Glioblastoma (GBM) is the most malignant tumor of the central nervous system. Current first-line post-surgery regimens for GBM including radiotherapy and temozolomide (TMZ) chemotherapy show very limited efficacy, with a median overall survival of only 15 months. Therefore, the development of therapeutic strategies and novel agents for GBM patients is an urgent need. Historically, natural products have played a key role in drug discovery, especially in the field of cancer treatment. We previously isolated stellettin B (STELB), an isomalabaricane triterpenoid, from marine sponge Jaspis stellifera and reported its remarkable and specific anticancer activities, which has attracted wide attention. Recently, a series of stellettins has been totally synthesized, removing a major barrier in drug development for the whole family of these chemicals. Notably, previous structure-activity relationship (SAR) studies have shown that stellettin A, B, and E share a singular trans-syn-trans perhydrobenz[e]indene core that is indispensable for their anticancer effects. However, the specific mechanism and its role in regulating tumor biology remain largely unknown.