ATP7A and LIAS promote lung adenocarcinoma progression through regulation of cuproptosis

Cuproptosis has been implicated in lung adenocarcinoma (LUAD), but whether it contributes to the biological functions of ATPase copper transporting alpha (ATP7A) and lipoic acid synthetase (LIAS) remains unclear. This study aimed to investigate the roles of ATP7A and LIAS in LUAD progression and their association with cuproptosis-related alterations. ATP7A and LIAS expression was assessed in LUAD-related human tissues (n = 20 per group) and LUAD cell lines (A549 and PC9) by RT-qPCR, western blotting, and immunohistochemistry. Gain- and loss-of-function experiments were used to evaluate cell proliferation, migration, and epithelial–mesenchymal transition (EMT) (CCK-8, wound-healing, and Transwell assays, with molecular analyses). Cuproptosis-related changes were assessed using FDX1 expression, pyruvate and α-ketoglutarate levels, mitochondrial ultrastructure, and lipoylation-related readouts. Nude mouse subcutaneous xenografts were used for in vivo validation, with an additional independent cohort for Ki-67 immunohistochemistry and TUNEL staining. ATP7A and LIAS were significantly upregulated in LUAD tissues and cell lines compared with controls (all p < 0.05) and were associated with poorer differentiation, lymph node metastasis, and more advanced TNM stage (p < 0.05). Downregulation of ATP7A or LIAS significantly inhibited LUAD cell proliferation and migration and suppressed EMT-related changes (p < 0.05), whereas LIAS overexpression partially reversed the inhibitory effects of ATP7A silencing (p < 0.05). Co-immunoprecipitation supported an interaction between ATP7A and LIAS, and LIAS knockdown reduced ATP7A expression (p < 0.01). ATP7A or LIAS depletion was associated with increased FDX1 expression, elevated pyruvate and α-ketoglutarate levels, mitochondrial structural abnormalities, and altered lipoylation-related readouts (p < 0.05), several of which were partially attenuated by LIAS overexpression (p < 0.05). Reduced cell viability after ATP7A or LIAS depletion was not prominently mediated by caspase-dependent apoptosis or ferroptosis (p > 0.05). In vivo, ATP7A or LIAS knockdown suppressed xenograft tumor growth (p < 0.01), with reduced Ki-67 staining and increased TUNEL positivity in the independent validation cohort (both p < 0.01). ATP7A and LIAS promote LUAD progression and are associated with cuproptosis-related alterations, supporting a role for ATP7A/LIAS-regulated cuproptosis-related pathways in LUAD.