Silicosis amelioration by chaetocin: a novel therapeutic strategy targeting the HIF1α-mediated PI3K/AKT/MMP9 pathway

Silicosis, a debilitating occupational lung fibrosis caused by chronic silica dust inhalation, currently lacks effective therapeutic interventions, and its underlying molecular pathogenesis remains incompletely understood. To address this critical gap, we employed an integrated strategy combining bioinformatics, network pharmacology, and experimental validation to systematically identify novel therapeutic targets and candidate compounds for silicosis. Through analysis of silicosis-related differentially expressed genes from the GEO database and in silico prediction using the cMap platform, we identified the natural product chaetocin as a promising candidate. In a murine model of silicosis, chaetocin administration significantly improved pulmonary function and alleviated lung inflammation and collagen deposition. Notably, at a dose of 1 mg/kg, chaetocin demonstrated superior efficacy to pirfenidone, a current standard-of-care agent. In vitro studies further confirmed that chaetocin effectively attenuated silica-triggered macrophage inflammatory responses, apoptosis, and reactive oxygen species (ROS) production, while also suppressing fibroblast migration and activation. Mechanistic investigations revealed that chaetocin exerts its anti-inflammatory and anti-fibrotic effects by directly targeting HIF1α, thereby inhibiting the downstream PI3K/AKT/MMP9 signaling axis. Collectively, our findings establish chaetocin as a novel naturally-derived therapeutic candidate with significant potential for the treatment of silicosis.