Targeting vulnerability in tumor therapy: Dihydroorotate dehydrogenase

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-04-03 DOI:10.1016/j.lfs.2025.123612

Fu Lin , Jiaxin Li , Lei Zhou , Rigui Yi , Yingge Chen , Shuai He

{"title":"Targeting vulnerability in tumor therapy: Dihydroorotate dehydrogenase","authors":"Fu Lin , Jiaxin Li , Lei Zhou , Rigui Yi , Yingge Chen , Shuai He","doi":"10.1016/j.lfs.2025.123612","DOIUrl":null,"url":null,"abstract":"<div><div>Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the de novo pyrimidine biosynthetic pathway and a recognized therapeutic target in various diseases. In oncology research, DHODH has gained increasing importance and become a hot target for various tumor therapy studies. This review highlights three key points: (1) DHODH enables its diverse biological functions through its unique structural features and dominates the regulation of tumor metabolism and cell fate; (2) DHODH activates oncogenic signals, drives metastatic adaptation, and remodels drug resistance networks in tumors, making it a metabolic-signaling dual hub; and (3) DHODH inhibitors have shown significant efficacy in preclinical models of various tumors but face multiple challenges in clinical trials, including drug-related limitations and external constraints. Given these challenges, future research should explore DHODH inhibitors as a foundation for overcoming technological and translational barriers while establishing a systematic framework for the clinical application of DHODH-targeted tumor therapies.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"371 ","pages":"Article 123612"},"PeriodicalIF":5.2000,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Life sciences","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0024320525002462","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

Abstract

Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the de novo pyrimidine biosynthetic pathway and a recognized therapeutic target in various diseases. In oncology research, DHODH has gained increasing importance and become a hot target for various tumor therapy studies. This review highlights three key points: (1) DHODH enables its diverse biological functions through its unique structural features and dominates the regulation of tumor metabolism and cell fate; (2) DHODH activates oncogenic signals, drives metastatic adaptation, and remodels drug resistance networks in tumors, making it a metabolic-signaling dual hub; and (3) DHODH inhibitors have shown significant efficacy in preclinical models of various tumors but face multiple challenges in clinical trials, including drug-related limitations and external constraints. Given these challenges, future research should explore DHODH inhibitors as a foundation for overcoming technological and translational barriers while establishing a systematic framework for the clinical application of DHODH-targeted tumor therapies.

Abstract Image

查看原文本刊更多论文

靶向易损性肿瘤治疗：二氢乙酸脱氢酶。

二氢乳酸菌脱氢酶（Dihydroorotate dehydrogenase， DHODH）是新的嘧啶生物合成途径中的关键酶，是多种疾病公认的治疗靶点。在肿瘤学研究中，DHODH越来越受到重视，成为各种肿瘤治疗研究的热点靶点。本文综述的重点有三点：(1)DHODH通过其独特的结构特征实现其多种生物学功能，主导肿瘤代谢和细胞命运的调控；(2) DHODH激活肿瘤致癌信号，驱动转移适应，重塑肿瘤耐药网络，使其成为代谢-信号双枢纽；(3) DHODH抑制剂在多种肿瘤的临床前模型中显示出显著的疗效，但在临床试验中面临药物相关限制和外部约束等多重挑战。鉴于这些挑战，未来的研究应探索DHODH抑制剂作为克服技术和翻译障碍的基础，同时为DHODH靶向肿瘤治疗的临床应用建立系统框架。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.