TNALP promotes epithelial oxidative stress and fibrosis via SIRT3-dependent mechanisms in tracheal injury.

Benign tracheal stenosis (BTS) remains a clinical challenge due to high postoperative restenosis rates and the absence of effective pharmacological treatments. Although fibrosis has traditionally been attributed to fibroblast activation, epithelial injury is increasingly recognized as an early initiating event. This study identified tissue-nonspecific alkaline phosphatase (TNALP) as a key mediator of epithelial damage and fibrotic progression in BTS. Analyses of patient specimens, animal models, and cultured epithelial cells revealed that TNALP suppressed SIRT3 expression level, a mitochondrial deacetylase that can regulate oxidative stress and apoptosis. Pharmacological inhibition of TNALP with tetramisole restored SIRT3 expression level, attenuated oxidative damage, reduced epithelial cell death, and mitigated tissue fibrosis. These preclinical findings highlight TNALP as a potential therapeutic target and support further investigation into the repurposing of TNALP inhibitors as antifibrotic agents to reduce restenosis following tracheal surgery.