Science子刊：老药新用！刘志红院士团队破解阿卡波糖保护肾脏新机制

Core Viewpoint - The study reveals the critical role of the deubiquitinating enzyme USP46 in maintaining podocyte function and regulating podocyte injury in diabetic nephropathy (DN), highlighting the potential of targeting USP46 for therapeutic intervention in DN [3][4][10]. Group 1: Research Findings - The research published in Science Translational Medicine demonstrates that USP46 expression is significantly correlated with renal function in patients, with higher levels associated with better kidney function and lower proteinuria [5]. - The study constructed podocyte-specific Usp46 knockout mice, which exhibited spontaneous proteinuria and severe podocyte injury, indicating that USP46 is essential for podocyte structural integrity [5]. - In vitro studies showed that knocking down USP46 led to the accumulation of ubiquitinated proteins, particularly TDP-43, suggesting a proteinopathy characteristic in diabetic conditions [6]. Group 2: Mechanism of Action - USP46 maintains podocyte function by preventing the cytoplasmic mislocalization and aggregation of TDP-43, which is crucial for podocyte health [6][10]. - The research identified that the interaction between USP46 and its ligands WDR20 and WDR48 is essential for its enzymatic activity, leading to the discovery that acarbose can activate USP46 [8][9]. Group 3: Therapeutic Implications - Acarbose, traditionally an oral hypoglycemic agent, was found to have a direct protective effect on podocytes when administered subcutaneously, independent of its glucose-lowering effects [9][10]. - The study suggests that acarbose can significantly improve podocyte injury and reduce proteinuria in diabetic models, providing a new therapeutic avenue for DN [9][10]. - The findings support the development of new drugs targeting the ubiquitin-proteasome system (UPS) to stabilize podocyte function and treat chronic kidney diseases [10].