CYP27A1 suppresses brain metastasis via ferroptosis in lung adenocarcinoma: a six-gene signature predicting the immunotherapy response and clinical outcomes.

BACKGROUND: Lung adenocarcinoma (LUAD) brain metastasis has limited therapeutic options and a poor prognosis. This study aimed to identify molecular drivers, construct a prognostic model, and assess immunotherapy response. METHODS: We integrated scRNA-seq data from 4 LUAD patients (GSE117570) and bulk RNA-seq data from the TCGA-LUAD cohort. Brain metastasis-associated differentially expressed genes (DEGs) were identified via Seurat. CellChat was used to analyse intercellular communication. A LASSO Cox prognostic model was constructed, and the function of CYP27A1 was validated in vitro. RESULTS: Six brain metastasis-linked genes (CD9, CYP27A1, HLA-DQB1, PEBP1, PECAM1, and TUBB) formed a risk model. High-risk patients had worse overall survival (HR = 1.91, p < 0.0001) and a reduced immunotherapy response. scRNA-seq revealed that M1 macrophages are involved in metastasis, with CYP27A1 significantly downregulated in LUAD cells. Functionally, CYP27A1 overexpression inhibited proliferation, migration, and invasion by inducing ferroptosis via iron homeostasis and lipid peroxidation (p < 0.05). High-risk patients presented lower immune scores/stromal components. A nomogram integrating the risk score, stage, and EGFR status showed robust 1-3 year predictive accuracy (AUC: 0.749-0.780). CONCLUSIONS: CYP27A1 is implicated as a suppressor of LUAD brain metastasis via ferroptosis. The six-gene model facilitates risk stratification, and macrophage-driven microenvironment remodelling informs potential immunotherapy strategies, advancing LUAD precision oncology.