ACSS1 co-opts acetyl-CoA metabolism to drive DNA repair and undermine radiotherapy efficacy in breast cancer.

Breast cancer remains a leading cause of cancer-related mortality worldwide, with radiotherapy serving as a cornerstone of treatment. However, the development of radioresistance significantly compromises therapeutic efficacy and patient outcomes. Through integrative analysis of TCGA and GEO datasets combined with quantitative proteomics, we identified acetyl-CoA synthetase 1 (ACSS1) as a key driver of radioresistance in breast cancer. ACSS1 is aberrantly overexpressed in breast cancer and correlates with poor prognosis following radiotherapy. Functional studies revealed that overexpressed ACSS1 is able to enhance radioresistance both in vitro and in vivo. Mechanistically, ACSS1 amplifies the ionizing radiation (IR)-induced metabolic coupling of pyruvate with ROS for acetate synthesis, which fuels energy production and expands the nuclear acetyl-CoA pool, enabling histone acetylation at DNA damage sites. Such acetylation promotes chromatin relaxation at damage sites, facilitating the recruitment of homologous recombination (HR) repair machinery and ultimately leading to radioresistance. Our findings reveal that ACSS1 orchestrates acetyl-CoA-driven histone acetylation to enhance DNA repair efficiency, highlighting a metabolic-epigenetic crosstalk that sustains radioresistance in breast cancer. Targeting ACSS1 represents a promising therapeutic strategy to sensitize tumours to radiotherapy and improve clinical outcomes in breast cancer patients.