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Hypoxia drives cisplatin resistance in BCa by analyzing the TCGA-BLCA cohort, where hypoxia signatures predicted poor overall survival. In\u00a0vitro, hypoxia elevated lactate production via LDHA, inducing H3K18la catalyzed by KAT2B, which activated RBM15 transcription. RBM15 stabilized IGFBP3 mRNA via m\n                    <jats:sup>6<\/jats:sup>\n                    A modification depending on its SPOC domain, increasing IGFBP3 protein. Nuclear translocation of IGFBP3 complexed with p-EGFR\/p-DNA-PKcs, enhancing DNA repair and reducing cisplatin-induced damage. Clinically, BCa tissues exhibited elevated LDHA\/H3K18la\/RBM15\/IGFBP3, further amplifying post-cisplatin chemotherapy. Targeting this axis with LDHA inhibitor (stiripentol) and EGFR inhibitor (gefitinib) synergistically reversed cisplatin resistance in\u00a0vitro and in\u00a0vivo. This study unveils the \u201chypoxia\u2013H3K18la\u2013RBM15\u2013IGFBP3\u201d axis as a central driver of cisplatin resistance and proposes dual metabolic\u2013epigenetic inhibition as a therapeutic strategy for refractory BCa.\n                  <\/jats:p>","DOI":"10.34133\/research.0970","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T09:17:39Z","timestamp":1760951859000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":13,"title":["Hypoxia-Induced Histone Lactylation Drives Cisplatin Resistance in Bladder Cancer by Promoting RBM15-Dependent m\n                    <sup>6<\/sup>\n                    A Methylation of IGFBP3"],"prefix":"10.34133","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8343-1583","authenticated-orcid":false,"given":"Jiazhu","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Urology, The First Affiliated Hospital, \rZhejiang 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