Zhengyi Xie

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.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a dismal 5‑year survival rate of ~9%, primarily due to late diagnosis, aggressive metastasis and profound resistance to conventional therapies. Epithelial‑mesenchymal transition (EMT) has been identified as a pivotal driver of these malignant phenotypes, facilitating early invasion, dissemination and treatment failure. The present review systematically elaborated on the multidimensional mechanisms underlying EMT in PDAC, emphasizing its operation as a spectrum of hybrid epithelial/mesenchymal states rather than a binary switch. Key molecular mechanisms include the activation of core transcription factors (such as Snail, ZEB, Twist), intricate crosstalk within the tumor microenvironment (such as transforming growth factor-β and hepatocyte growth factor signaling from stromal cells) and dynamic epigenetic reprogramming. Furthermore, EMT critically contributes to the acquisition of cancer stem cell properties and enhances the survival and colonization of circulating tumor cells. The present review also outlined emerging translational strategies targeting EMT‑related pathways, highlighting agents such as STNM01 that have entered early-phase clinical trials. By synthesizing unprecedented insights into EMT's plastic spectrum states and subtype‑specific regulatory networks, this work establishes a paradigm‑shifting framework for advancing EMT‑targeted therapies; offering transformative potential to overcome PDAC's historical therapeutic barriers and substantially improve patient survival outcomes. By synthesizing current insights from molecular pathways to therapeutic applications, the present review confirmed EMT as a promising therapeutic target and provides a strategic framework for advancing PDAC treatment, with the ultimate goal of improving clinical outcomes.

This review provides an in-depth exploration of the intricate energy metabolism pathways within the brain, with a particular focus on the dynamic interplay between neurons, astrocytes, and microglia. Neurons, with their high energy demands, primarily rely on oxidative phosphorylation and the tricarboxylic acid (TCA) cycle to sustain synaptic activity and neurotransmitter synthesis. In contrast, astrocytes predominantly engage in glycolysis, producing lactate and glutathione, which are essential for supporting neuronal function and protecting against oxidative stress. Additionally, microglia, the brain’s resident immune cells, exhibit a metabolic flexibility that allows them to shift between oxidative phosphorylation and glycolysis, depending on their activation state, which significantly influences neuroinflammation and synaptic plasticity. The review highlights the critical role of astrocyte-neuron metabolic coupling, particularly through the lactate shuttle and glutathione metabolism, in maintaining neuronal homeostasis and facilitating synaptic function. It also delves into the metabolic underpinnings of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Amyotrophic Lateral Sclerosis, illustrating how disruptions in brain energy metabolism contribute to disease progression. By synthesizing recent findings, this review not only underscores the centrality of brain energy metabolism in both normal and pathological conditions but also identifies potential therapeutic targets aimed at modulating these metabolic pathways to mitigate the effects of neurodegenerative disorders. This comprehensive analysis offers valuable insights that could propel further research and innovation in the field of neurology, making it essential reading for experts interested in the molecular mechanisms underlying brain function and disease.