Abstract

This study investigates how cholesterol metabolism promotes metastasis in triple-negative breast cancer (TNBC). By integrating public databases, we identified a positive correlation between the cholesterol metabolism transcription factor SREBP2 and the membrane receptor CCDC25 in TNBC, and their co-high expression was strongly associated with poor patient prognosis. Mechanistically, we found that SREBP2 directly binds to the promoter region of CCDC25 and activates its transcription, upregulating its expression. Functionally, the SREBP2-CCDC25 axis enhanced TNBC cells migration and invasion and promoted neutrophil extracellular traps (NETs) formation. In vivo, SREBP2 overexpression accelerated lung metastasis in TNBC, increased levels of NETs markers and elevated CCDC25 expression in metastatic lesions. Importantly, pharmacological inhibition of the SCAP-SREBP2 pathway with Fatostatin or Lycorine suppressed CCDC25 expression, reduced NETs formation, and attenuated metastasis. Collectively, these findings define a cholesterol-driven SCAP-SREBP2-CCDC25-NETs axis that promotes TNBC metastasis and highlight this pathway as a potential therapeutic target.