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  3. Lactylation of XLF promotes non-homologous end-joining repair and chemoresistance in cancer

Lactylation of XLF promotes non-homologous end-joining repair and chemoresistance in cancer

  • Mol Cell. 2025 Jul 17;85(14):2654-2672.e7. doi: 10.1016/j.molcel.2025.06.019.
Mingpeng Jin 1,  Bingsong Huang 2,  Xiaoning Yang 3,  Shuyang Wang 4,  Jinhuan Wu 2,  Yiming He 5,  Xin Ding 2,  Xuanhe Wang 5,  Zhe Wang 2,  Jie Yang 6,  Rui Li 2,  Xuan Zhou 7,  Qianwen Wang 1,  Yunhui Li 2,  Lei Li 2,  Wen Zheng 8,  Zhikai Zeng 6,  Chenxi Zhao 9,  Jiaqi Liu 10,  Qian Zhu 7,  Zhihua Kang 11,  Ke Li 3,  Shikang Liang 12,  Yuping Chen 13,  Jian Yuan 14
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China; Cancer Center, Tongji University School of Medicine, Shanghai 200331, China.
  • 2 State Key Laboratory of Cardiology and Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Cancer Center, Tongji University School of Medicine, Shanghai 200331, China.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 4 School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, S.A.R 999077, China.
  • 5 Cancer Center, Tongji University School of Medicine, Shanghai 200331, China; Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
  • 6 Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China.
  • 7 Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 8 Medical and Radiation Oncology, Department of the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
  • 9 Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.
  • 10 Department of Burn, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 11 Department of Laboratory Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200040, China.
  • 12 School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, S.A.R 999077, China. Electronic address: shikang@hku.hk.
  • 13 Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Department of Anesthesiology and Perioperative Medicine, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China; Cancer Center, Tongji University School of Medicine, Shanghai 200331, China. Electronic address: 1610600@tongji.edu.cn.
  • 14 State Key Laboratory of Cardiology and Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China; Cancer Center, Tongji University School of Medicine, Shanghai 200331, China. Electronic address: yuanjian229@hotmail.com.
PMID: 40680721 DOI: 10.1016/j.molcel.2025.06.019
Abstract

Metabolic reprogramming and DNA damage repair are essential in tumorigenesis and chemoresistance, yet their link remains elusive. Here, we show that LDHA deficiency impairs NHEJ and class switch recombination. Additionally, glycolysis-derived lactate promotes XLF lactylation at K288 within its Ku-binding motif (X-KBM) to regulate NHEJ. Mechanistically, DNA damage triggers ATM-mediated GCN5 phosphorylation to increase GCN5-XLF interaction and XLF lactylation, enhancing XLF-Ku80 binding, XLF recruitment to DSBs, and NHEJ efficiency. Cryo-EM structural analysis demonstrates that lactylated X-KBM (laX-KBM) forms a more extensive interface with Ku70/80, inducing conformational changes in the Ku80 vWA domain. XLF lactylation deficiency impairs NHEJ and sensitizes Cancer cells to chemotherapy. A specific XLF K288 lactylation peptide inhibitor plus 5-fluorouracil synergistically kills colorectal Cancer cells in PDX models with XLF hyperlactylation. These findings highlight that the GCN5-XLF lactylation axis is a critical NHEJ regulator and that targeting XLF lactylation can improve chemotherapy efficiency.

Keywords

Warburg effect; XLF; cell-penetrating peptide; chemoresistance; lactylation; non-homologous end-joining repair.

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