Diabetic nephropathy (DN) pathogenesis remains elusive due to the lack of comprehensive spatial molecular characterization related to tissue pathological signatures. Here, we construct the spatial single-cell atlas of human DN kidneys using clinical formalin-fixed paraffin-embedded (FFPE) biopsies, integrating spatial transcriptomics, metabolomics, and scRNA-seq across 39,006 cells. We identify podocytes as spatial metabolic-inflammatory hubs orchestrating DN progression, exhibiting conserved dysregulation of glycerolipid metabolism and MAPK signaling in human and diabetic mice kidneys. Spatial multi-omics of inflammatory and glomerular injury zones reveal 179 and 234 differentially expressed genes enriched in MAPK pathways. Crucially, urinary MMP3, traced to glomerular injury zones, emerges as a non-invasive diagnostic biomarker. We further demonstrate that astragaloside IV (ASIV) attenuates DN by dual targeting: rescuing DUSP4-mediated MAPK suppression (reducing p-p38/JNK) and normalizing glycerolipid metabolites (D-glycerate, 3-PGA), thereby downregulating MMP3/IL-6/IL-1β and suppressing oxidative stress in podocytes. This work redefines DN as a disorder of spatially organized metabolic-inflammation synergy, establishing urinary MMP3 for clinical detection and ASIV as a therapeutic agent targeting the DUSP4-MAPK-glycerolipid axis, providing a roadmap for precision interventions in DN.
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