Comprehensive Evaluation of Triptolide's Therapeutic Mechanisms in Diabetic Kidney Disease via Meta-Analysis, Network Pharmacology, Molecular Docking, and Mendelian Randomization.

Introduction: Diabetic kidney disease (DKD) is a devastating complication of diabetes for which there are few potent treatments.Triptolide (TP), an active compound from Tripterygium wilfordii, has shown potential in early studies, but its therapeutic mechanisms in DKD are not fully understood. This study aims to systematically evaluate TP's efficacy and mechanisms using meta-analysis, network pharmacology, molecular docking, and Mendelian randomization (MR).

Methods: A comprehensive search across Chinese and English databases identified animal randomized controlled trials (RCTs) assessing the effects of TP on DKD. A total of 27 studies were incorporated, and a metaanalysis was conducted via Review Manager. TP's drug and disease targets were identified through network pharmacology and molecular docking, while bioinformatics methods were employed to explore the mechanisms. MR analysis was performed to assess potential causal relationships between TP and DKD-related targets.

Results: Meta-analysis showed that TP significantly reduced urinary protein, blood lipids, and glucose levels, while improving renal function, renal weight, and renal index (all p < 0.05). Seven core targets-IFNG, CXCL8, TNF, TGFB1, IL2, IL4, and RELA-were identified via network pharmacology, involving key pathways such as lipid-atherosclerosis, AGE-RAGE, and IL-17 signaling. Molecular docking demonstrated strong binding affinities between TP and these targets, with binding energies below -7.00 kJ/mol. Although MR analysis did not establish direct causal relationships between these core genes and DKD, a significant negative correlation between TNF, IL4, and GFR was observed, suggesting their involvement in DKD progression.

Discussion: TP may exert therapeutic effects on DKD through coordinated regulation of immune and inflammatory pathways. The integration of multi-omics approaches supports its multi-target pharmacological mechanisms. Although MR analysis did not confirm direct causal relationships, the identified gene associations further reinforce the potential biological relevance of TP. However, this study was primarily based on public datasets and lacks experimental validation in vivo and in vitro.

Conclusion: TP exerts therapeutic effects on DKD through multi-target and multi-pathway mechanisms, primarily involving immunomodulation, anti-inflammation, anti-oxidation, and anti-fibrosis processes.