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

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

  • Cell Death Dis. 2025 Dec 18. doi: 10.1038/s41419-025-08300-w.
Xiao Fu # 1 2,  Yingyu Zhu # 1 2,  Xin Lu 3,  Xingjie Gao 1 2,  Lingbiao Xin 1 2,  Yuanyuan Ren 1 2,  Xin Liu 1 2,  Lin Ge 1 2,  Jihui Hao 1 4,  Zhi Yao 1 2,  Lei Shi 5 6,  Jie Yang 7 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Experimental Hematology, Key Laboratory of Cellular and Molecular Immunology in Tianjin, and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Science, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Tianjin Medical University, Tianjin, China.
  • 2 Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Science, Tianjin Medical University, Tianjin, China.
  • 3 TianJin Medical University General Hospital Medical Laboratory, Tianjin, China.
  • 4 Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
  • 5 State Key Laboratory of Experimental Hematology, Key Laboratory of Cellular and Molecular Immunology in Tianjin, and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Science, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Tianjin Medical University, Tianjin, China. [email protected].
  • 6 Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Science, Tianjin Medical University, Tianjin, China. [email protected].
  • 7 State Key Laboratory of Experimental Hematology, Key Laboratory of Cellular and Molecular Immunology in Tianjin, and Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Science, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Tianjin Medical University, Tianjin, China. [email protected].
  • 8 Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Science, Tianjin Medical University, Tianjin, China. [email protected].
  • # Contributed equally.
PMID: 41413018 DOI: 10.1038/s41419-025-08300-w
Abstract

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.

Figures
Products