胰腺癌症的双重代谢阻断：线粒体靶向糖酵解和OXPHOS抑制剂的有效抗癌活性
Dual Metabolic Blockade in Pancreatic Cancer: Potent Anticancer Activity of Mitochondria-Targeted Glycolysis and OXPHOS Inhibitors.
摘要(中文译文)
同时靶向糖酵解和氧化磷酸化（OXPHOS）是克服胰腺导管腺癌（PDAC）代谢可塑性的一种有效策略。在本研究中，我们提出了化合物，一种经合理设计的、靶向线粒体的小分子，可破坏PDAC能量代谢。化合物在体外和体内均显著抑制PDAC细胞糖酵解和线粒体功能，表现为PDKs抑制以及OXPHOS相关蛋白（包括SDHB和SIRT3）的下调。在机制上，该化合物诱导铁死亡性细胞死亡，伴随脂质过氧化、氧化还原失衡和线粒体功能障碍。重要的是，该化合物还引发了免疫原性细胞死亡（ICD）的标志性特征，包括钙网蛋白暴露和HMGB1释放。在同基因PANC02模型中，该化合物抑制肿瘤生长且全身毒性极小，并重现了体外观察到的代谢抑制和ICD相关表型。这些发现支持该化合物可作为PDAC治疗中的双重代谢抑制剂和ICD诱导剂。
Abstract
Simultaneous targeting of glycolysis and oxidative phosphorylation (OXPHOS) is an effective strategy for overcoming the metabolic plasticity of pancreatic ductal adenocarcinoma (PDAC). In this study, we present compound , a rationally designed, mitochondria-targeted small molecule that disrupts PDAC energy metabolism. Compound markedly inhibited PDAC cell glycolysis and mitochondrial function, as evidenced by the PDKs inhibition and the downregulation of OXPHOS-associated proteins, including SDHB and SIRT3, in vitro and in vivo. Mechanistically, induced ferroptotic cell death, accompanied by lipid peroxidation, redox imbalance, and mitochondrial dysfunction. Importantly, also elicited hallmarks of immunogenic cell death (ICD), including calreticulin exposure and HMGB1 release. In a syngeneic PANC02 model, suppressed tumor growth with minimal systemic toxicity and recapitulated the metabolic inhibition and ICD-associated phenotypes observed in vitro. These findings support that could be used as a dual metabolic inhibitor and ICD inducer in PDAC therapy.
如何引用
AMA
Haibo Yan, Dongsheng Li, Min Yang, Mingyang Xu, Ying Yang, Zhenzhen Dai, et al. Dual Metabolic Blockade in Pancreatic Cancer: Potent Anticancer Activity of Mitochondria-Targeted Glycolysis and OXPHOS Inhibitors.. Journal of medicinal chemistry. 2026; doi:10.1021/acs.jmedchem.6c00430.
APA
Haibo Yan, Dongsheng Li, Min Yang, Mingyang Xu, Ying Yang, Zhenzhen Dai, et al (2026). Dual Metabolic Blockade in Pancreatic Cancer: Potent Anticancer Activity of Mitochondria-Targeted Glycolysis and OXPHOS Inhibitors.. Journal of medicinal chemistry. https://doi.org/10.1021/acs.jmedchem.6c00430
GB/T 7714
Haibo Yan, Dongsheng Li, Min Yang, Mingyang Xu, Ying Yang, Zhenzhen Dai, et al. Dual Metabolic Blockade in Pancreatic Cancer: Potent Anticancer Activity of Mitochondria-Targeted Glycolysis and OXPHOS Inhibitors.[J]. Journal of medicinal chemistry, 2026 doi:10.1021/acs.jmedchem.6c00430.
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