Lactylation in pancreatic cancer: From molecular mechanisms to therapeutic perspectives

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterized by intense metabolic reprogramming and an immunosuppressive tumor microenvironment. The recent discovery of lactylation, a novel post-translational modification derived from lactate, provides a direct molecular link between glycolysis and the regulation of gene expression. This review synthesizes the emerging role of lactylation in PDAC pathogenesis. We detail how a lactate-rich microenvironment fuels the lactylation of histones and non-histone proteins, driving oncogenic processes such as transcriptional reprogramming, maintenance of lineage plasticity, and therapeutic resistance. Furthermore, lactylation in stromal and immune cells reinforces immunosuppression, facilitating tumor progression. We critically evaluate the translational potential of targeting this axis through inhibitors of lactate production, transport, or the epigenetic writers themselves. While promising, these strategies face significant challenges, including achieving molecular specificity and overcoming drug delivery barriers in PDAC. We conclude that lactylation represents a critical metabolic-epigenetic link in PDAC and a compelling therapeutic target worthy of further investigation.