<p>Small-cell lung cancer (SCLC) is an aggressive malignancy characterized by rapid progression, poor prognosis, and a high recurrence rate following chemotherapy. Despite recent advances in immunotherapy, treatment options remain limited, underscoring the urgent need for novel anticancer agents. Triptolide, a natural diterpenoid, has been reported to exhibit cytotoxic activity against various cancer cell lines. However, its effects on SCLC cells, particularly its ferroptosis-inducing activity, remain largely unknown. In this study, we investigated the cytotoxic, apoptotic, and ferroptotic activities of triptolide in SBC-3 human SCLC cells. Triptolide exhibited potent dose- and time-dependent cytotoxicity and induced apoptosis through both intrinsic and extrinsic pathways, as evidenced by activation of caspases-3, -8, and -9, a decreased Bcl-2/Bax ratio, Bid cleavage, mitochondrial membrane depolarization, and excessive reactive oxygen species generation. Notably, triptolide induced ferroptosis through multiple mechanisms of action, including suppression of the p62-Nrf2 antioxidant axis, leading to decreased xCT and glutathione peroxidase 4 expression, upregulation of cellular iron uptake via increased transferrin and CD71 expression, and induction of lipid peroxidation. Triptolide also induced autophagy in SBC-3 cells, which may contribute to ferroptosis via ferritinophagy. Furthermore, triptolide demonstrated synergistic cytotoxic effects when combined with cisplatin or etoposide. To our knowledge, this study is the first to provide evidence that triptolide simultaneously induces apoptosis and ferroptosis in SCLC cells. These findings highlight triptolide as a promising therapeutic candidate for SCLC treatment, at least based on in vitro studies, particularly when combined with conventional chemotherapeutic agents.</p> Graphical abstract <p></p>