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<p>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.</p>

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ESM1 drives H4K8 lactylation to promote vasculogenic mimicry and bevacizumab resistance in ovarian cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Yukun Li,
  • Juan Zou,
  • Li Yang,
  • Xiongjin Tan,
  • Xing Tang,
  • Peiting Wu,
  • Xueru Liu,
  • Xun Chen,
  • Daichao Wu,
  • Xing Yu

摘要

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.