Abstract
BACKGROUND: Cholesterol is essential for tumor proliferation and progression. Cholesterol homeostasis has emerged as a key focus in cancer metabolism research. However, its role in clear cell renal cell carcinoma (ccRCC) remains poorly understood. METHODS: RNA-sequencing and clinical data of ccRCC patients were obtained from The Cancer Genome Atlas and the Gene Expression Omnibus databases. The E-MTAB-1980 dataset served as an external validation cohort. Nonnegative Matrix Factorization was employed to construct the cholesterol homeostasis cluster. A cholesterol homeostasis signature (CHS) was constructed using the least absolute shrinkage and selection operator regression method to characterize the cholesterol metabolic status of ccRCC. RESULTS: Two distinct molecular clusters associated with cholesterol homeostasis were identified, exhibiting divergent prognostic and immunological profiles. Analysis of immune cell infiltration revealed that Cluster C2 displayed immunosuppressive features, with enrichment of pro-tumor and immune-related pathways. The CHS was found to be predictive of both tumor immune status and clinical outcomes. Furthermore, we examined SREBF2, a key transcription factor in cholesterol regulation, and found that its high expression was associated with immune activation and favorable prognosis. Down-regulation of SREBF2 in ccRCC may lead to decreased cholesterol uptake and synthesis. CONCLUSION: Cholesterol homeostasis signature serves as a potential biomarker for prognosis, immune microenvironment status, and clinicopathological characteristics in ccRCC. Genes related to cholesterol homeostasis, such as SREBF2, may offer new therapeutic targets for immunomodulation in ccRCC.