YAP/TAZ inhibition refines TGF-β signaling to prevent laryngeal fibrosis

ABSTRACT Voice disorders affect nearly 20 million Americans and cost more than $13 billion annually. Vocal fold (VF) fibrosis, a major cause of chronic dysphonia, disrupts normal vocal fold vibration by replacing the flexible extracellular matrix with stiff fibrotic tissue. Although TGF-β drives fibrosis, it also activates intrinsic negative feedback mechanisms, including SMAD7 induction and SMAD3 downregulation, to restrain excessive signaling. Broad inhibition of TGF-β or canonical SMAD signaling may disrupt these protective feedback loops and impair normal tissue homeostasis. An ideal anti-fibrotic strategy should differentially target the pro-fibrotic output of TGF-β. Here, we show YAP/TAZ inhibition selectively suppresses pro-fibrotic TGF-β signaling in VF fibroblasts. Pharmacologic inhibition of YAP/TAZ blocked TGF-β-induced fibroblast activation and fibrotic gene expression, while only modestly affecting canonical SMAD feedback responses. Integrated RNA-seq and ChIP-seq analyses demonstrated YAP/TAZ primarily regulate non-canonical TGF-β signaling and pro-fibrotic transcriptional programs. In a rat model of VF fibrosis, YAP/TAZ inhibition reduced nuclear YAP/TAZ localization and attenuated scar formation. Together, these findings identify YAP/TAZ inhibition as a promising therapeutic strategy for VF fibrosis and other fibrotic diseases.