嘌呤是细胞基因组的构建块，并且过量的嘌呤核苷酸可以在肿瘤中发现。然而，嘌呤代谢在肿瘤中的失调以及其对肿瘤发生的影响仍然不清楚。在全球最致命的癌症之一肝细胞癌（HCC）的62名患者中，我们对嘌呤生物合成和嘌呤降解途径进行了转录组和代谢组分析，包括肿瘤和相关非肿瘤肝组织。我们发现，HCC肿瘤中嘌呤合成中的大多数基因被上调，而嘌呤降解的基因被抑制。高嘌呤合成与特异的体细胞突变签名相关联，与患者预后有关。从机理上讲，我们发现增加嘌呤合成可以通过上调RNA N6-甲基腺苷修饰来促进DDR机制的表观转录调控。高嘌呤合成的HCC对DDR靶向药物敏感，但对标准HCC治疗方法不敏感，这与包含724名患者的五个独立HCC队列中的临床结局相关。我们进一步展示高嘌呤合成在5种HCC细胞系的体外和体内决定对DDR靶向药物的敏感性。我们的结果揭示了嘌呤合成在调节DDR中的中心作用，这可以在HCC中通过治疗手段得到利用。版权所有©2023年美国肝病研究协会。

Purines are building blocks for cellular genome and excessive purine nucleotides are seen in tumors. However, how purine metabolism is dysregulated in tumor and impacting tumorigenesis remains elusive.Transcriptomic and metabolomic analysis of purine biosynthesis and purine degradation pathways were performed in the tumor and associated non-tumor liver tissues obtained from 62 patients with hepatocellular carcinoma (HCC), one of the most lethal cancers worldwide. We found that most genes in purine synthesis are upregulated while genes in purine degradation are inhibited in HCC tumors. High purine anabolism is associated with unique somatic mutational signatures linked to patient prognosis. Mechanistically, we discover that increasing purine anabolism promotes epitranscriptomic dysregulation of DDR machinery through upregulating RNA N6-methyladenosine modification. High purine anabolic HCC is sensitive to DDR-targeting agents but not to standard HCC treatments, correlating with the clinical outcomes in five independent HCC cohorts containing 724 patients. We further showed that high purine anabolism determines the sensitivity to DDR-targeting agents in 5 HCC cell lines in vitro and in vivo.Our results reveal a central role of purine anabolism in regulating DDR, which could be therapeutically exploited in HCC.Copyright © 2023 American Association for the Study of Liver Diseases.