Construction of senescence-related prognostic model for prostate cancer based on multi-omics and evaluation of its predictive value for biochemical recurrence

LÜ Yang; WANG Jiaying; YIN Lu; CHEN Hongqi; LI Qiang; WANG Weizhuo; LIU Kui; MENG Fanxi; LI Jian

doi:10.13263/j.cnki.nja.2025.12.001

Abstract：Objective The aim of this study is to explore the role of cellular senescence in prostate cancer and to estab-lish a senescence-related risk score model(SRRS),evaluating the application of its core genes in prognosis.Methods Single-cell transcriptomic data of prostate cancer were downloaded from the GEO database(GSE137829).The seurat package was used to construct a senescence score and identify epithelial cell subpopulations with high senescence features along with associated dif-ferentially expressed genes.The SRRS model was established using the Least Absolute Shrinkage and Selection Operator(LASSO)with TCGA-PRAD data,and its performance in predicting biochemical recurrence was evaluated through nomograms,ROC curves and calibration curves.Additionally,core gene HTRA2 was screened for analysis of its expression features,prognos-tic value,immune infiltration correlation and drug sensitivity.GSEA was utilized to further explore the potential mechanisms,and its broad clinical significance was assessed using pan-cancer data.Results Single-cell analysis identified Cluster 3 as the epithelial cell subpopulation with high senescence features,enriched with 119 senescence-related genes.The SRRS model,con-structed with patient clinical features,significantly differentiated patients with distinct prognoses,with AUC values for predicting 1-,3-,and 5-year survival probabilities of 0.801,0.801 and 0.789,respectively.HTRA2 was identified as a key gene in the model,with high expression significantly associated with poor prognosis and positively correlated with clinical features such as tumor stage and Gleason score.Immune analysis showed that HTRA2 expression was positively correlated with regulatory T cells and negatively correlated with CD4 T cells,indicating an immune-suppressive profile.Drug sensitivity analysis revealed that high expression of HTRA2 was associated with enhanced responses to Docetaxel and Vorinostat.IHC validated strong expression of HTRA2 in high-grade tumor tissues,and GSEA analysis revealed significant enrichment of pathways related to cell cycle and DNA repair.Pan-cancer analysis further confirmed that HTRA2 was highly expressed in various cancer types which was associat-ed with poor prognosis.Conclusion The SRRS model developed in this study effectively predicts the risk of biochemical recur-rence in prostate cancer patients.As a key molecule in the SRRS model,HTRA2 may promote the progression of prostate cancer by regulating cellular senescence phenotypes,remodeling the immune microenvironment,and activating cell cycle-related path-ways.It thus holds promise as a novel target for precision therapy in prostate cancer.