Pan-cancer multi-dimensional characterization and biological significance of cholesterol 25-hydroxylase (CH25H)

BACKGROUND: CH25H encodes an interferon-inducible hydroxylase that converts cholesterol to 25-hydroxycholesterol (25-HC), linking lipid homeostasis to immune regulation. Its pan-cancer relevance remains incompletely defined. METHODS: We integrated TCGA/GTEx transcriptomes with TCGA copy-number, mutation and DNA-methylation data, and immune infiltration estimates (TIMER/MCP-COUNTER/ssGSEA). For each cancer type, overall survival was modeled by an identical multivariable Cox regression (high vs. low CH25H by within-cancer median) adjusting for age, sex and pathologic stage; proportional hazards were assessed. RESULTS: CH25H was dysregulated across multiple malignancies with tumor-type-specific directions. Copy-number losses and promoter hypermethylation jointly associated with reduced mRNA levels. Survival analyses revealed a context-dependent pattern: higher CH25H aligned with favorable outcomes in several immune-active tumors, but with poorer prognosis in selected gastrointestinal cancers. CH25H positively correlated with effector immune infiltration and IFN-γ-dominant/inflammatory immune subtypes. These directions were concordant with multivariable Cox estimates; full per-cancer results are provided in Supplementary Table S1. CONCLUSIONS: CH25H exhibits a context-dependent, biphasic role in cancer: on one hand, it may exert tumor-suppressive effects by enhancing anti-tumor immunity; on the other, it can promote tumor progression in specific cancer types or stages. Its expression is co-regulated by CNV and promoter methylation. CH25H and its enzymatic product, 25-HC, hold promise as both prognostic biomarkers and therapeutic targets in cancer immunotherapy.