异柠檬酸脱氢酶（IDH）1和2作为能量代谢中的关键酶，在多种实体瘤尤其是结直肠癌（CRC）的生存和药物耐药性中发挥重要作用。然而，其潜在的分子机制仍然不清楚。在本研究中，我们使用无偏的热蛋白质组学分析（TPP）策略，将IDH1确定为天然衍生的抗CRC小分子利科力的关键细胞靶点。我们发现，利科力直接靶向IDH1的独特C端结构域，破坏了IDH1与去乙酰化酶sirtuin 1（SIRT1）的相互作用，从而显著促进了IDH1的乙酰化修饰。然后，利科力明显地诱导了CRC细胞的氧化应激，导致线粒体膜损伤，并进一步促进线粒体分裂。特异性敲低IDH1或SIRT1明显加剧了利科力介导的CRC细胞氧化应激和线粒体碎裂。此外，利科力与SIRT抑制剂烟酰胺（NAM）的联合治疗在CRC细胞中展示了协同的治疗效果。总之，我们的结果揭示了IDH1可能作为治疗CRC的有前途的靶点，通过药理学方式驱动氧化应激依赖的线粒体动力学失衡。版权所有 © 2023. Elsevier B.V. 发表。

Isocitrate dehydrogenase (IDH) 1 and 2, as essential enzymes in energy metabolism, contribute to the survival and drug resistance of a variety of solid tumors, especially for colorectal cancer (CRC). However, the underlying molecular mechanism still remains unclear. In this study, IDH1 was identified as a crucial cellular target of a natural-derived anti-CRC small molecule lycorine, using the unbiased thermal proteome profiling (TPP) strategy. We found that lycorine directly targeted a unique C-terminal domain of IDH1, and disrupted IDH1 interaction with deacetylase sirtuin 1 (SIRT1), thereby significantly promoting IDH1 acetylation modification. Then, lycorine noticeably triggered oxidative stress in CRC cells to cause mitochondrial membranes injury, and subsequently facilitated mitochondrial fission. Specific knockdown of IDH1 or SIRT1 markedly aggrieved lycorine-mediated oxidative stress and mitochondrial fragmentation in CRC cells. Furthermore, the combination of lycorine and sirtuins blocker nicotinamide (NAM) exhibited a synergic therapeutic effect in CRC cells. Collectively, our results reveal that IDH1 may serve as a promising therapeutic target for CRC via pharmacologically driving oxidative stress-dependent mitochondrial dynamics imbalance.Copyright © 2023. Published by Elsevier B.V.