Abstract Breast cancer (BC) heterogeneity, particularly in triple-negative (TNBC) and HER2-positive subtypes, underpins therapeutic challenges and cancer-related mortality worldwide. Here, we identify the transmembrane oxidoreductase CYB561 as a pivotal oncoprotein that drives BC malignancy by coordinating lipid metabolic reprogramming and oncogenic signaling. CYB561 was significantly overexpressed in BC tissues, especially in HER2-positive (70%) and TNBC (60%) cases, and its expression correlated with advanced T stage, metastasis, and poor patient survival. Functionally, CYB561 potently promoted proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and tumor growth in vitro and in vivo. Mechanistically, CYB561 directly bound IRE1, triggering the IRE1–XBP1–SREBF1 axis to induce lipogenic enzyme expression and lipid droplet accumulation. Concurrently, it activated the FAK–ERK signaling pathway. Crucially, IRE1 knockdown abolished CYB561-induced lipogenesis and malignant phenotypes, while ERK inhibition partially attenuated these effects, revealing a synergistic crosstalk between metabolic and signaling axes. Our findings establish CYB561 as a master regulator of BC progression and nominate it as a promising therapeutic target for aggressive breast cancers.
Yang et al. (Mon,) studied this question.