wide association studies, sequencing analyses, tissue-level ciliary assessments, and functional perturbation experiments in model organisms to integrate current understanding of ciliary defects and their mechanistic contribution to BA.

Genetic analyses identified both common and rare variants in cilia-related genes-polycystin 1 like 1 (PKD1L1), kinesin family member 3B (KIF3B), tetratricopeptide repeat domain 17 (TTC17), and ciliogenesis and planar polarity effector (CPLANE) complex members-particularly in BA patients with laterality defects. Histological evaluation of BA liver tissues consistently demonstrated shortened, misoriented, or absent cholangiocyte cilia, while patient-derived organoids reproduced these structural abnormalities alongside disrupted epithelial polarity. Functional studies in zebrafish and mouse models showed that loss of ciliary genes impaired bile duct morphogenesis, delayed biliary drainage, and induced progressive cholangiopathy, closely mirroring human BA. Perturbation of cilia-dependent signaling pathways, including Hedgehog (Hh), further exacerbated disease phenotypes, underscoring the causal role of ciliary dysfunction.

Taken together, these findings support the emerging view of BA as a cilia-related developmental disorder. This review offers new insights into disease mechanisms and provides a basis for advancing early diagnosis, risk stratification, and targeted therapeutic strategies of BA.