A Huaxian Formula Nanoformulation Confers Protection Against Acute Radiation-Induced Lung Injury by Targeting Ferroptosis.

Acute radiation-induced lung injury (RILI) remains a major dose-limiting complication of thoracic radiotherapy with limited therapeutic options. Here, we develop an inhalable nanoformulation of the traditional Chinese medicine Huaxian Formula (NHXF) with favorable physicochemical stability and enhanced pulmonary delivery properties. In vitro and in vivo studies demonstrate that NHXF attenuates radiation-induced alveolar epithelial injury, accompanied by reductions in oxidative stress and apoptosis. NHXF also suppresses secondary inflammatory responses, as evidenced by decreased pro-inflammatory cytokine production and neutrophil infiltration, which may contribute to its protective effects against acute RILI. Importantly, NHXF displays a favorable safety profile throughout treatment. Transcriptomic analysis highlights ferroptosis-related pathways associated with NHXF-mediated protection. Our findings indicate that NHXF treatment is associated with the attenuation of ferroptosis-related alterations in iron homeostasis and lipid peroxidation. Pharmacological activation of ferroptosis significantly diminishes the protective effects of NHXF against radiation-induced injury, further supporting a functional contribution of ferroptosis modulation to NHXF-mediated protection, while acknowledging that additional direct mechanistic evidence is warranted to establish causal dependency. Collectively, these findings support NHXF as a potential inhalable nanotherapeutic for acute RILI and highlight pulmonary delivery of nanoformulated traditional Chinese medicine combined with ferroptosis modulation as a promising strategy for RILI management.