Norepinephrine promotes lung cancer cell progression via PFKFB3-promoted histone lactylation-mediated activation of the NF-κB signaling pathway.

This study aims to investigate molecular mechanisms by which norepinephrine (NE) exposure influences lung cancer cell behavior, identify key factors and pathways involved in stress-related signaling in lung cancer cells. NE was used to treat lung cancer cells (H1975) to simulate a stress-related signaling environment. PFKFB3 mRNA expression and phosphorylation levels of epithelial-mesenchymal transition (EMT) markers and key proteins in NF-κB signaling pathway were evaluated. NE significantly enhanced lung cancer cell proliferation, specifically upregulated PFKFB3 mRNA expression, promoted EMT marker (N-cadherin and Vimentin) expression, and increased cell migration capacity. Knockdown of PFKFB3 or inhibition of glycolysis reduced cell viability, lactate production, ATP levels, and expression of glycolysis-related enzymes (LDHA and GLUT1) and EMT markers, while suppressing cell migration. Combined interventions exhibited synergistic inhibitory effects. Mechanistic studies revealed that PFKFB3 knockdown inhibited phosphorylation of NF-κB pathway proteins (IKKβ, IκBα, and p65), blocked pathway activation, and reduced histone lactylation levels, particularly at the H4K12la modification site. These effects were reversed by NE intervention. This study suggests a mechanism whereby NE upregulates PFKFB3, activates glycolysis, promotes lactate production to drive histone lactylation, and activates the NF-κB signaling pathway, which is associated with EMT and cell migration.