High levels of urinary lactate are an increased risk of progression in patients with diabetic kidney disease (DKD). However, it is still unveiled how lactate drive DKD. Epithelial-mesenchymal transition (EMT), which is characterized by the loss of epithelial cells polarity and cell-cell adhesion, and the acquisition of mesenchymal-like phenotypes, is widely recognized a critical contributor to DKD. Here, we found a switch from oxidative phosphorylation (OXPHOS) toward glycolysis in AGEs-induced renal tubular epithelial cells, thus leading to elevated levels of renal lactic acid. We demonstrated that reducing the lactate levels markedly delayed EMT progression and improved renal tubular fibrosis in DKD. Mechanically, we observed lactate increased the levels of histone H3 lysine 14 lactylation (H3K14la) in DKD. ChIP-seq & RNA-seq results showed histone lactylation contributed to EMT process by facilitating KLF5 expression. Moreover, KLF5 recognized the promotor of cdh1 and inhibited its transcription, which accelerated EMT of DKD. Additionally, nephro-specific knockdown and pharmacological inhibition of KLF5 diminished EMT development and attenuated DKD fibrosis. Thus, our study provides better understanding of epigenetic regulation of DKD pathogenesis, and new therapeutic strategy for DKD by disruption of the lactate-drived H3K14la/KLF5 pathway.

Six new benzofuran neolignans (1–6) were isolated from the EtOAc-soluble fraction of the aerial part of Aristolochia fordiana, together with twelve known analogues (7–18). The structures of the isolated compounds were elucidated by spectroscopic methods. All isolates were evaluated for their inhibitory effects on nitric oxide production in lipopolysaccaride-activated RAW264.7 macrophages and for their cytotoxic activities on three human cancer cell lines. Compound 2 showed significant nitric oxide production inhibitory activity with an IC₅₀ value of 10.00 µM, while compound 16 exhibited cytotoxic activity with an IC₅₀ value of 11.9 µM against MG-63 and compound 18 of 9.15 µM against HepG2 cell lines, respectively.