Abstract

Small cell lung cancer (SCLC) is an aggressive malignancy characterized by limited therapeutic options. In this study, we identified GL-V9 as a potent anti-SCLC agent that induces apoptosis through oxidative stress. GL-V9 significantly reduced SCLC cell viability in a dose-dependent manner and triggered apoptosis both in vitro and in xenograft models. Mechanistically, GL-V9 increased reactive oxygen species (ROS) levels and lipid peroxidation while impairing mitochondrial function, suggesting that its cytotoxic effects are mediated by oxidative stress. Drug-target interaction analyses revealed that GL-V9 directly binds to STEAP3, a key regulator of iron metabolism, and promotes its degradation via the ubiquitin-proteasome pathway. The loss of STEAP3 disrupted iron homeostasis and exacerbated oxidative stress. In contrast, STEAP3 overexpression attenuated ROS accumulation, mitochondrial damage, and apoptosis both in vitro and in vivo . Further investigation demonstrated that STEAP3 degradation decreased the stability of CISD2, a [2Fe-2S] cluster-containing mitochondrial protein essential for redox balance. GL-V9 downregulated CISD2 in a STEAP3-dependent manner, and restoring CISD2 expression significantly rescued cells from GL-V9-induced oxidative stress and apoptosis. Clinically, both STEAP3 and CISD2 are upregulated in SCLC tumors, and their elevated expression correlates with poor patient survival. Co-expression analysis associated these proteins with pathways involved in oxidative stress and mitochondrial dysfunction. Overall, these findings suggest that GL-V9 induces apoptosis in SCLC by targeting STEAP3 for proteasomal degradation, thereby disrupting the STEAP3-CISD2 axis and promoting oxidative stress-driven cell death. This study identifies a previously unrecognized redox regulatory pathway in SCLC and proposes a potential therapeutic strategy centered on