PSMD14‐Mediated LDHA Deubiquitination Upregulates ACLY Expression via H3K18 Lactylation to Promote Lipid Synthesis and Pancreatic Cancer Progression

Abstract Aberrant lipid metabolism is intimately linked to tumor progression. As a pivotal post‐translational 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) to promote malignant progression via fatty acid synthesis pathway activation. This study reveals a previously unrecognized role of PSMD14‐derived lactate in mediating histone lactylation‐coupled lipid deposition and tumor progression. Therapeutic co‐targeting of PSMD14 and glycolytic lactylation significantly suppresses tumor growth in patient‐derived xenograft models, suggesting a promising combinatorial strategy for pancreatic cancer treatment.