YAP/TAZ Signaling in the Pathobiology of Pulmonary Fibrosis

Abstract

Pulmonary fibrosis (PF) is a severe, irreversible lung disease characterized by progressive scarring, with idiopathic pulmonary fibrosis (IPF) being the most prevalent form. IPF's pathogenesis involves repetitive lung epithelial injury leading to fibroblast activation and excessive extracellular matrix (ECM) deposition. The prognosis for IPF is poor, with limited therapeutic options like nintedanib and pirfenidone offering only modest benefits. Emerging research highlights the dysregulation of the yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling pathway as a critical factor in PF. YAP and TAZ, components of the Hippo pathway, play significant roles in cell proliferation, differentiation, and fibrosis by modulating gene expression through interactions with TEA domain (TEAD) transcription factors. The aberrant activation of YAP/TAZ in lung tissue promotes fibroblast activation and ECM accumulation. Targeting the YAP/TAZ pathway offers a promising therapeutic avenue. Preclinical studies have identified potential treatments, such as trigonelline, dopamine receptor D1 (DRD1) agonists, and statins, which inhibit YAP/TAZ activity and demonstrate antifibrotic effects. These findings underscore the importance of YAP/TAZ in PF pathogenesis and the potential of novel therapies aimed at this pathway, suggesting a new direction for improving IPF treatment outcomes. Further research is needed to validate these approaches and translate them into clinical practice.

Keywords: Hippo pathway; TAZ; YAP; idiopathic pulmonary fibrosis; pulmonary fibrosis.

Figure 1

YAP/TAZ signaling pathway in the pathogenesis of PF. YAP and TAZ are highly expressed in fibrotic lung tissue, with TAZ showing prominent nuclear expression in spindle-shaped fibroblastic cells. At a molecular level, TBK1 and SPHK1 promote the fibrotic effects of YAP/TAZ, which are regulated through interactions with PAI-1 and Twist1. TGF-β signaling augments the expression of PAI-1. (A) The role of YAP/TAZ in the TGF-β cascade. GPCR ligands, such as LPA, S1P, and thrombin, facilitate the accumulation of YAP in the nucleus through the mediation of Rho. TGF-β activates Smad2/3/4 complexes, leading to their translocation into the nucleus, where they utilize YAP as a coactivator to drive the transcription of fibrogenic YAP/Smad target genes. (B) In the pathogenesis of IPF, YAP/TAZ interacts with several other signaling pathways, such as EGFR, Wnt, and Notch, to promote lung fibroblast activation and pulmonary fibrosis. This figure was created based on the tools provided by Biorender.com (https://biorender.com/; accessed 5 August 2024). EGFR: epidermal growth factor receptor, GPCR: G protein-coupled receptor, IPF: idiopathic pulmonary fibrosis, LPA: lysophosphatidic acid, PAI-1: plasminogen activator inhibitor-1, Rho: ras homolog family member, S1P: sphingosine-1-phosphate, Smad: mothers against decapentaplegic homolog, SPHK1: sphingosine kinase 1, TAZ: transcriptional coactivator with PDZ-binding motif, TBK1: TANK binding kinase 1, TGF-β: transforming growth factor beta, Twist1: Twist Family BHLH transcription factor 1, Wnt: wingless-related integration site, YAP: yes-associated protein.

Figure 2

The role of YAP/TAZ in regulating glycolytic reprogramming in lung fibrosis. YAP/TAZ enhances the expression of glycolytic enzymes, boosting glucose metabolism and lactate production. Integrins, through signaling pathways like PI3K/Akt and MAPK/ERK, further regulate glycolysis, impacting glucose utilization and energy metabolism. Integrins/FAK regulate glycolysis via the YAP/TAZ axis. This axis facilitates the nuclear translocation of YAP/TAZ, enhancing their fibrotic effects. Additionally, HK2, a key glycolytic enzyme, is crucial for YAP/TAZ nuclear translocation. The activation of lung fibroblasts is often marked by upregulation of glycolytic enzymes, such as PFK1, which interacts with YAP/TAZ coactivator TEADs, promoting fibroblast differentiation. This figure was created based on the tools provided by Biorender.com (https://biorender.com/; accessed 5 August 2024). Akt: protein kinase B, ERK: extracellular signal-regulated kinase, FAK: focal adhesion kinase, HK2: hexokinase 2, MAPK: mitogen-activated protein kinase, PI3K: phosphoinositide 3-kinase, PFK1: phosphofructokinase-1, TEADs: TEA domain transcription factors, YAP: yes-associated protein, TAZ: transcriptional coactivator with PDZ-binding motif.