Abstract / Summary
Abstract Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease worldwide, yet the mechanisms driving its progression are poorly understood. Here, through integrated multi-omics analyses of clinical serum samples and db/db mice, we identified a marked depletion of the glutathione biosynthetic intermediate γ-glutamylcysteine (γ-GC), which demonstrated strong diagnostic potential (AUC = 0.986). Metabolic pathway enrichment implicated γ-GC deficiency in ferroptosis regulation. Spatial transcriptomics of human renal biopsies combined with single-cell RNA sequencing of diabetic mouse kidneys revealed podocytes as the principal cell type exhibiting ferroptosis-associated transcriptional activation. In vitro, high glucose induced ferroptotic injury in podocytes, characterized by glutathione depletion, lipid peroxidation, and iron accumulation, which was blocked by the ferroptosis inhibitor Ferrostatin-1. We further showed that astragaloside IV (AS-IV) ameliorates renal dysfunction and podocyte injury by restoring γ-GC levels and suppressing ferroptosis, acting through coordinated upregulation of SLC7A11/GPX4 and inhibition of SAT1-mediated pro-ferroptotic signaling. Importantly, direct γ-GC supplementation mimicked the protective effects of AS-IV, establishing γ-GC as a critical endogenous mediator. Collectively, this study establishes a novel pathophysiological paradigm for DKD centered on γ-GC depletion-driven podocyte ferroptosis and highlights the γ-GC–ferroptosis axis as a promising therapeutic target.