Identification of capsazepine as a novel anti-silicosis agent via TRPV1/PI3K/AKT axis inhibition

Silicosis is a progressive and irreversible fibrotic lung disease resulting from chronic inhalation of crystalline silica (CS), for which no specific targeted therapy is clinically available. Thus, novel therapeutic agents and their molecular targets are urgently needed. Using GEO-based differential expression analysis and cMap drug prediction, this study identified capsazepine (CPZ) as a potential anti-silicosis agent. In vivo, CPZ dose-dependently ameliorated pulmonary dysfunction, reduced inflammatory cell infiltration and pro-inflammatory cytokine release, and suppressed collagen deposition and epithelial-mesenchymal transition (EMT) in lung tissues of silicosis model mice. In vitro, CPZ directly countered CS-induced inflammatory activation, apoptosis, and oxidative stress in macrophages, while inhibiting aberrant migration and fibrotic activation in fibroblasts, confirming its dual anti-inflammatory and anti-fibrotic effects at the cellular level. Mechanistically, CPZ bound to TRPV1 and subsequently blocked aberrant phosphorylation of the PI3K/AKT signaling pathway, thereby delaying silicosis progression. Collectively, this study is the first to demonstrate that CPZ is a candidate anti-silicosis drug with clinical translational potential, offering a new theoretical and experimental basis for targeted silicosis therapy.