DLST drives lung adenocarcinoma progression by modulating cuproptosis-related copper homeostasis and apoptosis via an EP300-dependent mechanism.

BACKGROUND: Dihydrolipoamide S-succinyltransferase (DLST), a key enzyme in the tricarboxylic acid cycle, has recently been implicated in cuproptosis. However, its role in lung adenocarcinoma (LUAD) remains unclear. METHODS: DLST expression and clinical relevance were analyzed using TCGA and GEO datasets. Functional assays, including western blotting, flow cytometry, and copper ion detection, were performed in LUAD cell lines. In vivo tumor models were established to evaluate tumor growth. Bioinformatics analyses, co-immunoprecipitation, and single-cell RNA sequencing were conducted to investigate upstream and downstream regulatory mechanisms. RESULTS: DLST was significantly upregulated in LUAD tissues and was associated with advanced stage and poor prognosis. Mechanistically, upstream, EP300 interacted with DLST and enhanced its phosphorylation. At the core, DLST overexpression increased intracellular copper levels, upregulated the cuproptosis-related proteins HSP70 and SLC31A1, and inhibited apoptosis, these effects were partially reversed by copper chelation. Downstream, DLST exerted anti-apoptotic effects through upregulation of DLD. In vivo experiments confirmed that DLST promoted tumor growth. Single-cell analysis further revealed co-expression of DLST and EP300 in immune-related cell populations, suggesting a potential role of this axis in the tumor microenvironment. CONCLUSION: DLST promotes LUAD progression by regulating cuproptosis and apoptosis through the EP300-DLST-DLD axis, suggesting that this axis may represent a candidate for future therapeutic exploration in LUAD.