ESM1 drives H4K8 lactylation to promote vasculogenic mimicry and bevacizumab resistance in ovarian cancer
6 affiliations
- 1School of Basic Medical Sciences, Hunan Normal University, Changsha, Hunan 410000 China
- 2Department of Assisted Reproductive Centre, The Affiliated Zhuzhou Hospital of Xiangya Medical School, Central South University, Zhuzhou, Hunan 412007 China
- 3Tumor ImmunoMetabolism Institute (TIMI), The Affiliated Zhuzhou Hospital of Xiangya Medical School, Central South University, Zhuzhou, Hunan 412007 China
- 4Hunan Normal University Affiliated Xiangnan Hospital, 922 Hospital of PLA, Hunan Normal University, Hengyang, Hunan 410011 China
- 5Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001 China
- 6Cancer Research Institute, Hunan Cancer Hospital, Hunan Normal University, Changsha, Hunan 410000 China
Abstract
Despite the significant clinical value of bevacizumab in treating advanced ovarian cancer (OC), acquired resistance to treatment remains a critical challenge. Bevacizumab therapy is frequently associated with metabolic reprogramming in tumor cells. Our prior studies demonstrated that endothelial cell-specific molecule 1 (ESM1) promotes vascular mimicry (VM) formation and lactate production in OC cells. Here, we elucidated the molecular mechanism by which ESM1 drives VM formation and bevacizumab resistance through histone lactylation modifications, specifically H4K8 lactylation (H4K8la). Mechanistically, ESM1 facilitates H4K8la-mediated transcriptional activation of ERBB2, inducing heterodimerization between ERBB2 and EGFR to activate the downstream Akt/mTOR cascade. This cascade suppresses autophagy and activates STAT3 signaling, ultimately promoting VM formation. Pharmacological inhibition of lactylation or ERBB2 signaling effectively blocks VM formation and synergizes with bevacizumab in patient-derived preclinical models, significantly enhancing therapeutic efficacy. Our findings reveal ESM1 as a metabolic switch bridging transcriptional regulation and metabolic reprogramming via histone lactylation. The results of this study indicate that targeting ESM1 modulation could be a strategy to overcome bevacizumab resistance in OC.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12964-026-03071-z.
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BibTeX
@article{li2026esm1,
title = {{ESM1 drives H4K8 lactylation to promote vasculogenic mimicry and bevacizumab resistance in ovarian cancer}},
author = {Yukun Li and Juan Zou and Li Yang and Xiongjin Tan and Xing Tang and Peiting Wu and Xueru Liu and Xun Chen and Daichao Wu and Xing Yu},
journal = {Cell Communication and Signaling : CCS},
year = {2026},
month = jul,
doi = {10.1186/s12964-026-03071-z},
url = {https://doi.org/10.1186/s12964-026-03071-z},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - ESM1 drives H4K8 lactylation to promote vasculogenic mimicry and bevacizumab resistance in ovarian cancer
AU - Yukun Li
AU - Juan Zou
AU - Li Yang
AU - Xiongjin Tan
AU - Xing Tang
AU - Peiting Wu
AU - Xueru Liu
AU - Xun Chen
AU - Daichao Wu
AU - Xing Yu
PY - 2026
DA - 2026/07/30
JO - Cell Communication and Signaling : CCS
DO - 10.1186/s12964-026-03071-z
UR - https://doi.org/10.1186/s12964-026-03071-z
AB - Despite the significant clinical value of bevacizumab in treating advanced ovarian cancer (OC), acquired resistance to treatment remains a critical challenge. Bevacizumab therapy is frequently associated with metabolic reprogramming in tumor cells. Our prior studies demonstrated that endothelial cell-specific molecule 1 (ESM1) promotes vascular mimicry (VM) formation and lactate production in OC cells. Here, we elucidated the molecular mechanism by which ESM1 drives VM formation and bevacizumab resistance through histone lactylation modifications, specifically H4K8 lactylation (H4K8la). Mechanistically, ESM1 facilitates H4K8la-mediated transcriptional activation of ERBB2, inducing heterodimerization between ERBB2 and EGFR to activate the downstream Akt/mTOR cascade. This cascade suppresses autophagy and activates STAT3 signaling, ultimately promoting VM formation. Pharmacological inhibition of lactylation or ERBB2 signaling effectively blocks VM formation and synergizes with bevacizumab in patient-derived preclinical models, significantly enhancing therapeutic efficacy. Our findings reveal ESM1 as a metabolic switch bridging transcriptional regulation and metabolic reprogramming via histone lactylation. The results of this study indicate that targeting ESM1 modulation could be a strategy to overcome bevacizumab resistance in OC. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12964-026-03071-z.
SN - 1478-811X
ER -