Detachment‐Induced FAK‐STAT3‐NNMT Inhibits CTCs Anoikis to Promote Breast Cancer Metastasis by Enhancing Fatty Acid Oxidation

ABSTRACT Breast cancer metastasis claims the majority of breast cancer‐related deaths. Anoikis resistance is a key prerequisite for CTCs survival and metastasis. Previous studies have demonstrated that Nicotinamide N‐methyltransferase (NNMT) plays a crucial role in cancer metastasis and apoptosis resistance. However, whether NNMT participates in breast cancer CTCs anoikis remains unexplored. In this study, the upregulation of NNMT was observed in CTCs from breast cancer patients and mouse CTCs models. NNMT in detached breast cancer cells is induced by FAK‐STAT3 axis and resists anoikis through FAO activation, promoting CTCs survival. Mechanistically, NNMT promotes the expression of CPT1A and CD36 by suppressing PP2A methylation to enhance FAO. Furthermore, NNMT‐induced FAO accelerates ROS clearance by maintaining NADP+/NADPH balance. In vivo experiments show that NNMT‐knockdown, NNMT inhibitors and FAO inhibitors can all reduce lung metastases formation, suggesting that targeting NNMT‐FAO suppresses the metastatic potential of breast cancer. Our study revealed that the upregulation of NNMT is induced by FAK‐STAT3 axis, which contributes to CTCs anoikis resistance in breast cancer by activating FAO. Targeting NNMT may provide new therapeutic targets for metastatic breast cancer.