Lactate promotes epithelial-mesenchymal transition (EMT) in diabetic kidney disease (DKD) through the H3K14la/KLF5 pathway. High levels of urinary lactate are associated with increased DKD progression. EMT, characterized by loss of epithelial cell polarity and acquisition of mesenchymal traits, is a key contributor to DKD. This study shows that in AGEs-induced renal tubular epithelial cells, metabolic shift from oxidative phosphorylation to glycolysis increases lactate production, leading to EMT progression and renal fibrosis. Mechanistically, lactate increases H3K14la, which facilitates KLF5 expression. KLF5 binds to the CDH1 promoter, inhibiting E-cadherin expression and accelerating EMT. Knockdown or pharmacological inhibition of KLF5 reduces EMT and improves DKD fibrosis. These findings highlight the role of lactate-driven H3K14la/KLF5 pathway in DKD pathogenesis and suggest it as a potential therapeutic target. The study provides insights into the epigenetic regulation of DKD and offers a new therapeutic strategy.Lactate promotes epithelial-mesenchymal transition (EMT) in diabetic kidney disease (DKD) through the H3K14la/KLF5 pathway. High levels of urinary lactate are associated with increased DKD progression. EMT, characterized by loss of epithelial cell polarity and acquisition of mesenchymal traits, is a key contributor to DKD. This study shows that in AGEs-induced renal tubular epithelial cells, metabolic shift from oxidative phosphorylation to glycolysis increases lactate production, leading to EMT progression and renal fibrosis. Mechanistically, lactate increases H3K14la, which facilitates KLF5 expression. KLF5 binds to the CDH1 promoter, inhibiting E-cadherin expression and accelerating EMT. Knockdown or pharmacological inhibition of KLF5 reduces EMT and improves DKD fibrosis. These findings highlight the role of lactate-driven H3K14la/KLF5 pathway in DKD pathogenesis and suggest it as a potential therapeutic target. The study provides insights into the epigenetic regulation of DKD and offers a new therapeutic strategy.