The interplay of Drp1 post-translational modifications as a regulatory network driving mitochondrial fission in diabetic kidney disease

Diabetic Kidney Disease (DKD) is the primary cause of end-stage renal disease (ESRD), with renal interstitial fibrosis being the core driver of its progression. Mitochondrial dynamics imbalance, particularly excessive fission, has become a key mechanism driving fibrosis. This review focuses on post-translational modifications (PTMs) of dynamin-related protein 1 (Drp1), systematically elucidating how it acts as a dynamic regulatory node to abnormally activate in the metabolic dysregulation microenvironment of diabetes, thereby initiating the pathological cascade of mitochondrial hyperfission. This review transcends the limitations of single modification research by elucidating the regulatory mechanisms and cross-talk of PTMs networks under DKD from the perspective of Drp1, revealing the fine encoding of “modifier codes” for pathological activation of Drp1. This process promotes fibrosis progression through three pathways: impairing renal tubular epithelial cell function, triggering mitochondrial derived inflammation, and activating fibroblasts. In addition, this review summarizes the model and methodological advancements in DKD fibrosis research. It objectively analyzes the technical bottlenecks, spatiotemporal complexity, and translational challenges in PTMs network studies. The study explores therapeutic strategies involving direct targeting of Drp1 and its pathological modification sites, as well as indirect modulation of upstream pathways. The aim is to provide theoretical foundations and prospective directions for interventions in diabetic kidney fibrosis.