Lactate-induced epithelial-mesenchymal transition: a metabolic nexus in pancreatic cancer metastasis

Lactate-driven epithelial-mesenchymal transition (EMT) constitutes a pivotal metabolic hub in pancreatic ductal adenocarcinoma (PDAC). PDAC is a highly lethal malignancy characterized by early metastasis, pronounced chemotherapy resistance, and poor prognosis, in which epithelial-mesenchymal plasticity (EMP) acts as the core mechanism driving malignant progression. Metabolic reprogramming represented by the Warburg effect leads to massive lactate accumulation in PDAC. Lactate is no longer regarded as an inert metabolic end product, but serves as a critical energy substrate, signaling molecule, and epigenetic modifier that mediates histone lactylation. This review systematically elaborates the unique characteristics of lactate metabolism in PDAC, including efficient lactate production driven by oncogenic mutations and hypoxic microenvironment, transmembrane transport via monocarboxylate transporters (MCTs), intracellular metabolic fate, and protein lactylation modification. It further summarizes the core mechanisms by which lactate metabolism regulates EMP, including direct regulation through lactate itself and lactylation modification, activation of signaling pathways such as TGF-β, GSK-3β, and YAP/TAZ-Hedgehog, as well as remodeling of tumor microenvironment (TME) involving cancer-associated fibroblasts (CAFs) and immune cells. Finally, therapeutic strategies targeting the lactate metabolism-EMP axis are discussed, covering inhibition of lactate production and transport, precise intervention of lactylation modification, and neutralization of TME acidification, aiming to provide novel theoretical basis and intervention targets for overcoming metastasis and chemotherapy resistance in PDAC.