Integrating lipidomics, 16S rRNA sequencing, and network pharmacology to explore the mechanism of Qikui granule in treating diabetic kidney disease mice.

Qikui granule (QKG), a hospital preparation of traditional Chinese medicine, has been widely used for diabetic kidney disease (DKD) in clinical practice. However, its holistic therapeutic effects and the underlying therapeutic mechanisms remain unclear. In the present study, the integrated analysis of network pharmacology, 16S rRNA sequencing, and non-targeted lipidomics was performed to explore the anti-DKD effects of QKG and the underlying mechanisms in db/db mouse DKD model. The results of the network pharmacology analysis identified the PI3K-AKT, EGFR, MAPK, JAK-STAT, FoxO, and AGE-RAGE signaling pathways as the potential molecular mechanisms responsible for the efficacy of QKG. Importantly, these signaling pathways were found to be closely related to lipid metabolism and gut microbiota. The therapeutic effectiveness of QKG against DKD was manifested by reducing body weight, alleviating oxidative stress, improving kidney function indicators, promoting the recovery of renal histopathological damage, and regulating the lipid metabolic profile of serum and kidney in db/db mice. A total of 26 lipid metabolites were identified as potential pharmacological biomarkers (PPBs) of QKG for the treatment of DKD, which were mainly involved in glycerophospholipid metabolism. Meanwhile, QKG could alleviate DKD-induced gut microbiota dysbiosis primarily by enriching Candidatus_Arthromitus, which showed a negative correlation with all 26 lipid PPBs as well as 5 biochemical parameters, including 2 oxidative stress factors and 3 kidney function indices. In conclusion, our findings suggest that QKG may upregulate the gut level of Candidatus_Arthromitus to suppress the abnormal activation of PI3K-AKT related signaling pathway, thereby reducing the levels of PC and LPC in the glycerophospholipid metabolism, to finally ameliorate the progression of DKD in db/db mice.