2. Academic Validation
  3. Lactylation Enhances the Activity of Lactate Dehydrogenase A and Promotes the Chemoresistance to Cisplatin Through Facilitating DNA Nonhomologous End Junction in Lung Adenocarcinoma

Lactylation Enhances the Activity of Lactate Dehydrogenase A and Promotes the Chemoresistance to Cisplatin Through Facilitating DNA Nonhomologous End Junction in Lung Adenocarcinoma

  • Adv Sci (Weinh). 2025 Nov 5:e10733. doi: 10.1002/advs.202510733.
Jizhuo Li 1 2 3 4,  Wenze Xun 1 2 3 4,  Xijie Wang 4,  Ruiguang Luo 1 2 3 4,  Qifan Hu 1 2 3,  Zhaocai Zhou 5,  Jian Yuan 6,  Yanan Wang 1 2 7 8 9,  Xiaorui Wan 1 2 7 8 9,  Tao Zhao 4,  Tianyu Han 1 2 7 8 9,  Jian-Bin Wang 1 2 3 4
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.
  • 2 The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China.
  • 3 Jiangxi Provincial Key Laboratory of Tumor Biology, Nanchang University, Nanchang, Jiangxi, 330031, China.
  • 4 School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi, 330031, China.
  • 5 State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
  • 6 State Key Laboratory of Cardiology and Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
  • 7 Jiangxi Provincial Key Laboratory of Respirtory Diseases, Jiangxi Institute of Respiratory Disease, The Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China.
  • 8 Jiangxi Clinical Research Center for Respiratory Diseases, Nanchang, Jiangxi, 330006, China.
  • 9 China-Japan Friendship Jiangxi Hospital, National Regional Center for Respiratory Medicine, Nanchang, Jiangxi, 330006, China.
PMID: 41190808 DOI: 10.1002/advs.202510733
Abstract

Lactylation is a novel post-translational modification closely related to the glycolytic process, but the regulatory mechanisms between lactylation and glycolysis are far from being elucidated. Lactate Dehydrogenase A (LDHA) catalyzes the formation of lactate, which provides the modifying group for protein lactylation. However, whether lactylation occurs on LDHA itself remains unknown. Here, it is found that lactylation promotes the enzymatic activity of LDHA in lung adenocarcinoma (LUAD), which in turn enhances the overall level of cellular lactylation through a positive feedback loop. Screening identified Lys81 and Lys318 as key LDHA lactylation sites, with alanyl-tRNA synthetase 1 (AARS1) serving as the mediating lactyltransferase. Mass spectrometry reveals that numerous proteins involved in DNA nonhomologous end junction (NHEJ), including FEN1, XRCC5, and XRCC6 might be regulated by lactylation. Delactylation of these proteins significantly hinders the formation of FEN1-RAD1-RAD9A-HUS1 complex, thereby leading to dysfunction of NHEJ and increasing the sensitivity of Cancer cells to cisplatin. In summary, this work identifies LDHA lactylation as a critical mechanism for accelerating the progression of LUAD and reveals how this lactylation influenced cisplatin sensitivity of LUAD cells, which deepen the understanding of lactylation-mediated tumor progression and provide a potential new Anticancer strategy.

Keywords

DNA damage repair; LDHA; glycolysis; lactylation.

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