Aldometanib Alleviates Vocal Fold Fibrosis in A Rat Model by Activating AMPK and Inhibiting the JAK2-STAT3 Signaling Pathway.

BACKGROUND: Vocal fold fibrosis (VFF), characterized by excessive extracellular matrix deposition, leads to permanent voice impairment, with current therapies often failing to restore vocal function. Current treatments are limited by suboptimal efficacy and high recurrence rates. Dysregulated energy metabolism is emerging as a critical driver of fibrosis. AMP-activated protein kinase (AMPK), a central cellular energy sensor, exerts broad antifibrotic effects in multiple organs, yet the therapeutic potential of novel AMPK activators, such as Aldometanib, in VFF remains to be fully characterized. This study aimed to evaluate the therapeutic potential and mechanisms of Aldometanib, a novel AMPK activator, in vocal fold fibrosis. METHODS: A controlled animal study was conducted using an SD rat vocal fold injury model. Animals were randomly allocated into four groups: control, injury, and injury treated with low or high doses of Aldometanib. Primary vocal fold fibroblasts were isolated and cultured, then stimulated with TGF-β1 to induce fibroblast activation, followed by treatment with different concentrations of the AMPK activator Aldometanib. Key outcome measures included histopathological analysis of collagen deposition (Alcian blue and EVG staining), protein and gene expression levels of fibrotic markers (α-SMA, COL1A1, FN1), and components of the JAK2/STAT3 signaling pathway (p-AMPK, p-JAK2, p-STAT3). RESULTS: In vivo, compared with the injury only group, Aldometanib treatment significantly improved the histological architecture of the vocal fold lamina propria. These changes were accompanied by increased p-AMPK levels and decreased expression of p-JAK2, p-STAT3, α-SMA, COL1A1, and FN1. In vitro, Aldometanib attenuated TGF-β1-induced fibroblast activation, and these effects were effectively reversed by co-treatment with the AMPK inhibitor DOX, confirming AMPK pathway dependency. CONCLUSION: Pharmacological activation of AMPK with Aldometanib effectively alleviates vocal fold fibrosis by inhibiting the JAK2/STAT3 signaling axis. This study identifies AMPK as a promising novel therapeutic target for vocal fold fibrosis, supporting future development of more potent or specific AMPK activators and localized delivery systems for clinical translation.