ENO1 lactylation drives bevacizumab resistance through metabolic reprogramming and angiogenesis in ovarian cancer

  • Drug Resist Updat. 2026 Jul:87:101413. doi: 10.1016/j.drup.2026.101413.
Tian Zeng  1 ,  Qianqian Wang  2 ,  Lei Li  3 ,  Xiongjin Tan  4 ,  Jing He  5 ,  Yan Liu  5 ,  Xiaodong Wang  6 ,  Rongfang He  7 ,  Gouping Ding  6 ,  Xinyi Zeng  8 ,  Xing Tang  1 ,  Xun Chen  9 ,  Hao Huang  10 ,  Yukun Li  11
Affiliations
  • 1. Tumor ImmunoMetabolism Institute (TIMI), The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412007, China.
  • 2. Tumor ImmunoMetabolism Institute (TIMI), The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412007, China; Department of Oncology, The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412007, China.
  • 3. Tumor ImmunoMetabolism Institute (TIMI), The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412007, China; Department of Pathology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China.
  • 4. 922 Hospital of PLA, Hengyang, Hunan 410011, China.
  • 5. Department of Oncology, The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412007, China.
  • 6. Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
  • 7. Department of Pathology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421001, China.
  • 8. Loudi Central Hospital, Loudi, Hunan 417000, China.
  • 9. Tumor ImmunoMetabolism Institute (TIMI), The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412007, China. Electronic address: [email protected].
  • 10. Tumor ImmunoMetabolism Institute (TIMI), The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412007, China; Department of Ophthalmology, The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412007, China. Electronic address: [email protected].
  • 11. Tumor ImmunoMetabolism Institute (TIMI), The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412007, China. Electronic address: [email protected].
PMID: 42134086 DOI: 10.1016/j.drup.2026.101413
Abstract

Bevacizumab, a monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF), is a cornerstone therapy for Ovarian Cancer (OC). However, acquired resistance to bevacizumab remains a major clinical challenge. Metabolic reprogramming in the tumor microenvironment, particularly lactate-driven lactylation modifications, has been implicated in drug resistance; however, the specific mechanisms underlying bevacizumab resistance are poorly understood. This study identifies Enolase 1 (ENO1) lactylation as a key driver of drug resistance through the integration of lactylation proteomics in patient samples, functional validation in cell lines and in vivo models Patient-Derived Xenograft (PDX), zebrafish, and chicken Chorioallantoic Membrane (CAM)). We observed significantly elevated pan-lactylation in bevacizumab-resistant OC tissues, correlating with enhanced angiogenesis and poor prognosis. Mechanistically, alanyl-tRNA synthetase 1 (AARS1) mediated lactylation of ENO1 at lysine 71 (K71) augmented lactate synthesis and promoted histone lactylation marks (Lysine lactylation of histone H3 at lysine 9 (H3K9la) and Lysine Lactylation of Histone H3 at Lysine 14 (H3K14la)). This epigenetic reprogramming upregulated the transcription of the angiogenic factor Endothelial cell-specific molecule 1 (ESM1), establishing a positive feedback loop for ENO1 expression. Secreted ESM1 stabilized the transcription factor YY1 in endothelial cells by competitively inhibiting Smurf2-mediated ubiquitination, leading to YY1-dependent recruitment of E1A Binding Protein p300 (EP300) and Histone H3 Lysine 27 (H3K27) acetylation at the B-cell lymphoma 2-related protein A1 (BCL2A1) promoter. This cascade enhanced endothelial cell survival and angiogenesis, ultimately fostering resistance to bevacizumab. Our findings reveal a metabolic-epigenetic axis centered on ENO1 K71 lactylation that perpetuates resistance to bevacizumab, highlighting its potential as a therapeutic target to restore bevacizumab efficacy in OC.

Keywords
Angiogenesis; Bevacizumab resistance; ENO1; Lactylation modification.
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