Plumbagin Triggers <scp>STING</scp> Pathway Activation to Suppress Non‐Small Cell Lung Cancer Progression

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Plumbagin (PLBG), a naturally occurring active naphthoquinone derived from Chinese herbal plants, exhibits anti-cancer effects across multiple cancer types. However, the mechanisms underlying PLBG-induced anti-tumor activity in NSCLC remain incompletely understood. Our study demonstrated that PLBG significantly inhibited NSCLC cell proliferation and induced apoptosis by elevating intracellular and mitochondrial reactive oxygen species (ROS), leading to mitochondrial dysfunction. The ROS scavenger N-acetylcysteine (NAC) abrogated PLBG-induced apoptosis and restored cell viability. Notably, RNA sequencing analysis revealed that differentially expressed genes in PLBG-treated cells were enriched in the cytosolic DNA-sensing pathway and STING pathway. Mechanistically, PLBG treatment activated the STING pathway and upregulated key chemokines (CXCL10, CXCL9, CCL5) in NSCLC cells. Critically, STING inhibition by H151 attenuated PLBG-induced apoptosis, confirming the essential role of STING. These results suggest that PLBG exerts potent anti-NSCLC effects through ROS-mediated apoptosis, STING pathway activation, and chemokine induction, while concurrently inhibiting pro-survival signaling. These findings position PLBG as a promising therapeutic candidate for NSCLC treatment.