<p>Pulmonary fibrosis is a chronic progressive lung disease that can lead to lung structural damage and respiratory failure. This study aimed to investigate whether paeonol could improve pulmonary fibrosis in mice by regulating through the EP300/Foxp3 axis. We established a mouse model of pulmonary fibrosis. Total glucosides of white peony (TGP) were used to treat the animal model, and lung injury was observed using HE and Masson staining. Inflammatory factor levels in bronchoalveolar lavage fluid were detected using ELISA. Network pharmacology analysis was conducted to explore the components, shared targets, and signaling pathways of pulmonary fibrosis and TGP. Molecular docking was performed to observe the binding of paeonol, a component of TGP, to the target EP300. CD4+T cells were collected and co-cultured with MPPF cells, followed by intervention with TGP and paeonol. The ratio of CD4+T/Treg cells was measured in vitro, and immunofluorescence was used to detect the intensity of α-SMA. Network pharmacology revealed that one of the key components of TGP is paeonol, and the signaling pathway associated with pulmonary fibrosis is the Foxp3 signaling pathway. TGP effectively inhibited the secretion of lung inflammatory factors TGF-β1, IFN-γ, IL-2, and IL-17 in mic. Paeonol, an effective component of TGP, could bind to EP300 at the molecular level. Both TGP and paeonol inhibited the expression of EP300 in CD4+T and MPPF cells, enhanced the proportion of Treg cells in CD4+T, and reduced the expression of Collagen I and α-SMA in MPPF cells. TGP can effectively inhibit lung inflammation and fibrosis progression in mice. Paeonol regulating CD4+Treg cell differentiation through the EP300/Foxp3 axis. This study may provide new insights into how TGP improves pulmonary fibrosis in mice.</p>