Global profiling of protein lactylation in pancreatic ductal adenocarcinoma.

Cancer cells dramatically increase L-lactate production, fueling lysine lactylation (Kla) – a posttranslational modification that rewires protein function and links metabolic flux to gene and pathway regulation. Although emerging studies implicate Kla in diverse diseases, its role in pancreatic ductal adenocarcinoma (PDAC) remains poorly understood. Here, we performed global lactylomic profiling of immunoprecipitated lactylated proteins from PDAC and normal pancreatic cell lines, as well as from patient-derived tumors and adjacent normal tissues. Mass spectrometry revealed distinct Kla signatures that separated PDAC from normal pancreas, with a higher number of Kla sites per protein in tumors. Functional enrichment analysis with the Database for Annotation, Visualization, and Integrated Discovery (DAVID) revealed significant enrichment of lactylated proteins involved in metabolic and signaling pathways, including insulin resistance and choline metabolism, in PDAC. The analysis also shows that PDAC cells and tumors exhibit preferential Kla associated with neurodevelopmental disorders, particularly intellectual disability. These findings suggest that Kla distinguishes PDAC from normal pancreas and may provide molecular insight into the metabolic and neurological comorbidities observed in cancer.