Triple-negative breast cancer (TNBC) is a particularly aggressive cancer type marked by few effective therapies and generally unfavorable survival rates. Although rs3810151 (p.Val94Ala) in the ZNF526 gene has been linked to breast cancer risk as a susceptibility variant, its precise biological contributions and mechanisms of action in TNBC remain unclear. Here, we report that ZNF526 is strongly upregulated in TNBC specimens, and higher levels of this protein are associated with significantly worse patient survival. Through a series of functional tests, we determined that increasing ZNF526 levels drives enhanced growth of TNBC cells, while reducing its expression curbs tumor development. At the molecular level, ZNF526 promotes SHMT1 expression, thereby increasing activity in the serine-glycine-one-carbon (SGOC) metabolic pathway. This change elevates glutathione (GSH) synthesis, lowers reactive oxygen species (ROS) buildup, and improves the cell’s ability to handle oxidative stress, all of which help advance TNBC progression. Overall, our data position ZNF526 as an important new factor controlling redox status in TNBC by influencing SHMT1 and associated metabolism, making it a candidate for future targeted treatments.
