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Non‐small‐cell lung cancer (NSCLC) stands as a primary contributor to cancer‐related deaths worldwide. It has been demonstrated that Lycorine (LYD), a naturally occurring active sesquiterpene present in Chinese medicinal plants, exhibits anti‐cancer properties across various cancer cell lines. However, the underlying mechanisms of LYD‐induced anti‐tumor in NSCLC are not fully known. This study demonstrated that LYD significantly reduced the proliferation of NSCLC and induced apoptosis by increasing intracellular ROS levels. The inhibition of ROS using N‐acetylcysteine (NAC) eliminated the apoptosis effects of LYD, resulting in increased cell viability. Additionally, LYD treatment significantly activated the STING pathway in NSCLC and induced the expression of CXCL10, CXCL9 and CCL5 in NSCLC cells. Mechanistically, LYD was found to significantly reduce the protein levels of P70S6K and S6K, which are key proteins involved in cell growth and survival. Notably, in vivo experiments demonstrated that LYD significantly inhibited the growth of H358 xenograft and LLC1 tumor, exhibiting anti‐tumor activity by elevating CD8+ T cells in the NSCLC mouse model. Our findings suggest that LYD possesses potent anti‐cancer properties in NSCLC by inducing apoptosis through ROS generation and modulating the STING pathway and key chemokines. Furthermore, LYD also exerts its antitumor effects by inhibiting crucial proteins involved in cell growth. Overall, LYD shows promise as a potential therapeutic agent for NSCLC treatment. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer death. Pyronaridine, a synthetic drug of artemisinin, has been used in China for over 30 years for the treatment of malaria, but its effect on non‐small cell lung cancer (NSCLC) cells is rarely reported. In this study, we determined the efficacy of pyronaridine in four different NSCLC cell lines and explored its mechanism in H1975. The data showed that pyronaridine could upregulate the expression of TNF‐related apoptosis‐inducing ligand (TRAIL)‐mediated death receptor 5 to promote cellular apoptosis. Meanwhile, the JNK (c‐Jun N‐terminal kinase) level was detected to be significantly increased after treating with pyronaridine. We used JNK inhibitor and found that it could partially inhibit cell apoptosis. The results showed that epidermal growth factor receptor (EGFR), PI3K, and AKT were downregulated after the treatment of pyronaridine. In summary, pyronaridine can selectively kill NSCLC by regulating TRAIL‐mediated apoptosis and downregulating the protein level of EGFR. It is a promising anticancer drug for NSCLC. [ABSTRACT FROM AUTHOR]