Abstract
Background: Small cell lung cancer (SCLC) is a highly aggressive malignancy with limited therapeutic options. Triptolide (TPL), a natural compound derived from the traditional Chinese herbal medicine Tripterygium wilfordii Hook F., exhibits broad antitumor effects. However, its role in SCLC remains unexplored. Methods: We evaluated the effects of TPL on SCLC cell proliferation, migration, and invasion through in vitro assays, including Cell Counting Kit-8, clonogenic, 5-ethynyl-2'-deoxyuridine, cell cycle, and Transwell assays. To predict the potential antitumor targets of TPL against SCLC, we performed a network pharmacology analysis. Pyroptosis was examined by morphological observation, lactate dehydrogenase release assay, and Western blot analysis. The in vivo role of TPL was confirmed using a mouse xenograft model and immunohistochemical assays. Results: TPL inhibited proliferation, triggered cell cycle arrest at the S-phase, and concomitantly produced a dose-dependent inhibition of SCLC cell invasion and migration. Network pharmacology analysis revealed that the antitumor effect of TPL in SCLC was associated with its potential to regulate inflammatory and apoptotic pathways, indicating the specific mode of cell death induced by TPL in SCLC cells. We confirmed that TPL induces caspase-3/GSDME-mediated pyroptosis in NCI-H1688 and NCI-H1339 cells. Furthermore, TPL induced pyroptosis by promoting reactive oxygen species (ROS) accumulation, whereas ROS inhibition significantly abolished these pyroptotic effects. Additionally, TPL suppressed tumor growth in mice with SCLC xenografts and induced pyroptosis in vivo. Conclusions: This study demonstrated the antitumor role of TPL in SCLC and its ability to trigger caspase-3/GSDME-mediated pyroptosis through ROS accumulation, providing new insights into SCLC treatment.