Background <p>Pulmonary fibrosis (PF) is an interstitial lung disease with macrophage polarization playing a critical role. Previous research has demonstrated that essential oil from <i>Radix Curcumae</i> (RCEO) significantly ameliorates pulmonary sarcoidosis, an effect attributed to the modulation of macrophage polarization. However, the therapeutic potential of RCEO in PF and its underlying mechanisms remain to be elucidated.</p> Purpose <p>To investigate whether RCEO ameliorates pulmonary function in PF mice by suppressing the polarization of M1 and M2 macrophages via suppressing the Pi3k/Akt/β-catenin and Tlr4/Myd88/Nf-κb signaling pathways.</p> Methods <p>Bioinformatics and network pharmacology approaches were employed to predict the potential therapeutic targets of RCEO for PF. The main components of RCEO and the primary constituents of RCEO deposited in lung tissue following inhalation were analyzed using GC–MS. PF models were established both in vivo and in vitro using bleomycin. Changes in pulmonary function were assessed by whole-body plethysmography. HE staining and Masson staining were used to observe histopathological alterations and fibrosis progression in lung tissues. ELISA was performed to measure changes in fibrosis-related mediators in blood. Flow cytometry was utilized to investigate macrophage polarization and apoptosis levels in lung tissues. Immunofluorescence analysis was applied to quantify the expression and distribution of Tlr4 and Pi3k, as well as their fluorescence co-localization with macrophages, in lung tissues. PCR and WB were conducted to evaluate changes in mRNA expression levels and protein abundance associated with the Tlr4/Myd88/Nf-κb and Pi3k/Akt/β-catenin signaling pathways in lung tissues.</p> Results <p>Bioinformatics and Network Pharmacology analyses predicted that the therapeutic effect of RCEO on PF is associated with the modulation of macrophage differentiation via the Tlr4/Myd88/Nf-κb pathway and the Pi3k/Akt/β-catenin signaling pathway. In a PF mouse model, RCEO significantly alleviated pathological alterations and collagen deposition in lung tissues and improved pulmonary function. Results from both in vivo and in vitro flow cytometry demonstrated that RCEO concurrently suppressed the differentiation of macrophages into both M1 and M2 phenotypes, promoted apoptosis in 3T3 cells while inhibiting apoptosis in MLE-12 cells, and reduced the levels of profibrotic mediators. Further PCR and Western blot analyses indicated that RCEO modulates macrophage polarization and extracellular matrix expression by inhibiting the Tlr4/Myd88/Nf-κb and Pi3k/Akt/β-catenin signaling pathways. Immunofluorescence assays revealed that RCEO effectively downregulated the expression of Tlr4 and Pi3k in macrophages, thereby exerting a protective effect against pulmonary fibrosis.</p> Conclusion <p>RCEO ameliorates PF by suppressing both M1 and M2 polarization of macrophages via inhibition of the Pi3k/Akt/β-catenin and Tlr4/Myd88/Nf-κb signaling pathways. This leads to reduced release of pro-inflammatory and pro-fibrotic cytokines, decreased extracellular matrix (ECM) deposition, and overall attenuation of fibrotic progression.</p> Graphical abstract <p></p>