Abstract

Radiation-induced lung injury (RILI) remains a serious complication of thoracic radiotherapy, with limited treatment options. While reduced glutathione (GSH) has therapeutic potential, its efficacy is hindered by poor pulmonary bioavailability via systemic administration. This study developed a novel glutathione dry powder inhaler (GSH-DPI) through rational formulation optimization. The optimized GSH-DPI exhibited excellent aerosol performance, with a fine particle fraction of 84.48% and sustained release in simulated lung fluid. In a murine RILI model, GSH-DPI (50 mg/kg, intrapulmonary administration) demonstrated superior efficacy in alleviating histopathological damage, restoring immune homeostasis, and reducing oxidative stress and pro-inflammatory cytokine expression compared to equimolar liquid GSH or high-dose oral administration. Mechanistically, analyses of single-cell RNA sequencing data revealed that RILI involves substantial alveolar type II epithelial cell (AT2) loss, compensatory oxidative stress (Nrf2/HO-1 activation), and progressive pyroptosis. GSH-DPI improved the survival of AT2 cells, simultaneously enhancing Nrf2 response and suppressing GSDMD-N-mediated pyroptosis, thereby interrupting the “oxidative stress-pyroptosis-inflammation” vicious cycle. This study highlights GSH-DPI as a promising pulmonary-targeted strategy for RILI, leveraging dual antioxidative and antipyroptotic mechanisms.