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Here we identify histone H3K18 lactylation (H3K18la), induced by GEM\u2010driven lactate accumulation, as a key epigenetic mechanism of chemoresistance. H3K18la functions as a transcriptional activator of ribosomal protein L11(RPL11) Elevated RPL11 establishes a dual, compartmentalized pro\u2010survival program: in the cytoplasm, RPL11 binds and stabilizes eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) to enhance global protein synthesis; in the nucleus, RPL11 serves as a noncanonical transcriptional coactivator of (ADP\u2010ribose) polymerase 14 (PARP14), augmenting DNA damage repair and attenuating GEM cytotoxicity. Pharmacologic or genetic inhibition of lactate production or RPL11 expression synergizes with GEM to overcome resistance and suppress PDAC progression in xenograft models. These findings define a lactate\u2013H3K18la\u2013RPL11axis that couples metabolic and epigenetic remodeling to translational control and genome maintenance, revealing actionable vulnerabilities in PDAC chemoresistance.<\/jats:p>","DOI":"10.1002\/advs.78160","type":"journal-article","created":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T07:19:32Z","timestamp":1791443972000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lactate\u2010H3K18la\u2010RPL11 Axis Drives Gemcitabine Resistance in Pancreatic Cancer by Integrating Protein Synthesis and DNA Damage Repair"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0906-8314","authenticated-orcid":false,"given":"Lijun","family":"Zhao","sequence":"first","affiliation":[{"name":"Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology Fourth Military Medical University  Xi'an Shaanxi 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