Oncoprotein CYB561, acting in IRE1-XBP1-SREBF1 and FAK-ERK pathway, promotes breast cancer lipogenesis and progression

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.