MAPK14/SLC7A11/GPX4 axis dysregulation drives podocyte ferroptosis via mediating glycerophospholipid metabolism

Diabetic nephropathy (DN), the leading cause of end-stage renal disease, lacks effective therapies due to an incomplete understanding of its cell-type-specific pathogenesis. Here, through an integrative multi-omics approach, we have decoded the molecular architecture of DN, identify novel therapeutic targets, and validates a promising intervention. Single-cell RNA sequencing of human diabetic kidneys reveals the podocyte as the central cellular nexus of DN, exhibiting specific dysregulation in ferroptosis and glycerophospholipid metabolism, and possessing superior diagnostic potential. High-resolution analysis of podocyte heterogeneity identifies ferroptosis as a key driver of glomerular injury, centered on the dysregulated genes MAPK14/SLC7A11/GPX4. We further demonstrated that astragaloside IV (ASIV) exerts potential protective effects by specifically targeting the ferroptosis pathway, reversing the diabetic transcriptional landscape and preserving podocyte integrity. Spatial metabolomics uncovers profound anatomical compartmentalization of metabolic dysregulation in the renal cortex and medulla, which is effectively regulated by ASIV. Integrated transcriptomic and metabolomic profiling in vitro definitively establishes ferroptosis inhibition as the core mechanism of ASIV-mediated podocyte protection. Finally, clinical metabolomic profiling identifies urinary metabolic intermediates of glycerophospholipid metabolism as highly sensitive and specific non-invasive biomarkers for its diagnosis. Our study delineates a fundamental research framework for DN, from basic mechanism to targeted therapy and precision diagnostics.