DLST Succinylation‐Mediated Mitochondrial Metabolic Remodeling and Cuproptosis Resistance Promote Malignant Progression of Lung Adenocarcinoma

Metabolic remodeling is one of the hallmarks of malignant tumors, and post-translational modifications of proteins, such as succinylation, play an important role in the process of metabolic remodeling by regulating the function of metabolic enzymes. However, the role of succinylation modifications of key mitochondrial metabolic enzymes in lung adenocarcinoma (LUAD) remains unclear. Here, using succinylation proteomics, it is demonstrated that the succinylation level of lysine 409 (K409) on dihydrolipoamide S-succinyltransferase (DLST) is significantly increased in LUAD. Further, DLST K409 succinylation (K409succ), which is catalyzed by carnitine palmitoyltransferase 1A (CPT1A), can affect oxidative phosphorylation (OXPHOS) and redox homeostasis by regulating enzyme activity, thereby promoting the malignant progression of LUAD. Notably, the succinylation of DLST can enhance the cuproptosis resistance by inhibiting its lipoylation. Subsequently, a small-molecule inhibitor SI409-1 that can specifically target DLST K409 has been developed. In vitro and in vivo experiments show that SI409-1 can inhibit the LUAD growth and enhance the sensitivity to cuproptosis inducers. Collectively, these findings provide a novel predictive target and intervention strategy for the clinical diagnosis and treatment of LUAD.