Nicotine drives lung cancer progression by suppressing cuproptosis through the LIAS-DLAT axis and promoting M2...

Cuproptosis is a recently defined, copper-dependent, regulated cell death pathway characterized by the aggregation of lipoylated mitochondrial enzymes; however, the mechanisms by which lung cancer cells evade this process under environmental stressors such as nicotine remain largely unknown. By combining in silico transcriptomic analysis with tissue microarray (TMA) validation, functional assays, metabolic profiling, and single-cell RNA sequencing, this study identifies DLAT and DLD as critical cuproptosis-related markers that are significantly overexpressed in lung adenocarcinoma (LUAD) and correlate with poor patient survival, particularly in cohorts with a smoking history. Mechanistically, while normal lung epithelial cells remain susceptible to nicotine-induced copper-dependent proteotoxic stress characterized by increased lipoylated DLAT and DLAT oligomerization, LUAD cells display high basal DLAT abundance but low lipoylated DLAT and minimal oligomerization. Upon nicotine exposure, LUAD cells upregulate LIAS without altering DLAT lipoylation or oligomerization, indicating a pre-existing cuproptosis-resistant mitochondrial state that preserves TCA cycle activity and ATP production. Furthermore, this metabolic rewiring orchestrates an immunosuppressive microenvironment by promoting M2 macrophage polarization, thereby fostering a pro-tumorigenic niche. Ultimately, these findings reveal a novel survival strategy in which nicotine promotes lung cancer progression by protecting cells from cuproptosis via LIAS-mediated metabolic regulation and immune reshaping, establishing the LIAS-DLAT axis as a promising therapeutic target for smoking-associated LUAD.