Multi-omics genetic study revealing ferroptosis regulator CTSB driving prostate cancer progression by modulating the immune microenvironment.

The progression and mechanisms of drug resistance in prostate cancer are highly complex, with the ferroptosis pathway playing a critical role. We utilized multi-omics Mendelian randomization (MR) to assess the genetic causal link between ferroptosis gene/protein expression and prostate cancer, investigating potential mediation by 731 immune cell types. Furthermore, differential expression analysis, immune infiltration analysis, single-cell RNA sequencing, gene set enrichment analysis (GSEA), and drug prediction were integrated for multidimensional validation and mechanistic insight. Our results identified cathepsin B (CTSB) as a key causal risk factor associated with iron death in the development of prostate cancer (odds ratio (OR) > 1, p < 0.01). Colocalization analysis (SNP.PP.H4 > 0.95) ruled out confounding biases. Mediation MR analysis revealed that CTSB partially mediates its carcinogenic effects by regulating various immune cells, such as PD-L1 + monocytes and CD45 + T cells (OR > 1, p < 0.05). Further analysis indicated that CTSB gene/protein expression was highly expressed in normal prostate basal epithelial cells and myeloid cells, while it was downregulated in tumor tissues and neoplastic epithelial cells (p < 0.05). Notably, its expression was positively correlated with the infiltration of multiple immune cell types (cor > 0, p < 0.05). GSEA demonstrated that high CTSB expression was significantly enriched in pro-cancer pathways, including epithelial-mesenchymal transition, angiogenesis, inflammatory response, and apoptosis (normalized enrichment score (NES) > 2, false discovery rate (FDR) < 0.001). Drug prediction analyses suggested that targeting CTSB (e.g., with bortezomib) in combination with immunotherapy may represent a novel therapeutic strategy. This study provides the first evidence of the causal role of iron death-immune interactions in prostate cancer, offering new targets for precision treatment.