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  3. Irinotecan alleviates chemoresistance to anthracyclines through the inhibition of AARS1-mediated BLM lactylation and homologous recombination repair

Irinotecan alleviates chemoresistance to anthracyclines through the inhibition of AARS1-mediated BLM lactylation and homologous recombination repair

  • Signal Transduct Target Ther. 2025 Jul 10;10(1):214. doi: 10.1038/s41392-025-02302-y.
Xinyuan Li # 1 2,  Chunlin Zhang # 1 2,  Yuhua Mei # 1 2,  Wenlong Zhong # 3 4,  Wei Fan # 1,  Li Liu 5,  Zhenwei Feng 1 2,  Xuesong Bai 1 2,  Chuan Liu 6,  Mingzhao Xiao 1,  Weiyang He 7,  Tianxin Lin 8 9,  Xin Gou 10
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
  • 2 Chongqing Key Laboratory of Molecular Oncology and Epigenetics, Chongqing, PR China.
  • 3 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, PR China.
  • 4 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, PR China.
  • 5 Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
  • 6 Department of Urology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, PR China.
  • 7 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China. weiyang361@163.com.
  • 8 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, PR China. lintx@mail.sysu.edu.cn.
  • 9 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, PR China. lintx@mail.sysu.edu.cn.
  • 10 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, PR China. gouxincq@163.com.
  • # Contributed equally.
PMID: 40634292 DOI: 10.1038/s41392-025-02302-y
Abstract

Chemoresistance remains the major barrier to Cancer treatment. Metabolic and epigenetic reprogramming are involved in this process; however, the precise roles and mechanisms are largely unknown. Here, we report that lactate-induced lactylation promotes chemoresistance to anthracyclines by regulating homologous recombination (HR) repair. Using the global lactylome, we revealed the landscape of differentially lactylated sites and proteins in Cancer cells isolated from resistant and nonresistant tumors. Specifically, BLM, a crucial helicase in the HR repair process, is highly lactylated at Lys24 by AARS1 in response to chemotherapy. Mechanistically, hyperlactylation of BLM improves its stability by inhibiting MIB1-mediated ubiquitination and increasing its interaction with DNA repair factors, promoting DNA end resection and HR repair. Delactylation of BLM via the Lys24 mutation impairs HR repair and increases anthracycline chemosensitivity. Irinotecan shows synergistic effects and safety for alleviating anthracycline resistance by targeting BLM lactylation and suppressing HR repair in pancancer PDX models. A single-arm, phase I study (identifier NCT06766266) initiated by us suggested that the combination of irinotecan liposomes plus EPI is a feasible and safe treatment strategy for patients with anthracycline-resistant bladder Cancer who experience recurrence. These findings exemplify how glycolytic reprogramming regulates HR repair through promoting protein lactylation and highlight the promising therapeutic potential of irinotecan for reversing anthracycline chemoresistance by suppressing BLM lactylation.

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