贝伐单抗在转移性结直肠癌（CRC）的一线和二线治疗中起着重要作用。缺氧诱导和肿瘤对其的反应在确定抗血管生成疗法的疗效方面起着重要作用，而它们之间的联系尚不清楚。在这里，我们发现CRC肿瘤环境中乳酸积累，并充当组蛋白乳酸化的底物，这个过程在缺氧时进一步通过细胞增强的糖酵解被诱导出来。我们确定耐受贝伐单抗治疗的CRC患者表现出较高水平的组蛋白乳酸化，并且抑制组蛋白乳酸化有效地抑制了在缺氧条件下的CRC肿瘤发生、进展和生存。组蛋白乳酸化通过与BECN1（beclin 1）相互作用、介导Ⅲ类磷脂酰肌醇3-激酶复合物的招募和功能，促进了RUBCNL/Pacer的转录，并促进了自嗜体包涵体的成熟，这在缺氧的癌细胞增殖和生存中起重要作用。此外，组蛋白乳酸化抑制和宏自嗜作用/自嗜作用与贝伐单抗治疗的联合在贝伐单抗耐药患者衍生的临床前模型中表现出显著的治疗效果。这些发现为代谢重编程-表观遗传调控提供了新的探索和重要补充，并为通过抑制组蛋白乳酸化来提高贝伐单抗在CRC中的临床疗效提供了新的策略。

Bevacizumab plays an important role in the first and second line treatment for metastatic colorectal cancer (CRC). And induction of hypoxia and the tumors response to it plays an important role in determining the efficacy of antiangiogenic therapy while the connection between them remains unclear. Here, we found that lactate accumulated in the tumor environment of CRC and acted as substrates for histone lactylation, and this process was further induced by cellular enhanced glycolysis in hypoxia. We determined that CRC patients resistant to bevacizumab treatment presented with elevated levels of histone lactylation and inhibition of histone lactylation efficiently suppressed CRC tumorigenesis, progression and survival in hypoxia. Histone lactylation promoted the transcription of RUBCNL/Pacer, facilitating autophagosome maturation through interacting with BECN1 (beclin 1) and mediating the recruitment and function of the class III phosphatidylinositol 3-kinase complex, which had a crucial role in hypoxic cancer cells proliferation and survival. Moreover, combining inhibition of histone lactylation and macroautophagy/autophagy with bevacizumab treatment demonstrated remarkable treatment efficacy in bevacizumab-resistance patients-derived pre-clinical models. These findings delivered a new exploration and important supplement of metabolic reprogramming-epigenetic regulation, and provided a new strategy for improving clinical efficacy of bevacizumab in CRC by inhibition of histone lactylation.