VDAC1 regulates disulfidptosis susceptibility and associates with the immune microenvironment via multi-omics analysis in lung adenocarcinoma

Lung adenocarcinoma (LUAD), the predominant subtype of non‑small cell lung cancer, continues to exhibit high incidence and mortality due to tumor heterogeneity and therapy resistance, underscoring the need for novel biomarkers and therapeutic targets. This study aimed to systematically characterize the expression, prognostic value, immune‑microenvironment modulation, and functional role of VDAC1 in LUAD, with a focus on its regulation of glucose‑deprivation–induced disulfidptosis. By integrating multi‑omics data from public resources, we performed differential expression, copy‑number variation, survival, immune‑infiltration, pathway‑enrichment, and single‑cell/spatial transcriptomic analyses. Findings were validated using immunohistochemistry on 15 paired LUAD samples and functional assays in A549 and PC‑9 cell lines. VDAC1 was significantly upregulated at mRNA and protein levels in LUAD, and its high expression correlated with poor prognosis and therapy resistance. Genomic copy‑number amplification and promoter hypomethylation cooperatively drove VDAC1 overexpression. Single‑cell and spatial transcriptomics confirmed VDAC1 enrichment specifically in malignant epithelial cells. Immune‑microenvironment analysis revealed a positive correlation with antigen presentation and a negative correlation with CD4 + T‑cell recruitment, suggesting a role in fostering an immunosuppressive niche. Pathway analysis linked VDAC1 to pro‑tumor processes including cell‑cycle progression, hypoxia response, and DNA‑damage repair. Transcriptomic analysis further showed that VDAC1-high tumors were preferentially enriched for disulfidptosis core genes—including SLC7A11—distinguishing this program from ferroptosis and apoptosis. Functionally, VDAC1 knockdown suppressed cystine uptake, partially restored GSH/GSSG balance and NADPH levels, attenuated mitochondrial ROS accumulation, and ameliorated ultrastructural damage, thereby alleviating glucose‑deprivation–triggered disulfidptosis. In summary, this integrated multi‑omics and experimental study establishes VDAC1 as both an independent adverse prognostic factor and a key regulator of disulfidptosis in LUAD, highlighting its potential as a therapeutic target for selectively inducing tumor cell death.