Astragaloside IV Reprograms Spatial Glycolytic Metabolism in Diabetic Kidney: A Microenvironment‐Targeted Immunometabolic Therapeutic Strategy

ABSTRACT Diabetic nephropathy (DN) remains a major cause of kidney failure, yet current therapies do not adequately target the spatially organized immunometabolic dysfunction that drives disease progression. Astragaloside IV (ASIV), a bioactive saponin derived from Astragalus membranaceus , exhibits potential for multi‐target intervention, but its precise mechanisms of action within the renal microenvironment remain unclear. Here, we integrate high‐resolution spatial transcriptomics (10× Visium HD), matrix‐assisted laser desorption/ionization (MALDI) mass spectrometry imaging (10 µm), and single‐cell RNA‐seq to delineate how ASIV modulates podocyte–macrophage crosstalk in human diabetic kidney tissues. We reveal that ASIV restores glycolytic homeostasis by reversing a terminal glycolytic blockade characterized by lactate (Lac) and dihydroxyacetone phosphate accumulation, while simultaneously suppressing NF‐κB activation in macrophages and upregulating S1pr1 expression in podocytes. Spatially resolved metabolomics demonstrates that ASIV normalizes metabolite distribution and disrupts feedforward inflammatory‐metabolic loops. Clinically, the Lac/2‐PG ratio, reflective of this dysregulation, achieves a high diagnostic accuracy (AUC = 0.978). Our findings indicate that ASIV acts as a dual‐pathway immunometabolic modulator, providing a microenvironment‐targeted therapeutic strategy that shifts DN management toward spatially guided, natural product‐based interventions.