11‐Methoxytabersonine Induces Ferroptosis in Triple‐Negative Breast Cancer via <scp>YY1</scp> – <scp>CDKL1</scp> – <scp>GPX4</scp> Axis

The 11-Methoxytabersonine (11-MT), a monoterpenoid-indole alkaloid isolated from the leaves of Melodinus henryi, has shown promising therapeutic potential against triple-negative breast cancer (TNBC). This study aimed to evaluate the anti-tumor efficacy of 11-MT and to elucidate its underlying molecular mechanisms in the context of TNBC. The in vitro anti-cancer effects of 11-MT were assessed using Cell Counting Kit-8 (CCK-8), colony formation assays, and flow cytometry. In vivo efficacy and safety were evaluated in a xenograft mouse model using 7-week-old female BALB/cA-nu nude mice. To explore the potential of 11-MT in inducing ferroptosis, transmission electron microscopy (TEM), reactive oxygen species (ROS) detection, mitochondrial membrane potential (MMP) assays, and analysis of glutathione peroxidase 4 (GPX4) expression were conducted. Mechanistic investigations included lentiviral-mediated knockdown of Yin Yang 1 (YY1) and overexpression of cyclin-dependent kinase-like 1 (CDKL1), as well as co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and a series of rescue experiments to delineate the regulatory effect of 11-MT on GPX4 expression. The 11-MT significantly inhibited TNBC cell proliferation, induced cell cycle arrest, and promoted cell death in vitro. In vivo, treatment with 11-MT significantly suppressed tumor growth in TNBC xenograft models without evident toxicity to major organs. Mechanistic studies revealed that 11-MT primarily triggered ferroptosis through downregulation of GPX4, leading to excessive ROS accumulation independent of intracellular glutathione depletion. Furthermore, 11-MT reduced the expression of transcription factor YY1, suppressing CDKL1 transcription, which in turn led to the downregulation of GPX4. In summary, the results revealed that the 11-MT exerts potent anti-tumor activity against TNBC by inducing ferroptosis via the YY1-CDKL1-GPX4 signaling axis, highlighting its potential as a novel therapeutic agent for the treatment of TNBC.