Integrative CRISPR-Cas9 Screening Reveals Lethal Genes Driving Metastasis and Prognosis in Prostate Adenocarcinoma

Prostate adenocarcinoma (PRAD) has become one of the most prevalent malignancies in men worldwide. Although advances in diagnostic techniques and targeted therapies have improved clinical outcomes, a significant subset of patients still develops aggressive, metastatic disease with limited treatment options. At present, identifying reliable biomarkers for early risk stratification remains a critical unmet need in prostate cancer research.This study established a novel genetic signature through multi-omics integration to enhance risk stratification and identify therapeutic targets.Integrated analysis of CRISPR-Cas9 screening and bulk RNA sequencing data identified tumor-dependent genes essential for PRAD cell viability.Pathway enrichment analysis demonstrated critical involvement of these genes in cell cycle regulation and tumor progression.An 11-gene prognostic signature was constructed via LASSO regression, effectively stratifying patients into distinct low-risk and high-risk cohorts.The high-risk cohort demonstrated significantly reduced progression-free survival (PFS; log-rank p < 0.001).Among the hub genes identified, CDC45 exhibited marked upregulation in tumor tissues, which was confirmed by both Western blotting and qRT-PCR. Subsequent functional interrogation established CDC45 as a key driver of tumor proliferation. Collectively, this study not only establishes a robust prognostic signature for PRAD but also nominates CDC45 as a promising therapeutic target, thereby advancing precision oncology strategies.