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As a pivotal post\u2010translational modification, ubiquitination regulates diverse oncogenic processes. However, the interplay between ubiquitination and lipid metabolic dysregulation in pancreatic cancer (PC), along with its underlying molecular mechanisms, remains poorly understood. Here, it is demonstrated that glycolytic enzyme lactate dehydrogenase A (LDHA) potentiates lipid biosynthesis under the regulation of deubiquitinases. Specifically, PSMD14 directly binds and stabilizes LDHA through its deubiquitinase activity, resulting in intracellular lactate accumulation. Elevated lactate levels enhance histone lactylation marks, which transcriptionally activate ATP citrate lyase (ACLY)\u00a0to promote malignant progression via fatty acid synthesis pathway activation. This study reveals a previously unrecognized role of PSMD14\u2010derived lactate in mediating histone lactylation\u2010coupled lipid deposition and tumor progression. Therapeutic co\u2010targeting of PSMD14 and glycolytic lactylation significantly suppresses tumor growth in patient\u2010derived xenograft models, suggesting a promising combinatorial strategy for pancreatic cancer treatment.<\/jats:p>","DOI":"10.1002\/advs.202505762","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T23:41:07Z","timestamp":1759794067000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["PSMD14\u2010Mediated LDHA Deubiquitination Upregulates ACLY Expression via H3K18 Lactylation to Promote Lipid Synthesis and Pancreatic Cancer Progression"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7078-6862","authenticated-orcid":false,"given":"Ri\u2010Shang","family":"Lu","sequence":"first","affiliation":[{"name":"School of Clinical Medicine Guizhou Medical University  Guiyang 550004 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