This study investigates the role of lactate in driving epithelial-mesenchymal transition (EMT) in diabetic kidney disease (DKD) via the H3K14la/KLF5 pathway. Key findings include: 1. **Lactate Production and EMT**: High levels of urinary lactate are associated with an increased risk of DKD progression. The study found that lactate production increases in renal tubular epithelial cells (TECs) under conditions of oxidative stress, leading to elevated renal lactic acid levels. 2. **Mechanism of Action**: Reducing lactate levels significantly delayed EMT progression and improved renal tubular fibrosis in DKD. Mechanistically, lactate increased histone H3 lysine 14 acetylation (H3K14la), which contributed to EMT by facilitating KLF5 expression. 3. **KLF5 Regulation**: KLF5, a transcription factor, was identified as a key regulator in the EMT process. KLF5 expression was upregulated in DKD and AGEs-induced mTEC. Overexpression of KLF5 inhibited the transcription of *cdh1*, a gene involved in maintaining epithelial cell polarity, thereby promoting EMT. 4. **Therapeutic Implications**: Renal-specific knockdown of KLF5 or pharmacological inhibition of KLF5 with ML264 effectively improved EMT progression and reduced DKD fibrosis. These findings suggest that targeting the H3K14la/KLF5 pathway could be a potential therapeutic strategy for DKD. 5. **Conclusion**: The study provides new insights into the epigenetic regulation of DKD pathogenesis and highlights the potential of disrupting the lactate-driven H3K14la/KLF5 pathway as a therapeutic approach. This research contributes to the understanding of the complex etiology and mechanisms of DKD and offers a potential therapeutic target for improving renal function and reducing fibrosis in diabetic patients.This study investigates the role of lactate in driving epithelial-mesenchymal transition (EMT) in diabetic kidney disease (DKD) via the H3K14la/KLF5 pathway. Key findings include: 1. **Lactate Production and EMT**: High levels of urinary lactate are associated with an increased risk of DKD progression. The study found that lactate production increases in renal tubular epithelial cells (TECs) under conditions of oxidative stress, leading to elevated renal lactic acid levels. 2. **Mechanism of Action**: Reducing lactate levels significantly delayed EMT progression and improved renal tubular fibrosis in DKD. Mechanistically, lactate increased histone H3 lysine 14 acetylation (H3K14la), which contributed to EMT by facilitating KLF5 expression. 3. **KLF5 Regulation**: KLF5, a transcription factor, was identified as a key regulator in the EMT process. KLF5 expression was upregulated in DKD and AGEs-induced mTEC. Overexpression of KLF5 inhibited the transcription of *cdh1*, a gene involved in maintaining epithelial cell polarity, thereby promoting EMT. 4. **Therapeutic Implications**: Renal-specific knockdown of KLF5 or pharmacological inhibition of KLF5 with ML264 effectively improved EMT progression and reduced DKD fibrosis. These findings suggest that targeting the H3K14la/KLF5 pathway could be a potential therapeutic strategy for DKD. 5. **Conclusion**: The study provides new insights into the epigenetic regulation of DKD pathogenesis and highlights the potential of disrupting the lactate-driven H3K14la/KLF5 pathway as a therapeutic approach. This research contributes to the understanding of the complex etiology and mechanisms of DKD and offers a potential therapeutic target for improving renal function and reducing fibrosis in diabetic patients.