Metalloreductase STEAP4 suppresses TNBC progression via the ROS/NRF2/NOTCH1 signaling axis and is stabilized by lncRNA ENST00000595121.

The expression profile and functional role of STEAP4 in triple-negative breast cancer (TNBC) remain largely unexplored. This study aimed to investigate its significance and underlying mechanisms in TNBC progression. Analyses of clinical datasets, TNBC tissues, and cell lines revealed that STEAP4 was significantly downregulated in TNBC compared to normal tissue and other subtypes, and its low expression correlated with poor patient prognosis. Functionally, overexpression of STEAP4 potently inhibited TNBC cell proliferation, migration, invasion, colony formation, and wound healing in vitro, while also suppressing tumor growth and lung metastasis in vivo. Mechanistic investigations revealed that STEAP4 reduced intracellular reactive oxygen species (ROS) by selectively enhancing the activities of antioxidant enzymes SOD and GPX, independently of its canonical ferric reductase function. The consequent ROS reduction inhibited NRF2 nuclear translocation, which in turn suppressed NOTCH1 transcription through direct promoter binding; crucially, restoring ROS levels reversed this inhibitory effect. Furthermore, we identified that the upregulated long non-coding RNA ENST00000595121 directly bound to and stabilized the STEAP4 protein. From a therapeutic perspective, STEAP4 overexpression sensitized TNBC cells to cisplatin. In conclusion, by integrating clinical, functional, and mechanistic evidence, we establish STEAP4 as a potent tumor suppressor in TNBC. Its downregulation promotes progression and metastasis via a novel lncRNA ENST00000595121/STEAP4/ROS/NRF2/NOTCH1 axis. These findings propose that restoring STEAP4 function could be a viable strategy for TNBC treatment and overcoming cisplatin resistance, a premise that warrants further clinical investigation.