AI Insight
Vocal fold fibrosis is driven by TGF-beta signaling, which replaces flexible tissue with stiff scar tissue, impairing voice production. This study demonstrates that inhibiting YAP/TAZ, two transcriptional co-activators, selectively suppresses the pro-fibrotic branch of TGF-beta signaling in vocal fold fibroblasts without substantially disrupting the canonical SMAD feedback pathways that maintain normal tissue homeostasis. Using RNA-seq, ChIP-seq, and a rat model of vocal fold fibrosis, the authors show that YAP/TAZ inhibition reduces fibroblast activation, fibrotic gene expression, and scar formation in vivo.
Why it matters
Voice disorders affect approximately 20 million Americans and generate substantial economic burden, yet targeted anti-fibrotic treatments remain limited. If validated in further studies, YAP/TAZ inhibition could offer a more precise therapeutic approach for vocal fold fibrosis and potentially other fibrotic conditions by avoiding the adverse effects associated with broad TGF-beta suppression.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.
Source: YAP/TAZ inhibition refines TGF-β signaling to prevent laryngeal fibrosis