Network Pharmacology Combined With Gut Microbiome and Serum Metabolomics Reveals the Therapeutic Mechanisms of Hydroxysafflor Yellow A in Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a severe complication of diabetes, primarily driven by chronic inflammation, oxidative stress, and gut microbiota dysbiosis. Hydroxysafflor yellow A (HSY), a bioactive compound derived from Carthamus tinctorius L., demonstrates promising renoprotective effects. However, its mechanisms, especially through modulation of the gut–kidney axis, remain poorly understood. This study employed a combination of network pharmacology, a high‐fat diet/streptozotocin‐induced type 2 diabetic mouse model, 16S rRNA sequencing, and serum metabolomics to explore the therapeutic mechanisms of HSY. Renal function, oxidative stress, inflammation, and gut microbiota composition were evaluated. HSY significantly alleviated renal injury by reducing blood glucose, creatinine, and urea nitrogen levels ( p < 0.05), while enhancing renal antioxidant enzyme activity (GSH, SOD, CAT). Inflammatory markers (TNF‐α, IL‐1β) and AGE–RAGE signaling were suppressed. Analysis of the gut microbiota revealed that HSY enriched SCFA‐producing genera (e.g., Lactobacillus, Alloprevotella) and decreased the abundance of Schaedlerella. Serum metabolomics further indicated that HSY modulated riboflavin metabolism, linoleic acid metabolism, and steroid hormone biosynthesis, thereby linking microbial metabolites to renal protection. Spearman correlation analysis revealed strong associations between specific gut microbiota (e.g., Prevotella) and serum metabolites (e.g., eicosapentaenoic acid). HSY mitigates DKD by targeting AGE–RAGE‐mediated inflammation, oxidative stress, and gut microbiota dysbiosis while correcting metabolic disturbances. This study offers a novel multi‐omics approach to understanding HSY’s renoprotective effects, highlighting its potential as a therapeutic agent for DKD.