Prostate cancer is the most prevalent cancer among men worldwide and exhibits significant genetic heritability. In this study, we performed an integrative analysis combining chromatin accessibility profiling, transcriptomics, and two-stage case–control studies, alongside an unbiased phenome-wide exploration in the FinnGen cohort. This comprehensive approach identified the enhancer-associated SNP rs7077830 at chromosome 10q11 as a critical modulator of prostate cancer susceptibility. Mechanistic investigations revealed that rs7077830 exerted allele-specific enhancer activity, driving NCOA4 expression via a ZNF384-mediated enhancer–promoter interaction. CRISPR/Cas9-mediated single-nucleotide editing confirmed the direct regulatory role of rs7077830 on NCOA4 and its contribution to prostate cancer progression. Functional studies demonstrated that NCOA4 acted as a tumor suppressor by promoting ferroptosis. Furthermore, NCOA4 expression modulated sensitivity to ferroptosis-inducing agents. Strikingly, rs7077830 genotypes were directly linked to ferroptosis status in prostate cancer. These findings highlight the role of noncoding genetic variants in prostate cancer pathogenesis, provide insights into enhancer-driven ferroptosis regulation, and suggest a promising therapeutic avenue for patients with prostate cancer carrying specific rs7077830 genotypes. Significance: An enhancer mechanism mediated by a noncoding variant drives prostate cancer risk by regulating tumor suppressor expression and ferroptosis while conferring susceptibility to the potential of genotype-based precision therapeutic approaches.

Background: Despite advances in prostate cancer treatment, castration-resistant prostate cancer (CRPC) remains clinically challenging due to inherent therapy resistance and a lack of durable alternatives. Although traditional Chinese medicine offers untapped potential, the therapeutic role of paeoniflorin (Pae), a bioactive compound derived from Paeonia lactiflora, in prostate cancer has yet to be investigated. Methods: Using an integrative approach (network pharmacology, molecular docking, and experimental validation), we identified Pae key targets, constructed protein–protein interaction networks, and performed GO/KEGG pathway analyses. A Pae-target-based prognostic model was developed and validated. In vitro and in vivo assays assessed Pae effects on proliferation, migration, invasion, apoptosis, and tumor growth. Results: Pae exhibited potent anti-CRPC activity, inhibiting cell proliferation by 60% and impairing cell migration by 65% compared to controls. Mechanistically, Pae downregulated SRC proto-oncogene, non-receptor tyrosine kinase (SRC) mRNA expression by 68%. The Pae-target-based prognostic model stratified patients into high- and low-risk groups with distinct survival outcomes. Organoid and xenograft studies confirmed Pae-mediated tumor growth inhibition and SRC downregulation. Conclusions: Pae overcomes CRPC resistance by targeting SRC-mediated pathways, presenting a promising therapeutic strategy. Our findings underscore the utility of network pharmacology-guided drug discovery and advocate for further clinical exploration of Pae in precision oncology.

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies and the main cause of cancer-related death in men worldwide. Poly(ADP-ribose) polymerase inhibitors (PARPi) have been approved for the treatment of PCa harboring BRCA1/2 mutations. While the survival benefits conferred by PARPi may extend beyond this specific patient population based on evidence from recent clinical trials, the underlying mechanisms remain unexplored. Here, we demonstrate that PARPi substantially restored NK cell functions by promoting cyclophilin A (CypA) secretion from PCa cells, which correlated with improved prognosis in PCa patients from our and public cohorts. Mechanistically, tumor-derived CypA specifically from PCa cells bound to ANXA6 and activated the downstream FPR1 signaling pathway, leading to increased mitochondrial oxidative phosphorylation and NK cell activation. Pharmacological inhibition of CypA blocked FPR1/AKT signaling and diminished the cytotoxic effects of NK cells, thereby compromising the therapeutic efficacy of PARPi against PCa. Conversely, combining NK cell adoptive transfer therapy with PARPi markedly prolonged survival in mice bearing PCa. Collectively, we reveal a unique secretory crosstalk between PCa cells and NK cells induced by PARPi and propose a promising strategy for treating PCa.

NCOA4 affects prostate cancer sensitivity to ferroptosis-inducing drug in vivo.

Probes or primers sequence used in the study

Characteristics of patients with PCa tissues in this study