Andrographolide alleviates type 2 diabetic nephropathy through suppressing PI3K/AKT1/RRM2-triggered oxeiptosis

Type 2 diabetic nephropathy (T2DN) stands as a critical microvascular complication of type 2 diabetes, and current pharmacological interventions remain necessitate refinement and supplement. Through network pharmacology and preliminary screening, andrographolide (AND) emerged as a potential intervention. A canine T2DN model, established via high-fat and high-carbohydrate diet and streptozotocin, exhibited hallmark metabolic dysfunction (hyperglycemia, insulin resistance, hyperinsulinemia, glycosuria) and renal pathology (reduced Glomerular filtration capacity, fibrosis). AND administration ameliorated glycemic homeostasis, insulin sensitivity, and renal function. Integrated transcriptomic profiling revealed T2DN progression mechanistically linked to PI3K/AKT1 signaling activation, RRM2 upregulation, and hydrogen peroxide-predominant ROS response, with subsequent experimental validation confirming ROS-dependent oxeiptosis induction through PI3K/AKT1/RRM2 axis hyperactivation. Mechanistically, T2DN exacerbates renal damage via a self-amplifying loop: hyperglycemia-stimulated ROS overproduction drives PI3K/AKT1-mediated RRM2 upregulation, which in turn promotes oxeiptosis. Crucially, AND interrupts this pathogenic cascade by suppressing PI3K/AKT1/RRM2 signaling hyperactivity and inhibiting ROS-oxeiptosis crosstalk, thereby establishing its therapeutic potential as a novel multi-target supplement for T2DN management. These findings provide both translational guidance for clinical strategies targeting the PI3K/AKT1/RRM2-oxeiptosis axis and mechanistic rationale for AND-based therapeutic development.