To explore the molecular mechanism of Huoxue Jiangtang Decoction in the treatment of diabetic nephropathy.Methods:The diabetic nephropathy model was established by feeding high fat diet and injecting streptozotocin (STZ) through tail vein.The model rats were randomly divided into a diabetic nephropathy (DN) group,a model+biguanide+traditional Chinese medicine (DN+Met+ZY) model+biguanide+captopril (DN+Met+CP) group.The corresponding drugs were given by gavage,and another normal control group was set up,with 10 rats in each group.The changes of fasting blood glucose (FBG),blood lipid,serum urea nitrogen (BUN),serum creatinine (SCR),24 h urinary protein (24 h UTP) and urinary microalbumin (24h mAlb) were observed.The pathological changes of renal tissue were observed,and RNA-seq sequencing was performed in each group.Results:Compared with the model group,the levels of FBG,TC,TG,LDL-C,SCR,bun,24 h UTP and 24 h mAlb were significantly decreased in the Chinese medicine group and captopril group,but HDL-C had no significant change; compared with captopril group,FBG,TC,TG and LDL-C in Chinese medicine group decreased significantly,while there were no significant difference in HDL-C,SCR,bun,24 h UTP and 24 h mAlb.Compared with the model group,the Chinese medicine group and captopril group can significantly improve the renal pathological changes of diabetic nephropathy rats.The results of transcriptome sequencing showed that the total number of genes in the transcripts of model group vs normal group and traditional Chinese medicine group vs model group was close,and 10 bidirectional regulatory genes with the most obvious expression difference were screened out; the analysis of the first 20 KEGG rich pathways showed that the metabolic pathway and cAMP signaling pathway were involved in the model group vs the normal group and the Chinese medicine group vs the model group.Conclusion:Huoxue Jiangtang Drink combined with metformin can improve the disorder of glucose and lipid metabolism,reduce the excretion of urinary albumin,improve renal function and pathological changes,and delay the progression of diabetic nephropathy.Its mechanism may be mediated by multiple pathways such as CFTR,PDK4,ANGPTL4 and hmgcs2 etc.