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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\u2010succinyltransferase (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\u2010molecule inhibitor SI409\u20101 that can specifically target DLST K409 has been developed. In vitro and in vivo experiments show that SI409\u20101 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.<\/jats:p>","DOI":"10.1002\/advs.77528","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T02:32:11Z","timestamp":1788143531000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DLST Succinylation\u2010Mediated Mitochondrial Metabolic Remodeling and Cuproptosis Resistance Promote Malignant Progression of Lung Adenocarcinoma"],"prefix":"10.1002","author":[{"given":"Xuanxuan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Oncology National Clinical Research Center for Geriatric Disorders, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Xiangya Hospital Central South University  Changsha 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Clinical Research Center for Geriatric Disorders, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Xiangya Hospital Central South University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangfang","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Oncology National Clinical Research Center for Geriatric Disorders, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Xiangya Hospital Central South University  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5369-6724","authenticated-orcid":false,"given":"Jinwu","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Pathology Xiangya Hospital Central South University  Changsha China"},{"name":"Department of Pathology Xiangya Changde Hospital  Changde 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