Hippo/YAP信号通路在组织纤维化中的作用研究进展

Research progress of Hippo/YAP signaling pathway in tissue fibrosis

Hippo/YAP信号通路是一种进化上保守的蛋白质激酶级联反应,在多种生物过程如细胞增殖和分化、器官生长和组织再生中发挥重要作用。组织纤维化是一个持续且高度动态的过程,其特征是细胞外基质过度沉积造成不可逆的病理改变,最终导致多个组织器官衰竭。目前尚缺乏改善或逆转纤维化的靶向治疗策略。研究表明,异常激活的Hippo/YAP信号通路可通过调控胶原沉积、成纤维细胞过度增殖和上皮细胞分化等方式在纤维化发生发展过程中发挥作用,但具体作用机制尚未完全阐明。靶向Hippo/YAP信号通路主要涉及两方面机制:一是针对Hippo/YAP信号通路的上游分子进行靶向干预,主要通过抑制核心激酶活性或阻断与其他分子的相互作用而实现;二是针对Hippo/YAP信号通路下游YAP/TAZ的活性和YAP/TAZ-TEAD相互作用进行靶向干预。研究表明,当组织器官发生损伤时YAP/TAZ的磷酸化和亚细胞定位发生显著改变。本文对Hippo/YAP信号通路及其介导肺、心、肝、肾、胰腺和皮肤等纤维化的研究现状进行综述,以期为纤维化发病机制和靶向治疗药物研究提供新思路。

The Hippo/YAP signaling pathway is an evolutionarily conserved protein kinase cascade that plays an important role in a variety of biological processes,such as cell proliferation and differentia-tion,organ growth and tissue regeneration.Fibrosis is a continuous and highly dynamic process char-acterized by excessive deposition of extracellular matrix,resulting in irreversible pathological changes that eventually lead to the failure of multiple tissues and organs.Targeted therapeutic strategies to ameliorate or reverse fibrosis are lacking.Studies have shown that the aberrantly activated Hippo/YAP signaling pathway may play a role in the development of fibrosis by regulating collagen deposition,fibroblast overproliferation,and epithelial cell differentiation,but the specific mechanism of action has not been fully elucidated.Targeting the Hippo/YAP signaling pathway involves two mechanisms:one is to target the upstream molecules of the Hippo/YAP signaling pathway,which is mainly achieved by inhibiting the activity of the core kinase or blocking the interaction with other molecules;the other is to target the downstream activities of YAP/TAZ and YAP/TAZ-TEAD in the Hippo/YAP signaling pathway.Studies have shown that the phosphorylation and subcellular localization of YAP/TAZ are significantly altered when tissue and organ damage occurs.This article is intended to review the current research on Hippo/YAP signaling pathway and its mediation of fibrosis in the lung,heart,liver,kidney,pancreas and skin in hopes of providing new ideas for studies on the pathogenesis of fibrosis and targeted thera-peutic drugs.