Metabolite‐Guided Acetylation Therapy: Astragaloside IV Reverses Diabetic Nephropathy via Gna13‐Driven Purine Metabolic Reprogramming

ABSTRACT Diabetic nephropathy (DN) exhibits profound metabolic dysregulation, yet the spatial organization and posttranslational control of pathogenic pathways remain poorly understood. This study integrates high‐resolution MALDI mass spectrometry imaging (MSI) and acetylproteomics to unveil purine‐acetylation crosstalk in DN progression. Our spatial metabolomics approach revealed zonation‐specific accumulation of purine metabolites in diabetic kidneys, with distinct distribution patterns across cortical and medullary regions. Parallel acetylproteomic analysis identified 65 lysine acetylation sites, with Gna13‐K363 emerging as a critical regulatory node, showing marked downregulation in db/db mice. Astragaloside IV (ASIV), a bioactive compound from Astragalus membranaceus , restored Gna13 acetylation and normalized purine metabolite distributions. Multi‐platform validation across human DN sera, diabetic mouse tissues, and MPC‐5 cells demonstrated strong correlations between purine metabolites and clinical indicators, highlighting Gna13 acetylation status as a determinant of purine‐mediated renal injury. ASIV's therapeutic efficacy was linked to Gna13‐driven purine metabolic reprogramming, offering a novel metabolite‐guided acetylation therapy for DN. This study provides the spatial visualization of purine metabolic zonation in DN, proposing region‐specific metabolic therapy and establishing Gna13‐K363 as a promising therapeutic target. Our findings bridge food‐derived bioactive compounds with precision medicine, advancing dietary interventions for metabolic disorders.