ACSS2 Suppresses Ferroptosis to Drive Breast Cancer Brain Metastasis

Brain metastasis in patients with breast cancer represents a terminal disease stage, with a median survival typically measured in months. Tumors that colonize the brain must adapt to its unique microenvironment, such as high acetate levels. Primary brain tumor cells enhance acetate conversion to acetyl-CoA through phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by cyclin-dependent kinase 5 (CDK5), a process regulated by the nutrient sensor O-GlcNAc transferase (OGT). In this study, we showed that brain-metastatic breast cancer cells exhibited elevated O-GlcNAc, OGT, and phosphorylated ACSS2 (Ser267) compared with their parental counterparts. Both OGT and CDK5 were essential for in vivo tumor growth in the brain, and ACSS2 and a phosphomimetic S267D mutant drove progression of brain-metastatic breast cancer. Mechanistically, ACSS2 supported tumor cell survival by suppressing ferroptosis through early region 2-binding transcription factor (E2F1)-dependent transcription of the antiferroptotic protein solute carrier family 7 member 11 (SLC7A11). Treatment with brain-penetrant ACSS2 inhibitor AD-5584 induced ferroptosis and significantly suppressed breast cancer brain metastatic growth ex vivo and in vivo. Together, these findings identify ACSS2 as a key metabolic regulator of brain-metastatic breast cancer survival and a promising target for ferroptosis-inducing therapies. SIGNIFICANCE: Targeting ACSS2 with brain penetrant inhibitors induces ferroptosis in brain metastatic breast cancer by perturbing an E2F1/SLC7A11 axis, providing an efficacious strategy for treating brain metastatic tumors.