Metabolic Memory-Mediated Epigenetic Regulation of EMT in Diabetic Kidney Disease: Mechanisms and Therapeutic Implications

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, with renal fibrosis as its core pathological hallmark. A central driver of this fibrosis is epithelial–mesenchymal transition (EMT), during which renal tubular epithelial cells transform into matrix-producing myofibroblasts. Endothelial–mesenchymal transition (EndMT) has also emerged as a critical contributor, and together with EMT, accounts for the progressive accumulation of myofibroblasts and extracellular matrix. A major clinical challenge in halting DKD progression is “metabolic memory”, a phenomenon whereby renal injury persists and EMT/EndMT remain activated even after glycemic control is achieved. The molecular basis underlying this sustained activation remains incompletely understood. Emerging evidence indicates that metabolic memory is largely mediated by epigenetic mechanisms, including histone modifications, DNA methylation, and non-coding RNA dysregulation. These stable epigenetic imprints maintain the persistent activation of key pro-fibrotic signaling pathways, especially TGF-β, thereby continuously driving EMT, EndMT, and excessive extracellular matrix deposition. Although targeting epigenetic regulators has shown promising anti-fibrotic effects, a systematic review that integrates how metabolic memory orchestrates both EMT and EndMT through a multi-layered epigenetic network remains lacking. This review comprehensively summarizes the epigenetic mechanisms by which metabolic memory sustains EMT and EndMT in DKD, highlights key therapeutic targets, and discusses their translational and clinical implications.