Fig. 3

The conflicting roles of YAP/TAZ in the pathogenesis of IPF. Dysfunction of epithelial cells and activation of fibroblasts are the key components of IPF pathogenesis. Epithelial cell dysfunction is caused by repetitive damage due to various cellular stresses. The dysfunctional cells have impaired regeneration and differentiation, resulting in both dysregulation of homeostasis and fibrogenic effects. Meanwhile, the convergence of the Hippo, TGF-β, and Wnt signaling pathways affects the transcription of profibrotic molecules in fibroblasts, leading to excessive ECM deposition. Interestingly, YAP/TAZ mechanosignaling and ECM deposition (stiffness) form a positive feedback loop, representing the progressive feature of the pathogenesis of IPF. Conversely, YAP/TAZ maintain lung tissue homeostasis by counteracting the progression of IPF caused by epithelial dysfunction. The effects of YAP/TAZ on epithelial dysfunction and fibroblast activation appear to be in conflict; however, the timing of the effects might explain the discrepancy. In the early stage, YAP/TAZ can be assumed to prevent the pathogenesis of IPF by maintaining epithelial cell functions. When the negative feedback is ineffective, YAP/TAZ accelerate fibrosis by activating lung fibroblasts. Enhancing the homeostatic function in the early stage and inhibiting the profibrotic effect in the progressive state are promising therapeutic strategies