代谢重编程与肿瘤抗血管生成治疗的抗药性相关，然而其分子机制尚未清楚阐明。在这里，我们在结直肠癌（CRC）小鼠模型和人类参与者中鉴定了糖酵解酶烯醇酶2（ENO2）作为导致抗血管生成治疗抗药性的驱动因素。ENO2过表达诱导神经内分泌分化，在CRC中促进恶性行为并使其对抗血管生成药物失去敏感性。机制上，ENO2衍生代谢物磷酸烯醇丙酮酸（PEP）选择性抑制组蛋白去乙酰化酶-1（HDAC1）活性，增加β-连环蛋白的乙酰化并激活CRC中的β-连环蛋白通路。在体外和携带药物耐药CRC异种移植瘤的小鼠中，使用烯醇酶抑制剂AP-III-a4或POMHEX抑制ENO2能增强抗血管生成药物的疗效。综上，我们的发现揭示了ENO2作为CRC抗血管生成治疗抗药性的有效预测生物标记物和治疗靶点，并发现了PEP在调节抗血管生成治疗抗药性中作为内源性HDAC1抑制剂的以往未定义和与代谢无关的作用。©2023. 作者/出版公司享有Springer Nature Limited的专属许可。

Metabolic reprogramming is associated with resistance to antiangiogenic therapy in cancer. However, its molecular mechanisms have not been clearly elucidated. Here, we identify the glycolytic enzyme enolase 2 (ENO2) as a driver of resistance to antiangiogenic therapy in colorectal cancer (CRC) mouse models and human participants. ENO2 overexpression induces neuroendocrine differentiation, promotes malignant behaviour in CRC and desensitizes CRC to antiangiogenic drugs. Mechanistically, the ENO2-derived metabolite phosphoenolpyruvate (PEP) selectively inhibits histone deacetylase 1 (HDAC1) activity, which increases the acetylation of β-catenin and activates the β-catenin pathway in CRC. Inhibition of ENO2 with enolase inhibitors AP-III-a4 or POMHEX synergizes the efficacy of antiangiogenic drugs in vitro and in mice bearing drug-resistant CRC xenograft tumours. Together, our findings reveal that ENO2 constitutes a useful predictive biomarker and therapeutic target for resistance to antiangiogenic therapy in CRC, and uncover a previously undefined and metabolism-independent role of PEP in regulating resistance to antiangiogenic therapy by functioning as an endogenous HDAC1 inhibitor.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.