Abstract
Lung adenocarcinoma (LUAD) remains one of the leading causes of cancer mortality, underscoring the urgent need for biomarkers and therapeutic targets rooted in metabolic reprogramming. By integrating multi-omics analyses with experimental validation, we identified 67 lipid metabolism-related genes dysregulated in LUAD and constructed a five-gene prognostic signature via LASSO regression; lower expression of the signature genes correlated with poor survival. Single-cell and spatial transcriptomics revealed cell-type-specific dysregulation of the hub gene LIPA, which was upregulated in monocytes but downregulated in macrophages within the tumor microenvironment. Functional assays demonstrated that LIPA overexpression inhibited tumor proliferation in vitro and suppressed orthotopic tumor growth in vivo, at least in part through a ferroptosis-dependent mechanism involving TXNIP and ALOX5. Virtual screening further identified Castanospermine as a potential LIPA activator; treatment elevated LIPA expression, modulated the CD4+/CD8 + T-cell ratio, and attenuated tumor progression in mice. Collectively, these findings establish LIPA as a critical link between lipid metabolism, ferroptosis, and immune modulation in LUAD, and provide a prognostic signature for risk stratification as well as a candidate compound for targeting lipid metabolic vulnerabilities.