Nobiletin from Citrus reticulata Blanco alleviates pulmonary fibrosis through inhibiting the PI3K/AKT pathway and epithelial-mesenchymal transition.

Ethnopharmacological Relevance: Citrus reticulata Blanco, a traditional Chinese herb, has been utilized for bronchitis-related conditions. Nobiletin (NOB), the primary bioactive compound in Citrus reticulata Blanco, exhibits anti-inflammatory, antioxidant, and antifibrotic properties. However, the efficacy of NOB in pulmonary fibrosis (PF) and the underlying mechanisms remain ambiguous.

Aim Of The Study: This study is aimed to assess the effectiveness of NOB in the management of pulmonary fibrosis and to delineate the fundamental molecular mechanisms responsible for its action.

Materials And Methods: Bleomycin (BLM)-induced PF in C57BL/6 mice and transforming growth factor-β1 (TGF-β1)-induced molecular alterations in NIH3T3 and A549 cells, a number of techniques were used to study the efficacy and mechanism of NOB in PF, including Sirius Red collagen assays, Western blot (WB), immunofluorescence (IF), Micro-CT Imaging, pulmonary function assay, histopathological examination, proteomic analysis, wound healing, transwell, and immunocytochemistry (IHC) were utilized to analyze the efficacy and mechanism of NOB in PF.

Results: Our study demonstrated that NOB exhibited antifibrotic effects in TGF-β1-induced NIH3T3 cells, which was further corroborated in BLM-induced C57BL/6 mice. Utilizing proteomics analysis, we determined that the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling cascade and cellular adhesion processes were of significant importance. When A549 cells were induced with TGF-β1, our observations revealed that NOB could inhibit epithelial-mesenchymal transition (EMT) and display antifibrotic effects by modulating the PI3K/AKT pathway.

Conclusions: NOB could alleviate PF through inhibiting the PI3K/AKT pathway and EMT, suggesting it as a beneficial adjunct therapy for PF patients.