纤毛相关基因在儿童胆汁淤积性疾病中的研究进展

Research Progress on Ciliary-Related Genes in Childhood Cholestatic Diseases

摘要: 胆汁淤积性肝病是儿科领域重要的肝脏疾病类型，其病程呈持续性进展，可逐步发展为肝纤维化、肝硬化甚至肝衰竭，严重影响患儿长期预后。该病的发生与胆汁生成、胆管分泌、转运及排泄等多个生理环节的功能障碍密切相关，涉及多基因、多通路参与，尤其在儿童患者中，遗传因素常发挥关键作用。近年来研究证实，肝内胆管上皮细胞的初级纤毛作为一类关键的“机械–化学信号传感器”，在感知胆汁流体力学刺激、响应管腔微环境变化、调控胆汁成分以及维持胆管系统稳态中发挥核心作用。纤毛相关基因突变所引发的纤毛结构缺陷或信号转导功能障碍，已被认定为多种胆汁淤积性疾病的重要致病基础。然而，上述过程所涉及的具体分子机制、细胞层面因果联系及病理转化条件仍有待系统阐明。本文系统综述初级纤毛的基本结构与功能，探讨纤毛相关基因突变导致胆汁淤积的致病机制，并总结该领域在发病机理与治疗策略方面的最新研究进展，以期为儿童胆汁淤积性疾病的临床诊断与治疗提供新思路与方向。

Abstract: Cholestatic liver disease represents a significant category of pediatric liver disorders, characterized by a progressive course that can evolve into liver fibrosis, cirrhosis, and even hepatic failure, severely impacting long-term prognosis in children. The pathogenesis of cholestasis is closely linked to impairments in multiple physiological processes, including bile synthesis, secretion, transport, and excretion, involving polygenic and multi-pathway interactions, with genetic factors often playing a critical role, especially in pediatric patients. Recent studies have established that the primary cilia of intrahepatic cholangiocytes function as crucial “mechano‑chemical signal sensors,” playing a central role in sensing bile fluid dynamics, responding to changes in the ductal microenvironment, regulating bile composition, and maintaining biliary system homeostasis. Mutations in ciliary genes leading to structural defects or signaling dysfunction in cilia have been recognized as an important pathogenic basis of various cholestatic diseases. However, the specific molecular mechanisms, cell‑level causal relationships, and pathological transition conditions involved in these processes remain to be fully elucidated. This review systematically summarizes the basic structure and function of primary cilia, discusses the pathogenic mechanisms by which ciliary gene mutations contribute to cholestasis, and highlights recent advances in the pathogenesis and therapeutic strategies in this field, aiming to provide new perspectives and directions for the clinical diagnosis and treatment of cholestatic liver diseases in children.