Metabolic Reprogramming and Epigenetic Regulation: The Dual Role of Lactate and Lactylation in Pancreatic Ductal Adenocarcinoma Progression and Therapeutics

Pancreatic ductal adenocarcinoma is a highly aggressive gastrointestinal malignancy with an extremely poor prognosis. Metabolic reprogramming serves as a key driver of its growth and invasion. Substantial evidence indicates that lactate, a product of glucose metabolic reprogramming, plays a crucial role in tumorigenesis and progression. Beyond its traditional view as a waste product, lactate functions as a metabolic fuel, signaling molecule, and epigenetic modification substrate, exhibiting pleiotropic roles in tumor proliferation, invasion, and immune suppression. Notably, lactate-mediated histone and non-histone lactylation exerts crucial regulatory effects across tumor cells, immune cells, and stromal cells within the cancer microenvironment. Inhibitors targeting key lactate-metabolizing enzymes and transporters, along with combinatorial therapeutic strategies, represent potential avenues for the future precision treatment of pancreatic ductal adenocarcinoma. This systematic review summarizes research advances on lactate metabolism and lactylation modification in pancreatic ductal adenocarcinoma, aiming to provide insights for the future exploration of lactate regulatory networks and the development of precision targeted therapies.