美国癌症协会旗下影响因子最高（IF大约20）的Cancer Discovery杂志在其研究嘹望（Research Watch）栏目专文介绍了本实验室最新的研究成果，指出其理论及转化意义：

IDH Mutations Drive Tumorigenesis via Mitochondrial Hypersuccinylation
Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, which have been identified in multiple tumor types including gliomas, result in the reduction of α-ketoglutarate (α-KG) to the α-KG analogue (R)-2-hydroxyglutarate (R-2HG) and are associated with a hypermethylator phenotype. However, inhibition of R-2HG production results in a decrease in tumor growth but does not affect methylation levels. To ascertain how R-2HG accumulation promotes tumorigenicity, Li, He, Ye and colleagues investigated the role of R-2HG in succinylation, a common posttranslational lysine modification involving succinyl-CoA, which is converted into succinate in the tricarboxylic acid (TCA) cycle. In vitro studies revealed that R-2HG competitively inhibited the TCA cycle enzyme succinate dehydrogenase (SDH), which catalyzes the oxidation of succinate to fumarate in IDH1-mutant cells, leading to significantly increased levels of succinate. Furthermore, inactivation of SDH, treatment with a membrane-permeable R-2HG ester, or expression of R-2HG–producing IDH1 mutations in glioma cells resulted in increased succinyl-CoA levels and preferentially induced hypersuccinylation of mitochondrial proteins. Similarly, hypersuccinylation was present in IDH1-mutant gliomas from patients, most prominently in the mitochondria. Hypersuccinylation induced by a mutant IDH1 or knockdown of the desuccinylase sirtuin 5 (SIRT5) resulted in increased histone methylation and decreased activity of metabolism-related enzymes. Mechanistically, IDH mutation–induced hypersuccinylation increased tumor metabolism by driving mitochondrial depolarization and inhibiting mitochondrial respiration, and promoted apoptosis resistance by inducing localization of BCL2 to the mitochondrial membrane. SIRT5 overexpression or glycine supplementation resulted in decreased succinylation, increased sensitivity to apoptosis, and diminished growth of glioma in vitro and in vivo. Together, these results show that IDH mutant–derived R-2HG promotes tumorigenic increases in metabolism and apoptosis resistance by inducing hypersuccinylation, which represents a potential therapeutic target for hypersuccinylation-related tumors.