To observe the effects of Shenshuai Xiezhuo Decoction(SSXD) on chronic renal failure(CRF) rats induced by adenine and on fibrosis in human renal proximal tubular epithelial cells(HK-2 cells) intervened by transforming growth factor-β1(TGF-β1)，and to explore its potential mechanism via the let-7b-5p microRNA/TGF-β receptor I(TGF-βR1) axis.Methods:Thirty-two Sprague-Dawley(SD) rats were randomly divided into four groups:normal，model，and SSXD(18.75 g/kg，37.5 g/kg) groups，with 8 rats in each group.CRF was induced by oral administration of adenine for 21 days，and SSXD was administered to the corresponding groups for 28 days.The normal and model groups were given an equal volume of saline.HK-2 cells were divided into normal，model，10% drug-containing serum，and 20% drug-containing serum groups，with TGF-β1 treatment for 24 hours to construct a fibrosis model.Drug-containing serum groups were treated with the corresponding concentrations of drug-containing serum.Serum creatinine(Scr) and blood urea nitrogen(BUN) levels in rats were measured.Hematoxylin-eosin(HE) staining was used to evaluate kidney tissue pathology.Immunohistochemical analysis was performed to detect the expression of TGF-βR1，collagen I(Collagen I)，α-smooth muscle actin(α-SMA)，and fibronectin(FN) in kidney tissues.Quantitative real-time PCR(qRT-PCR) was used to measure the expression of let-7b-5p microRNA in kidney tissues and HK-2 cells.Western blot was used to detect the protein expression of TGF-βR1，Collagen I，α-SMA，and FN in HK-2 cells.Results:1) In vivo results:Compared with the normal group，the model group showed higher serum levels of Scr and BUN(P<0.05).Compared with the model group，the SSXD 18.75 g/kg and 37.5 g/kg groups had lower serum Scr and BUN levels(P<0.05).The SSXD 37.5 g/kg group showed significantly lower Scr and BUN levels than the 18.75 g/kg group(P<0.05).Compared with the model group，kidney tissue inflammation，fibrosis，and structural damage were improved in the SSXD groups，and crystal precipitation was reduced.In the model group，TGF-βR1，Collagen I，α-SMA，and FN protein expression in kidney tissue was higher than that in the normal group(P<0.05).Compared with the model group，the SSXD 18.75 g/kg and 37.5 g/kg groups had lower expression of TGF-βR1，Collagen I，α-SMA，and FN proteins in kidney tissue(P<0.05).The SSXD 37.5 g/kg group had significantly lower expression of Collagen I and FN than the 18.75 g/kg group(P<0.05).Compared with the normal group，let-7b-5p expression in the model group was lower(P<0.05)，while it was higher in the SSXD 18.75 g/kg and 37.5 g/kg groups compared to the model group(P<0.05).The SSXD 37.5 g/kg group had significantly higher let-7b-5p expression compared to the 18.75 g/kg group(P<0.05). 2) In vitro results:The half-maximal inhibitory concentrations(IC50) for 24-hour and 48-hour drug-containing serum intervention on HK-2 cells were 81.35% and 54.53%，respectively，and the subsequent treatment time was set at 24 hours with 10% and 20% drug-containing serum concentrations.Compared with the normal group，let-7b-5p expression in HK-2 cells of the model group was lower(P<0.05)，while the 10% and 20% drug-containing serum groups showed significantly higher expression of let-7b-5p compared to the model group(P<0.05).The 20% drug-containing serum group had significantly higher expression of let-7b-5p than the 10% group(P<0.05).Compared with the normal group，the model group showed higher expression of TGF-βR1，Collagen I，α-SMA，and FN proteins in HK-2 cells(P<0.05).The 10% and 20% drug-containing serum groups showed lower expression of TGF-βR1，Collagen I，α-SMA，and FN proteins compared to the model group(P<0.05).The 20% drug-containing serum group showed significantly lower expression of TGF-βR1，Collagen I，and FN proteins than the 10% drug-containing serum group(P<0.05).Conclusion:SSXD can alleviate kidney fibrosis in both in vivo and in vitro models.Its mechanism of action may be related to the let-7b-5p/TGF-βR1 axis.