Mechanistic Elucidation of Yiqi Yangyin Qingre Decoction in Diabetic Nephropathy Therapy via Network Pharmacology and In Vivo Validation
TL;DR
YQYYQR exerts a protective effect against DN progression by targeting core genes including GSK3β, regulating the GSK3β‐TFEB axis to restore autophagic flux via the autophagy‐lysosomal pathway, and inhibiting NLRP3‐mediated pyroptosis to mitigate excessive renal inflammation.
Abstract
Background Diabetic nephropathy (DN) is a serious microvascular complication of diabetes that urgently requires effective treatments with low toxicity. The traditional Chinese medicine formula Yiqi Yangyin Qingre decoction (YQYYQR) has demonstrated potential in alleviating DN, yet its pharmacological mechanism remains unclear. Methods UPLC‐MS/MS combined with network pharmacology was utilized to qualitatively analyze YQYYQR′s bioactive components and predict therapeutic targets. Integrating public databases and GEO‐derived DN‐related genes, core targets were identified via intersection and subjected to pathway enrichment. Molecular docking validated key component–core target interactions, with in vivo DN mouse experiments and transcriptome sequencing performed for verification. Results This study identified 376 bioactive components from YQYYQR, corresponding to 1284 potential therapeutic targets. Cross‐analysis between these targets and DN‐related genes yielded 57 overlapping targets, among which GSK3β and NFKB1 were screened as core hub genes. Network pharmacology and transcriptomic pathway enrichment analyses indicated that the mechanism of YQYYQR in intervening DN involves biological processes such as autophagy and inflammatory response. In vivo, YQYYQR significantly improved mouse proteinuria and renal function and alleviated pathological kidney damage. Mechanistically, YQYYQR enhanced the inhibitory phosphorylation of GSK3β at Ser9, thereby facilitating TFEB nuclear translocation and activating the autophagy‐lysosomal pathway. Simultaneously, it suppresses the NLRP3/ASC/caspase‐1/GSDMD‐N–mediated pyroptosis pathway, ultimately reducing renal inflammation. Conclusion YQYYQR exerts a protective effect against DN progression by targeting core genes including GSK3β, regulating the GSK3β‐TFEB axis to restore autophagic flux via the autophagy‐lysosomal pathway, and inhibiting NLRP3‐mediated pyroptosis to mitigate excessive renal inflammation.