Fibroblast-associated CTHRC1 as a key indicator of recurrence risk in prostate cancer

Prostate adenocarcinoma (PRAD) has substantial recurrence after primary treatment, and reliable prediction is clinically needed. We integrated clinical, genomic, and transcriptomic data to identify recurrence-associated genes, characterize their tumor microenvironmental context, and develop a prognostic model. Gene expression and clinical data were obtained from TCGA (training; n = 145) and the GEO dataset GSE54460 (validation; n = 106). Single-cell RNA-seq data were analyzed to resolve gene expression across cell types. Immune infiltration was estimated using ssGSEA and the ESTIMATE algorithm, and cell–cell communication was assessed with CellChat. Recurrence-associated genes were identified by univariate Cox regression, and a LASSO Cox model was used to construct and externally validate the risk score. Pathological T stage, N stage, Gleason score, and TP53 mutation were linked to higher recurrence risk. We identified six risk genes (AMH, CRYBA2, CTHRC1, EFNA2, BMP6, ARHGDIG) and two protective genes (CKMT2, IP6K3) and built a risk-score model that discriminated against PFS in the training and validation cohorts. Single-cell analysis localized CTHRC1 predominantly to a fibroblast subpopulation characterized by upregulated midkine (MDK) signaling and extensive intercellular communication. Drug–gene correlation screening nominated decitabine, tegafur, calusterone, EMD-1204831, and ARQ-680; expression of several risk genes positively correlated with CTLA4, suggesting testable sensitivity to checkpoint blockade. Clinical variables together with transcriptomic features—particularly a CTHRC1-high fibroblast program—associate with PRAD recurrence. The externally validated risk score and the stromal context of CTHRC1/MDK provide testable avenues for prognosis and therapeutic exploration.