Epigenetic regulation of tubular epithelial cell dysfunction in diabetic kidney disease.

Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease. Recent studies have shown that tubular epithelial cells (TECs) are not merely passive targets of injury, but rather key drivers throughout the initiation and progression of DKD. Under persistent hyperglycemia and metabolic stress, TECs undergo metabolic reprogramming, continuous inflammatory activation, and aberrant cell fate transitions, which ultimately promote the progression of tubulointerstitial fibrosis. Emerging studies further suggest that epigenetic regulation plays a central role in maintaining these pathological alterations and may represent a key molecular basis for the "metabolic memory" of DKD. In this review, we systematically summarize the epigenetic mechanisms associated with TEC dysfunction in DKD, including DNA methylation, histone modifications, non-coding RNAs, and RNA modifications. In addition, we comprehensively discuss recent therapeutic strategies targeting epigenetic abnormalities and discuss their translational potential and current challenges. In general, epigenetic regulation provides a new conceptual framework for understanding TEC dysfunction in DKD and provides a potential direction for the development of precision therapeutic strategies.