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

ABSTRACT 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.