A succinylation‐based classifier predicts chemotherapy response in prostate cancer and reveals KAT2A as a therapeutic target

BACKGROUND: Chemotherapy resistance remains a critical hurdle in advanced prostate cancer (PCa). Succinylation, an essential post-translational modification linking cellular metabolism with epigenetic regulation, has been implicated in tumour progression; however, its contribution to PCa chemoresistance remains poorly defined. OBJECTIVE: This study aimed to evaluate the prognostic significance of succinylation in PCa, develop a succinylation-based biomarker, and elucidate the mechanisms driving chemotherapy resistance. METHODS: We generated a succinylation score (SS) by applying single-sample gene set enrichment analysis (ssGSEA) to transcriptomic profiles from the TCGA-PRAD cohort. Its relationships with survival, the tumour microenvironment (TME), and treatment susceptibility were examined using CIBERSORT, GSEA, TIDE, oncoPredict, and single-cell RNA sequencing (scRNA-seq). Findings were functionally validated in patient-derived organoids, PCa cell lines, and xenograft models through genetic manipulation, chemosensitivity assays, and mechanistic studies. RESULTS: precursor exhausted T cells. High-SS tumours showed enhanced sensitivity to docetaxel and cisplatin. scRNA‑seq identified KAT2A as a key driver in low‑SS malignant clusters with chemoresistance features. KAT2A was elevated in chemoresistant tissues, cell lines, and organoids. KAT2A knockout sensitised cells to chemotherapy, while ectopic expression promoted resistance in vitro and in vivo. Mechanistically, KAT2A-mediated succinylation of PIK3R2 at K477 and K564 inhibited its ubiquitination and proteasomal degradation, stabilising PIK3R2 to drive chemoresistance. The KAT2A inhibitor Butyrolactone 3 synergised with standard chemotherapy to suppress tumour growth. CONCLUSION: The succinylation score serves as a robust prognostic biomarker integrating metabolic and immunological features in PCa. The KAT2A-PIK3R2 succinylation pathway represents a newly defined driver of chemoresistance and points to MB-3-based combination therapy as a potential strategy for resistant advanced disease. KEY POINTS: A transcriptome-based succinylation score (SS) stratifies prostate cancer by prognosis, immune contexture, and chemotherapy sensitivity. KAT2A is enriched in low-SS, chemoresistant tumours and promotes resistance by succinylating PIK3R2. KAT2A-mediated succinylation competitively inhibits PIK3R2 ubiquitination, stabilising PIK3R2 and driving chemoresistance. The KAT2A inhibitor MB-3 synergises with chemotherapy to suppress tumour growth in both chemoresistant and chemosensitive models.