ETHNOPHARMACOLOGICAL RELEVANCE: Manshenkang granule (MSKG) is a traditional Chinese medicinal formula used to treat chronic renal failure, comprising Rheum tanguticum Maxim. ex Balf., Salvia miltiorrhiza Bunge, Citrus × aurantium L., Codonopsis pilosula (Franch.) Nannf., Polygonatum cyrtonema Hua, Smilax glabra Roxb., Ostrea rivularis Gould, and Glycyrrhiza uralensis Fisch. However, their efficacies and mechanisms of action require further investigation. AIM OF THE STUDY: This study explored the role and underlying mechanisms of MSKG in alleviating adenine-induced renal fibrosis in chronic renal failure rats. MATERIALS AND METHODS: Serum and urine indicators were assessed. Alpha smooth muscle actin (α-SMA), phosphodiesterase 4b (PDE4b), and exchange protein, directly activated by cyclic adenosine monophosphate (cAMP) 1 (Epac1) protein expression levels, were determined by western blotting. Molecular docking and dynamics simulations were performed to evaluate the binding of the main components of MSKG to PDE4b. RESULTS: Compared with the model group, the serum levels of creatinine, urea nitrogen, K DISCUSSION AND CONCLUSION: MSKG effectively alleviated renal fibrosis in rats with adenine-induced chronic renal failure, and its mechanism may be related to regulation of the PDE4b/cAMP/Epac1 pathway.