YAP/TAZ activation in fibroblasts coordinates fibrotic remodeling, fibroinflammation, and epithelial dysfunction in pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease marked by progressive scarring with unknown causes and limited treatments. Myofibroblasts drive fibrosis by depositing excess matrix, however the mechanisms driving fibroblast-to-myofibroblast transformation and how myofibroblast-secreted factors disrupt the alveolar niche, undermining lung repair and regeneration remain poorly understood. Here we show that YAP and TAZ are activated in lung fibroblasts from pulmonary fibrosis patients and bleomycin-treated mice. Targeted deletion of Yap/Taz in fibroblasts significantly dampened the fibroinflammatory response, decreased myofibroblast activation, and ultimately resulted in attenuated fibrosis and enhanced regeneration of alveolar epithelial cells after bleomycin-induced injury. Conversely, fibroblast-specific overexpression of constitutively active YAP (YAP5SA) aggravated fibrosis by amplifying fibroinflammatory responses and simultaneously suppressing alveolar epithelial regeneration. Pharmacological inhibition of YAP/TAZ using verteporfin halted the development of bleomycin-induced fibrosis and even reversed established fibrosis in mice. Verteporfin effectively prevented fibroblast-to-myofibroblast transition and promoted collagen I degradation by lowering TIMP levels and enhancing activation of MMP1 and MMP9, demonstrating the significance of the YAP-TIMP-MMP1/9 axis in facilitating ECM breakdown. Furthermore, YAP activation in fibroblasts disrupted alveolar type II (AT2) cell homeostasis by inducing senescence through IGF1-IGF1R-mediated paracrine signaling. Blocking IGF1 signaling with a neutralizing antibody reduced the number of senescent AT2 cells, demonstrating the significance of the YAP-IGF1-IGF1R axis in maintaining alveolar epithelial cell homeostasis. Targeting YAP/TAZ may offer therapeutic strategies to mitigate pulmonary fibrosis by simultaneously mitigating pathological fibroblast activation, fibroinflammatory response, reducing AT2 cell senescence, and promoting alveolar epithelial regeneration.