Zingiber zerumbet rhizome attenuates bleomycin-induced pulmonary fibrosis by regulating TGF-β1 and TNF/NF-κB signaling to inhibit epithelial-mesenchymal transition and fibroblast activation

Ethnopharmacological relevance: Zingiber zerumbet (L.) Smith rhizome has long been employed in traditional medicine across Asia for managing respiratory disorders, suggesting its potential utility in chronic fibrotic lung diseases.Aim of the study: This study aimed to evaluate the antifibrotic effects of ethanolic Zingiber zerumbet rhizome extract and elucidate its mechanisms in regulating epithelial-mesenchymal transition (EMT), fibroblast proliferation, and inflammatory signaling in cell-based and animal models of pulmonary fibrosis. Materials and methods: The bioactive constituents of the extract were identified using LC-MS/MS. In vitro assays were performed on A549 epithelial cells and NIH3T3 fibroblast cells stimulated with TGF-β1 to assess EMT and fibroblast proliferation. In vivo therapeutic efficacy was investigated in a bleomycin-induced pulmonary fibrosis model using Sprague-Dawley rats. Results: Thirty metabolites were identified in the ethanolic extract. In NIH3T3 cells, treatment with Zingiber zerumbet significantly suppressed TGF-β1-induced fibroblast migration and differentiation. In A549 cells, the extract preserved E-cadherin expression, confirming inhibition of EMT. Western blot analysis demonstrated suppression of TNF/NF-κB signaling in both in vitro and in vivo models. In rats, treatment reduced lipid peroxidation, enhanced antioxidant defense, and improved lung histopathology by decreasing collagen deposition, inflammatory infiltration, and fibrotic remodeling. Conclusion: Zingiber zerumbet rhizome extract exhibits potent antifibrotic activity in preclinical models of pulmonary fibrosis by regulating TGF-β1 and TNF/NF-κB signaling. These findings highlight its potential as a multitarget phytotherapeutic agent for the management of pulmonary fibrosis.