The STEAP4 target NQO1 mediates colon tumorigenesis

Colorectal cancer (CRC) remains a major global health concern, necessitating advancements in therapeutic strategies. Understanding the mechanisms driving CRC is crucial for developing effective treatments. Previous studies, including our own, highlight the role of six-transmembrane epithelial antigen of prostate 4 (STEAP4) in promoting colon tumorigenesis through reactive oxygen species (ROS) generation, making it a promising target. Our research provides compelling evidence that STEAP4 knockout significantly reduces colon tumorigenesis in a genetically engineered mouse model. Suppressing STEAP4 via knockdown techniques effectively attenuated the nuclear factor erythroid 2-related factor 2 (NRF2)–NAD(P)H:quinone oxidoreductase 1 (NQO1) signaling pathway, inducing apoptosis and autophagy, leading to substantial reductions in xenograft tumor growth. In contrast, STEAP4 overexpression amplified ROS production and activated the NRF2–NQO1 pathway in a ferric iron (Fe³⁺)-dependent manner. Notably, bioactivatable drugs targeting NQO1 were highly effective at eradicating STEAP4-overexpressing colon cancer cells. These findings highlight the potential of targeted therapeutic interventions for CRC, particularly through STEAP4 modulation. In conclusion, our study advances understanding of the role of STEAP4 in colon tumorigenesis, offering promising avenues for novel CRC treatments.