GA-017 attenuates OA by activating YAP/TAZ.

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2025-10-03 DOI:10.1016/j.bcp.2025.117389

Xinhuo Li, Mingyang Lei, Qiannan Ding, Yangjun Xu, Xuanyuan Lu, Jiewen Zheng, Zhuolin Chen, Xuewen Liu, Xi Chen, Weiqi Han, Wei He, Wanglei Yang, Yu Qian

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引用次数: 0

Abstract

Osteoarthritis (OA) is a common disease that causes joint pain, mobility issues, and functional impairment in middle-aged and older individuals. However, effective medications for its treatment are lacking. YAP (Yes-associated protein) /TAZ (transcriptional co-activator with PDZ-binding motif) are important protective molecules that regulate the development of OA, and activating YAP/TAZ may be a potential treatment strategy. GA-017 is an inhibitor of LATS (large tumor suppressor kinase), an upstream molecule of YAP/TAZ in the Hippo signaling pathway, and has the potential to activate YAP/TAZ. However, whether GA-017 regulates chondrocyte metabolism and arthritis progression through YAP/TAZ activation remains unclear. In this study, we found that GA-017 activated YAP/TAZ and inhibited NF-κB (nuclear factor kappaB) signaling, thereby regulating anabolic and catabolic cell processes and inflammatory responses, ultimately suppressing OA in mouse and human knee cartilage. These results demonstrate that GA-017's activation of YAP/TAZ has significant potential in the treatment of OA and further suggest that drug-induced activation of YAP/TAZ is a feasible approach for treating OA.

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GA-017通过激活YAP/TAZ来减弱OA。

骨关节炎（OA）是一种常见的疾病，导致关节疼痛，活动问题，和功能障碍在中老年个体。然而，缺乏有效的治疗药物。YAP (Yes-associated protein) /TAZ （transcriptional co-activator with PDZ-binding motif）是调控OA发展的重要保护分子，激活YAP/TAZ可能是一种潜在的治疗策略。GA-017是大肿瘤抑制激酶（large tumor suppressor kinase， LATS）的抑制剂，LATS是Hippo信号通路中YAP/TAZ的上游分子，具有激活YAP/TAZ的潜力。然而，GA-017是否通过YAP/TAZ激活调节软骨细胞代谢和关节炎进展仍不清楚。在本研究中，我们发现GA-017激活YAP/TAZ，抑制NF-κB（核因子κ b）信号，从而调节合成代谢和分解代谢细胞过程和炎症反应，最终抑制小鼠和人膝关节软骨的OA。这些结果表明GA-017激活YAP/TAZ在OA的治疗中具有重要的潜力，进一步表明药物诱导激活YAP/TAZ是治疗OA的可行途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.