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

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

  • J Ethnopharmacol. 2025 Jun 12:349:119965. doi: 10.1016/j.jep.2025.119965.
Shishuang Yu 1,  Ke Liu 1,  Fengjiao Zhou 1,  Xiuli Yang 1,  Junru Zhang 1,  Kexin Yu 1,  Yi Zhu 1,  Ling Qin 2,  Ting Peng 3,  Chuantao Zhang 4,  Yujiao He 5
Affiliations

Affiliations

  • 1 Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
  • 2 Anti-infective Agent Creation Engineering Research Centre of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, 610106, China.
  • 3 Anti-infective Agent Creation Engineering Research Centre of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, 610106, China. Electronic address: pengting221@cdu.edu.cn.
  • 4 Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China. Electronic address: zhangchuantao@cdutcm.edu.cn.
  • 5 Department of Respiratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China; Anti-infective Agent Creation Engineering Research Centre of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, 610106, China; Chengdu Institute of Food Inspection, Chengdu, 611130, China. Electronic address: heyujiao@cdu.edu.cn.
PMID: 40354836 DOI: 10.1016/j.jep.2025.119965
Abstract

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.

Keywords

Epithelial–mesenchymal transition; Nobiletin; PI3K/AKT pathway; Pulmonary fibrosis.

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