Shi Qiu, Zhibo Wang, Sifan Guo, Dandan Xie, Ying Cai, Xian Wang, Qiang Yang, Qiqi Zhao, YU JIE GUAN, Chunsheng Lin, Hong Yao, Songqi Tang, Wenjie Sun, Yiqiang Xie, Aihua Zhang
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.