{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T06:02:15Z","timestamp":1784959335691,"version":"3.55.0"},"reference-count":42,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100010814","name":"Anhui Provincial Department of Education","doi-asserted-by":"publisher","award":["2024AH050764"],"award-info":[{"award-number":["2024AH050764"]}],"id":[{"id":"10.13039\/501100010814","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002947","name":"Anhui Medical University","doi-asserted-by":"publisher","award":["2023xkj061"],"award-info":[{"award-number":["2023xkj061"]}],"id":[{"id":"10.13039\/501100002947","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical & Translational Med"],"published-print":{"date-parts":[[2026,7]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Chemotherapy resistance remains a critical hurdle in advanced prostate cancer (PCa). Succinylation, an essential post\u2010translational modification linking cellular metabolism with epigenetic regulation, has been implicated in tumour progression; however, its contribution to PCa chemoresistance remains poorly defined.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n This study aimed to evaluate the prognostic significance of succinylation in PCa, develop a succinylation\u2010based biomarker, and elucidate the mechanisms driving chemotherapy resistance.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We generated a succinylation score (SS) by applying single\u2010sample gene set enrichment analysis (ssGSEA) to transcriptomic profiles from the TCGA\u2010PRAD cohort. Its relationships with survival, the tumour microenvironment (TME), and treatment susceptibility were examined using CIBERSORT, GSEA, TIDE, oncoPredict, and single\u2010cell RNA sequencing (scRNA\u2010seq). Findings were functionally validated in patient\u2010derived organoids, PCa cell lines, and xenograft models through genetic manipulation, chemosensitivity assays, and mechanistic studies.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n High SS correlated with favourable prognosis, lower Gleason scores, absent lymph node metastasis, and an immune\u2010active TME enriched in CD8\n +<\/jats:sup>\n precursor exhausted T cells. High\u2010SS tumours showed enhanced sensitivity to docetaxel and cisplatin. scRNA\u2011seq identified KAT2A as a key driver in low\u2011SS 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\u2010mediated 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.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n The succinylation score serves as a robust prognostic biomarker integrating metabolic and immunological features in PCa. The KAT2A\u2010PIK3R2 succinylation pathway represents a newly defined driver of chemoresistance and points to MB\u20103\u2010based combination therapy as a potential strategy for resistant advanced disease.<\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n A transcriptome\u2010based succinylation score (SS) stratifies prostate cancer by prognosis, immune contexture, and chemotherapy sensitivity.<\/jats:p>\n <\/jats:list-item>\n \n KAT2A is enriched in low\u2010SS, chemoresistant tumours and promotes resistance by succinylating PIK3R2.<\/jats:p>\n <\/jats:list-item>\n \n KAT2A\u2010mediated succinylation competitively inhibits PIK3R2 ubiquitination, stabilising PIK3R2 and driving chemoresistance.<\/jats:p>\n <\/jats:list-item>\n \n The KAT2A inhibitor MB\u20103 synergises with chemotherapy to suppress tumour growth in both chemoresistant and chemosensitive models.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n 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