Hippo通路效应因子YAP/TAZ在特发性肺纤维化中的研究进展

doi:10.12092/j.issn.1009-2501.2026.05.016

摘要/Abstract

摘要：

特发性肺纤维化（idiopathic pulmonary fibrosis，IPF）是一种慢性、进行性、年龄相关、不可逆、纤维化的间质性肺病。IPF诊断后的中位生存期仅为2～5年，其特征是成纤维细胞增生、细胞外基质（ECM）沉积、肺泡上皮修复失调，目前尚无肯定显著有效的治疗方法。越来越多的证据表明，Hippo信号通路与IPF密切相关。本文就近年来 Hippo信号通路效应因子YAP/TAZ对肺纤维化的研究现状以及现有的抑制剂干预YAP/TAZ延缓肺纤维化的研究成果予以综述，以期为肺纤维化的治疗提供参考。

关键词: 特发性肺纤维化, Hippo信号通路, YAP/TAZ, 成纤维细胞, 肺泡上皮细胞

Abstract:

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, age-related, irreversible and fibrotic interstitial lung disease. The median survival time after the diagnosis of IPF is only 2-5 years. It is characterized by the process of fibroblast proliferation, extracellular matrix deposition and dysregulated alveolar epithelial repair. Currently, there is no definite and significantly effective treatment. More and more evidence indicates that the Hippo signaling pathway is closely related to idiopathic pulmonary fibrosis (IPF). This article reviews the current research status of Hippo signaling pathway effector factors YAP/TAZ in pulmonary fibrosis and the research results of existing inhibitors to intervene YAP/TAZ to delay pulmonary fibrosis, in order to provide a reference for the treatment of pulmonary fibrosis.

Key words: idiopathic pulmonary fibrosis, Hippo signaling pathway, YAP/TAZ, fibroblasts, alveolar epithelial cells

中图分类号:

杨浩东, 李龙, 罗敬轩, 李静蕾. Hippo通路效应因子YAP/TAZ在特发性肺纤维化中的研究进展[J]. 中国临床药理学与治疗学, 2026, 31(5): 709-715.

Haodong YANG, Long LI, Jingxuan LUO, Jinglei LI. Research progress of Hippo pathway effector YAP/TAZ in idiopathic pulmonary fibrosis[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(5): 709-715.

图/表 1

参考文献 40

1	Savin IA, Zenkova MA, Sen'kova AV. Pulmonary fibrosis as a result of acute lung inflammation: molecular mechanisms, relevant in vivo models, prognostic and therapeutic approaches[J]. Int J Mol Sci, 2022, 23 (23): 14959.
2	Gokey JJ, Patel SD, Kropski JA. The role of Hippo/YAP signaling in alveolar repair and pulmonary fibrosis[J]. Front Med (Lausanne), 2021, 8, 752316. doi: 10.3389/fmed.2021.752316
3	Tang W, Li M, Yangzhong X, et al. Hippo signaling pathway and respiratory diseases[J]. Cell Death Discov, 2022, 8 (1): 213.
4	Zhu T, Ma Z, Wang H, et al. YAP/TAZ affects the development of pulmonary fibrosis by regulating multiple signaling pathways[J]. Mol Cell Biochem, 2020, 475 (1/2): 137- 149.
5	Pocaterra A, Romani P, Dupont S. YAP/TAZ functions and their regulation at a glance[J]. J Cell Sci, 2020, 133 (2): 230425.
6	Wu Z, Guan KL. Hippo signaling in embryogenesis and development[J]. Trends Biochem Sci, 2021, 46 (1): 51- 63.
7	Flinn MA, Link BA, O'Meara CC. Upstream regulation of the Hippo-Yap pathway in cardiomyocyte regeneration[J]. Semin Cell Dev Biol, 2020, 100, 11- 19.
8	Sarmasti Emami S, Zhang D, Yang X. Interaction of the Hippo pathway and phosphatases in tumorigenesis[J]. Cancers (Basel), 2020, 12 (9): 2438.
9	Yoshihara T, Nanri Y, Nunomura S, et al. Periostin plays a critical role in the cell cycle in lung fibroblasts[J]. Respir Res, 2020, 21 (1): 38.
10	Zhao H, Wang Y, Qiu T, et al. Autophagy, an important therapeutic target for pulmonary fibrosis diseases[J]. Clin Chim Acta, 2020, 502, 139- 147.
11	Chen Y, Zhao X, Sun J, et al. YAP1/Twist promotes fibroblast activation and lung fibrosis that conferred by miR-15a loss in IPF[J]. Cell Death Differ, 2019, 26 (9): 1832- 1844.
12	DiGiovanni GT, Han W, Sherrill TP, et al. Epithelial Yap/Taz are required for functional alveolar regeneration following acute lung injury[J]. JCI Insight, 2023, 8 (19): 173374.
13	Warren R, Lyu H, Klinkhammer K, et al. Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis[J]. Elife, 2023, 12, 85092.
14	Su W, Guo Y, Wang Q, et al. YAP1 inhibits the senescence of alveolar epithelial cells by targeting Prdx3 to alleviate pulmonary fibrosis[J]. Exp Mol Med, 2024, 56 (7): 1643- 1654.
15	Froidure A, Marchal-Duval E, Homps-Legrand M, et al. Chaotic activation of developmental signalling pathways drives idiopathic pulmonary fibrosis[J]. Eur Respir Rev, 2020, 29 (158): 190140.
16	Ji J, Hou J, Xia Y, et al. NLRP3 inflammasome activation in alveolar epithelial cells promotes myofibroblast differentiation of lung-resident mesenchymal stem cells during pulmonary fibrogenesis[J]. Biochim Biophys Acta Mol Basis Dis, 2021, 1867 (5): 166077.
17	Kim MK, Jang JW, Bae SC. DNA binding partners of YAP/TAZ[J]. BMB Rep, 2018, 51 (3): 126- 133.
18	Ferrari N, Ranftl R, Chicherova I, et al. Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts[J]. Nat Commun, 2019, 10 (1): 130.
19	Sun ZR, Gong XM, Zhu HM, et al. Inhibition of Wnt/β-catenin signaling promotes engraftment of mesenchymal stem cells to repair lung injury[J]. J Cell Physiol, 2014, 229 (2): 213- 224.
20	Maldonado H, Hagood JS. Cooperative signaling between integrins and growth factor receptors in fibrosis[J]. J Mol Med (Berl), 2021, 99 (2): 213- 224.
21	Andugulapati SB, Gourishetti K, Tirunavalli SK, et al. Biochanin-A ameliorates pulmonary fibrosis by suppressing the TGF-β mediated EMT, myofibroblasts differentiation and collagen deposition in in vitro and in vivo systems[J]. Phytomedicine, 2020, 78, 153298.
22	Liu F, Lagares D, Choi KM, et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis[J]. Am J Physiol Lung Cell Mol Physiol, 2015, 308 (4): L344- 357.
23	Huang LS, Sudhadevi T, Fu P, et al. Sphingosine kinase 1/S1P signaling contributes to pulmonary fibrosis by activating Hippo/YAP pathway and mitochondrial reactive oxygen species in lung fibroblasts[J]. Int J Mol Sci, 2020, 21 (6): 2064.
24	Link PA, Choi KM, Diaz Espinosa AM, et al. Combined control of the fibroblast contractile program by YAP and TAZ[J]. Am J Physiol Lung Cell Mol Physiol, 2022, 322 (1): L23- l32.
25	Zindel D, Mensat P, Vol C, et al. G protein-coupled receptors can control the Hippo/YAP pathway through Gq signaling[J]. Faseb J, 2021, 35 (7): e21668.
26	Zmajkovicova K, Bauer Y, Menyhart K, et al. GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1[J]. PLoS One, 2020, 15 (2): e0228195.
27	Wang Y, Liao R, Chen X, et al. Twist-mediated PAR1 induction is required for breast cancer progression and metastasis by inhibiting Hippo pathway[J]. Cell Death Dis, 2020, 11 (7): 520.
28	Haak AJ, Kostallari E, Sicard D, et al. Selective YAP/TAZ inhibition in fibroblasts via dopamine receptor D1 agonism reverses fibrosis[J]. Sci Transl Med, 2019, 11 (516): 6296.
29	Yang Y, Santos DM, Pantano L, et al. Screening for inhibitors of YAP nuclear localization identifies aurora kinase a as a modulator of lung fibrosis[J]. Am J Respir Cell Mol Biol, 2022, 67 (1): 36- 49.
30	Aravamudhan A, Haak AJ, Choi KM, et al. TBK1 regulates YAP/TAZ and fibrogenic fibroblast activation[J]. Am J Physiol Lung Cell Mol Physiol, 2020, 318 (5): L852- l863.
31	Zhang WT, Wang XJ, Xue CM, et al. The effect of cardiovascular medications on disease-related outcomes in idiopathic pulmonary fibrosis: a systematic review and meta-analysis[J]. Front Pharmacol, 2021, 12, 771804.
32	Park J, Lee CH, Han K, et al. Association between statin use and the risk for idiopathic pulmonary fibrosis and its prognosis: a nationwide, population-based study[J]. Sci Rep, 2024, 14 (1): 7805.
33	Santos DM, Pantano L, Pronzati G, et al. Screening for YAP inhibitors identifies statins as modulators of fibrosis[J]. Am J Respir Cell Mol Biol, 2020, 62 (4): 479- 492.
34	Nguyen V, Taine EG, Meng D, et al. Pharmacological activities, therapeutic effects, and mechanistic actions of trigonelline[J]. Int J Mol Sci, 2024, 25 (6): 3385.
35	Zeyada MS, Eraky SM, El-Shishtawy MM. Trigonelline mitigates bleomycin-induced pulmonary inflammation and fibrosis: insight into NLRP3 inflammasome and SPHK1/S1P/Hippo signaling modulation[J]. Life Sci, 2024, 336, 122272.
36	Huang H, Zhang ZF, Qin FW, et al. Icariin inhibits chondrocyte apoptosis and angiogenesis by regulating the TDP-43 signaling pathway[J]. Mol Genet Genomic Med, 2019, 7 (4): e00586.
37	Singh WR, Devi HS, Kumawat S, et al. Angiogenic and MMPs modulatory effects of icariin improved cutaneous wound healing in rats[J]. Eur J Pharmacol, 2019, 858, 172466.
38	Sun X, Cheng H, Liu B, et al. Icariin reduces LPS-induced acute lung injury in mice undergoing bilateral adrenalectomy by regulating GRα[J]. Eur J Pharmacol, 2020, 876, 173032.
39	Du W, Tang Z, Yang F, et al. Icariin attenuates bleomycin-induced pulmonary fibrosis by targeting Hippo/YAP pathway[J]. Biomed Pharmacother, 2021, 143, 112152.
40	Mullholand JB, Grossman CE, Perelas A. Non-pharmacological management of idiopathic pulmonary fibrosis[J]. J Clin Med, 2025, 14 (4): 1317.

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