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bioRxiv · 10.64898/2026.05.18.726086

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

Nakamura, R.·Bing, R.·Weber, H.·Yoshimatsu, M.·Gartling, G.·Garabedian, M. J.·Branski, R. C.
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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-{beta} drives fibrosis, it also activates intrinsic negative feedback mechanisms, including SMAD7 induction and SMAD3 downregulation, to restrain excessive signaling. Broad inhibition of TGF-{beta} 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-{beta}. Here, we show YAP/TAZ inhibition selectively suppresses pro-fibrotic TGF-{beta} signaling in VF fibroblasts. Pharmacologic inhibition of YAP/TAZ blocked TGF-{beta}-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-{beta} 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.

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Nakamura, R., Bing, R., Weber, H., Yoshimatsu, M., Gartling, G., Garabedian, M. J., Branski, R. C.. 2026-05-21. YAP/TAZ inhibition refines TGF-β signaling to prevent laryngeal fibrosis. https://doi.org/10.64898/2026.05.18.726086

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