The research reveals that lactate, the endogenous ligand of G protein-coupled receptor 81 (GPR81), promotes the production of the atheroprotective transcription factor kruppel-like factor 2 (KLF2) via the extracellular signal-regulated kinase 5 (ERK5) signaling pathway, which is crucial for preventing atherosclerosis. This evidence concerns the gene HCAR1 and atherosclerosis.