Aim Rhodiola rosea L.possesses a wide range of pharmacological properties including lungprotective,and it has been implemented in folk medicine for several 100 years.However, the accurate mechanisms of its lungprotective activity remain unclear.This study aimed at investigating the possible mechanisms of lungprotective activity of Rhodiola rosea L.in pulmonary fibrosis model.Methods Pathological observation, ROS detection and measurements of biochemical indexes on rat models proved lungprotective effect of Rhodiola rosea L.Identification of active compounds in Rhodiola rosea L.was executed through several methods including UPLCTOFMS.SEA docking, molecular modeling, molecular docking, and molecular dynamics (MD) simulation were applied in this study to explore possible mechanisms of the lungprotective potential of Rhodiola rosea L.Furthermore, in vitro cytological examination and Western blot were used for validating the efficacy of the selected compounds.Results Experiments on rat models showed a potent lungprotective effect of Rhodiola rosea L.Then we analyzed the chemical composition of Rhodiola rosea L.and found out their key targets.Moreover, in silico analysis results testified good interaction between selected compound 13 and key targets Akt1/Caspase1, and compound 10 also interacts well with Akt1.Further Western blot analysis proved changed expression levels of those target proteins, indicating that selected small compounds indeed acted on those targets.Conclusion In silico analysis and experimental validation together demonstrated that selected compound 10 in Rhodiola rosea L.targeted Akt1 in hepatocytes.Besides,compound 13 targeted both Caspase1 and Akt1.These small compounds may ameliorate pulmonary fibrosis by acting on their targets which are related to apoptosis or autophagy.The conclusions above may shed light on the complex molecular mechanisms of Rhodiola rosea L.acting on pneumonocyte and ameliorating pulmonary fibrosis.