ACSS2-mediated metabolic-epigenetic crosstalk drives Fulvestrant resistance and represents a novel therapeutic target.

Endocrine therapies targeting estrogen receptor alpha (ERα), expressed in ~70% of breast cancers, remain the standard of care for ER+ disease. However, 30-40% of patients experience recurrence and metastasis, with 5-year survival rates of only 31.9%. Using the Carle Foundation Hospital cohort and liver metastatic patient-derived xenograft models, we identified upregulated lipid metabolism and acetyl-CoA production as metabolic vulnerabilities. We demonstrate that combining Fulvestrant (Fulv) with an inhibitor of Acyl-CoA Synthetase Short Chain Family Member 2 (ACSS2) synergistically reduces metastatic breast cancer cell viability. Through isotope tracing, CUT&RUN sequencing, immunofluorescence, western blot, and RNA sequencing, we show that Fulv increases ACSS2 expression and acetate utilization, redirecting acetate flux from the TCA cycle toward fatty acid synthesis. Nuclear ACSS2 chromatin occupancy increases with Fulv treatment, expanding ERα/ACSS2/H3K27ac co-occupancy at tumor progression genes, an effect abolished by ACSS2 inhibition. RNA sequencing revealed that ACSS2 inhibition suppresses Fulv-induced metabolic and oncogenic transcriptional programs. In a therapy-resistant xenograft model, combination treatment reduced Fulv-dependent metastatic burden. These findings establish ACSS2 as a driver of endocrine resistance through nuclear acetyl-CoA provision for epigenetic reprogramming, representing a novel therapeutic target in metastatic breast cancer.