Astragaloside IV ameliorates diabetic kidney disease by modulating the PHD2/HIF-1α axis and inhibiting podocyte...

Diabetic kidney disease (DKD) lacks therapies that directly target podocyte injury, and the upstream regulation of HIF-1α-driven ferroptosis in podocytes remains unclear. This study investigated whether astragaloside IV (AS-IV) protects against DKD by regulating the PHD2/HIF-1α axis. A DKD mouse model was induced by a high-fat/high-sugar diet plus streptozotocin, followed by AS-IV intervention (100 mg/kg/day for 12 weeks). In vitro, podocytes were exposed to high glucose (30 mM) with AS-IV (40 μmol/L), along with the HIF-1α inhibitor LW6 or activator DMOG. Network pharmacology and molecular docking identified HIF-1α signaling as a core pathway, with stable binding of AS-IV to PHD2 and HIF-1α. AS-IV improved renal function and pathology in DKD mice without affecting blood glucose. In vivo and in vitro, AS-IV activated PHD2, promoted HIF-1α ubiquitination and degradation, and subsequently inhibited podocyte ferroptosis, as shown by reduced iron accumulation and lipid peroxidation, and upregulated GPX4 and SLC7A11. Additionally, AS-IV suppressed pyroptosis and inflammation (reduced NLRP3, GSDMD-NT, IL-1β, IL-18) and modulated apoptosis (increased Bcl2). In conclusion, the renoprotective effect of AS-IV is mediated through the PHD2/HIF-1α axis, reducing HIF-1α accumulation and thereby inhibiting podocyte ferroptosis, pyroptosis, inflammation, and fibrosis in DKD. These findings provide a novel mechanistic foundation for AS-IV as a prospective therapeutic agent for DKD.