Ligustilide activates cGAS-STING to chemoprevent tobacco carcinogen-induced lung tumorigenesis.

Lung cancer is a malignant tumor of the bronchial mucosa or glands, with the fastest increasing incidence and mortality rates. In this study, we elucidated for the mechanism of prevention of tobacco-specific nitrosamine (NNK)-induced lung carcinogenesis by Ligustilide (LIG), an active ingredient of traditional Chinese medicine (TCM), through activation of the cGAS-STING innate immune pathway. In the NNK-treated A/J mouse model, LIG (10/40 mg/kg) intervention significantly ameliorated lung histopathological injury, restored body weight, and down-regulated pro-inflammatory factor IL-6 and IL-1β expression. Mechanistic studies showed that LIG reversed NNK-induced inhibition of cGAS-STING pathway protein expression, promoted STING phosphorylation (p-STING), induced type I interferon production by initiating the TBK1-IRF3/NF-κB signaling axis, which induces type I interferon production and recruits alveolar CD8+ T cells, and synergistically activates the DNA damage response by elevating ROS levels and maintaining homeostasis. In vitro experiments further supporting LIG directly combines with STING and activates the cGAS-STING pathway and attenuates NNK damage in lung epithelial cells (MLE-12). This study has suggests that LIG provides a novel naturally derived strategy for lung cancer chemoprevention by targeting STING proteins and re-establishing the immunosurveillance microenvironment.