Background <p>Previous studies indicate an inverse association between systemic lupus erythematosus (SLE) and prostate cancer (PCa) risk. However, the underlying pathways remain unclear. Therefore, this study aims to elucidate the potential pathways through which SLE influences PCa and explore therapeutic targets.</p> Methods <p>First, we performed two-sample Mendelian randomization (MR) to confirm the causal relationship between SLE and PCa risk, followed by a two-step MR analysis to evaluate the mediation effects of immune cell characteristics and sex hormone levels. Next, comprehensive sensitivity analyses were conducted to ensure robustness, including heterogeneity testing, pleiotropy assessment, and leave-one-out validation. Then, we integrated transcriptomic data from SLE and PCa using weighted gene co-expression network analysis (WGCNA) to identify shared driver genes. Finally, we explored potential PCa therapeutic targets through: (1) summary-data-based MR (SMR), (2) colocalization analysis, and (3) phenome-wide association studies (PheWAS).</p> Result <p>The MR analysis indicated that SLE was associated with reduced PCa risk. Further, the two-step MR analysis showed that two sex hormones (total testosterone, bioavailable testosterone) and four immune-cell characteristics (IgD + CD24 + B cell %B cell, activated &amp; resting CD4 regulatory T cell absolute count, CD3 on terminally differentiated CD8 + T cell, and HLA DR on myeloid dendritic cell) could partially explain the protective effect of SLE on PCa. Additionally, we identified 48 shared driver genes involved in immune regulation-related biological processes. Ultimately, the SMR analysis and co-localization studies supported TOR1B as a potential therapeutic target for PCa.</p> Conclusion <p>Our study once again emphasizes the protective effect of SLE on PCa and confirms the mediating role of sex hormone and immune-cells, and highlights TOR1B as a potential therapeutic target for PCa.</p>