Qiling formula targets CDK5R1 to suppress enzalutamide resistance in prostate cancer: integrating prognostic modeling and function validation

Advanced prostate cancer (PCa) progression to enzalutamide resistance remains a major therapeutic challenge. Grounded in Traditional Chinese Medicine theory, the Qiling Formula (QLF) targets “Qi deficiency and blood stasis” and has shown anti-tumor potential. However, its molecular mechanisms and prognostic value remain unclear. This study integrates network pharmacology, TCGA transcriptomics, spatial transcriptomics, and cellular experiments to decode QLF’s effects. We identified a novel CDK5R1-centered prognostic signature that accurately stratifies patient risk and correlates with immune dysregulation. Spatial analysis revealed distinct tumor-immune niches, characterized by the co-localization of CDK5R1+ tumor cells with immunosuppressive SPP1+ macrophages. Mechanistically, Oridonin—a key bioactive monomer of QLF—disrupted the CDK5R1-AR axis, effectively restoring enzalutamide sensitivity in resistant cells. Molecular docking and dynamics simulations confirmed the stable binding of QLF monomers to key targets. While this work validates Oridonin as a lead compound, future investigations should focus on elucidating the functional immunomodulatory crosstalk within the TME, dissecting the synergistic contributions of other QLF constituents (e.g., astragaloside IV), and expanding the regulatory network via multi-omics integration to include other prognostically relevant genes (e.g., PTGES2). This study bridges traditional medicine and modern oncology through systems biology.