The Marine Triterpene Stellettin B Triggers Mitochondrial-to-Nuclear Translocation of AIF/EndoG and Reverses Epithelial-Mesenchymal Transition to Inhibit Oral Cancer Progression.

Oral squamous cell carcinoma (OSCC) is associated with aggressive clinical behavior and poor outcomes. In this study, we investigated the anticancer efficacy and underlying mechanisms of Stellettin B, an isomalabaricane triterpene isolated from the marine sponge Jaspis stellifera, in OSCC cells. Our results demonstrate that Stellettin B significantly inhibited the proliferation of HSC-3 and OC-2 cells while sparing normal oral keratinocytes. Mechanistically, Stellettin B triggers a predominantly caspase-independent apoptotic program, evidenced by the pronounced mitochondrial-to-nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) following DNA damage, whereas classical caspase activation functions as a dispensable, secondary event. Furthermore, Stellettin B suppressed migration and invasion by reversing epithelial-mesenchymal transition (EMT), characterized by E-cadherin upregulation and downregulation of Vimentin, Snail, Slug, and β-catenin. Transcriptomic profiling further revealed significant suppression of mTORC1 signaling and EDIL3 expression. In conclusion, these findings demonstrate that Stellettin B exerts multimodal antitumor activity in OSCC and highlight its therapeutic potential as a marine-derived anticancer agent.