The pyruvate dehydrogenase complex at the crossroads of cancer metabolism and cell death

IF 9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology Pub Date : 2026-07-16 DOI:10.1016/j.chembiol.2026.06.009

Xiutao Cai, Fangquan Chen, Ruirui Liang, Hu Tang, Qile Zhou, Junhao Lin, Rui Kang, Daolin Tang, Jiao Liu

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Abstract

The pyruvate dehydrogenase complex (PDHC) is a key metabolic hub that couples glycolysis-derived carbon flux to the tricarboxylic acid cycle and mitochondrial function. Its activity is regulated by pyruvate dehydrogenase kinases, phosphatases, and lysine acylation, enabling dynamic responses to metabolic and stress signals. In cancer, dysregulation of the PDK-PDHC axis reduces PDH flux, promotes aerobic glycolysis, and enhances adaptation to mitochondrial and oxidative stress, thereby influencing susceptibility to regulated cell death. Recent studies further suggest that PDHC exhibits considerable structural and functional plasticity under hypoxia and redox stress. Growing preclinical and translational evidence indicates that targeting the PDK-PDHC axis may redirect metabolic flux and improve therapeutic responses in selected tumor contexts. This review summarizes current understanding of PDHC regulation, its context-dependent roles in regulated cell death, and the therapeutic potential and challenges of exploiting PDH-related metabolic vulnerabilities in cancer.

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丙酮酸脱氢酶复合物在癌症代谢和细胞死亡的十字路口

丙酮酸脱氢酶复合物（PDHC）是一个关键的代谢中心，将糖酵解衍生的碳通量与三羧酸循环和线粒体功能结合起来。其活性受丙酮酸脱氢酶激酶、磷酸酶和赖氨酸酰化酶的调节，能够对代谢和应激信号做出动态反应。在癌症中，PDK-PDHC轴的失调会降低PDH通量，促进有氧糖酵解，增强对线粒体和氧化应激的适应，从而影响对受调节细胞死亡的易感性。最近的研究进一步表明，PDHC在缺氧和氧化还原应激下表现出相当大的结构和功能可塑性。越来越多的临床前和转化证据表明，靶向PDK-PDHC轴可能会改变代谢通量的方向，并改善特定肿瘤环境的治疗反应。本文综述了目前对PDHC调控的理解，其在受调控细胞死亡中的环境依赖性作用，以及在癌症中利用PDHC相关代谢脆弱性的治疗潜力和挑战。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

14.70

自引率

2.30%

发文量

143

期刊介绍： Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.