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<p>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) &gt; 1, <i>p</i> &lt; 0.01). Colocalization analysis (SNP.PP.H4 &gt; 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 &gt; 1, <i>p</i> &lt; 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 (<i>p</i> &lt; 0.05). Notably, its expression was positively correlated with the infiltration of multiple immune cell types (cor &gt; 0, <i>p</i> &lt; 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) &gt; 2, false discovery rate (FDR) &lt; 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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 发表日期：

    2025年9月29日

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  • Jucai Song,
  • Qi Zhang,
  • Miaomiao Ma,
  • Peng Ma,
  • Rubing Chen,
  • Zulong Wang

摘要

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.

Graphical Abstract