AIM: To explore the potential of Huangqi sanqi mixture (AP) in improving renal fibrosis by performing transcriptome sequencing of the kidneys of the unilateral ureteral ligation mouse group and the Huangqi sanqi mixture intervention group, and using bioinformatics to verify the signitficantly different IncRNAs mechanism. METHODS: Twenty-four C57 mice were divided into sham operation group, renal fibrosis group, Huangqi sanqi mixture intervention group (3.944 g/kg) and irbesartan positive control intervention group, with 6 mice in each group. A mouse model of renal fibrosis was established by unilateral ureteral ligation (UUO). The animals were given intragastric administration after operation, and the animals were sacrificed and the specimens were collected after seven consecutive days of administration. The changes of Huangqi sanqi mixture on renal fibrosis pathological damage were analyzed by HE and Masson staining, and the protein levels of Fn and α-SMA in renal tissue of each group were detected by Western blot and immunohistochemistry to evaluate the alleviating effect of Huangqi sanqi mixture on renal fibrosis. Subsequently, lncRNA expression information was obtained by transcriptome sequencing, and Quantitative Real-time PCR (qPCR) was performed after data quality, GO enrichment and differential lncRNA were analyzed. According to the differential lncRNA and target analysis results obtained by sequencing, lncRNA Gm51500/Adam12 was overexpressed in vitro, and its mechanism in the protection of renal fibrosis by Huangqi sanqi mixture was studied by immunohistochemistry, immunofluorescence staining and qPCR verification. RESULTS: Compared with the model group, the renal fibrosis of the mice in the Huangqi sanqi mixture intervention group was significantly reduced, and the protein levels of α-SMA and Fn and the expression of IncRNA in the renal tissue were significantly down-regulated (P<0.000 1). Three lncRNAs were screened and verified to increase in the model group and significantly decrease after AP intervention, namely lncRNA Gm29994, Gm51500 and Gm35391. Target analysis showed that lncRNA Gm51500 had the most significant relationship with Adam12. The results of animal experiments showed that Adam12 was highly expressed in the kidney of UUO mice and was significantly inhibited after AP intervention. Subsequent cell experiments confirmed that overexpression of lncRNA Gm51500 could up-regulate TGF-β-induced renal tubular cell fibrosis and Adam12 expression. Cell recovery experiments confirmed that Adam12 overexpression reversed the inhibitory effect of AP on renal tubular cell injury and fibrosis. CONCLUSION: Huangqi sanqi mixture can improve renal fibrosis. Based on transcriptomic sequencing, lncRNA Gm51500/Adam12 axis may be a potential target for Huangqi sanqi mixture to improve renal fibrosis.