Adiponectin in cigarette smoke-induced epithelial-mesenchymal transition

Cigarette smoke (CS) contributes to a wide range of chronic respiratory diseases by inducing epithelial-mesenchymal transition (EMT), which drives tissue remodeling, fibrosis, and tumor progression. In this scenario, adiponectin (Acrp30) has emerged as a potential EMT-negative regulator, inhibiting migration and invasion in non-small cell lung cancer cell lines. This study aimed to investigate ability of Acrp30 to prevent CS-induced EMT and profibrotic remodeling in normal and adenocarcinoma lung cells, through AdipoRon, a synthetic Acrp30 receptor agonist. BEAS-2B and A549 cells were used to preliminarily assess the optimal dose and timing for CS and AdipoRon exposure for subsequent evaluations by thiazolyl blue tetrazolium bromide assay. Expression of epithelial (E-cadherin), mesenchymal (vimentin), and profibrotic (α-smooth muscle actin, transforming growth factor-β, total collagen deposition, and collagen type I α1 chain) markers was examined through immunofluorescence, reverse transcription polymerase chain reaction, and Sirius Red staining. Wound-healing assay was used to assess CS and Acrp30 ability to influence cell migration. Reactive oxygen species levels were measured by 2',7'-dichlorofluorescin diacetate assay. Acrp30 prevents CS-induced dysregulation of E-cadherin and vimentin at both mRNA and protein levels, preserving the epithelial-mesenchymal balance in both cell lines. Furthermore, CS-induced increase in profibrotic marker expression was significantly attenuated by AdipoRon pretreatment in both BEAS-2B and A549 cells. The CS-induced increase in migratory capacity was significantly reversed by Acrp30 in both cell lines, confirming its ability to prevent EMT. Finally, Acrp30 also markedly reduced CS-induced reactive oxygen species overproduction in BEAS-2B and A549 cells, indicating a role in modulating oxidative stress-driven epithelial plasticity. Thus, Acrp30 effectively preserves epithelial markers, limits the mesenchymal shift and profibrotic remodeling, and reduces migratory capacity by mitigating oxidative stress. These results support Acrp30 as a promising therapeutic candidate for preventing airway remodeling and disease progression in smoking-related conditions. SIGNIFICANCE STATEMENT: Cigarette smoke (CS) induces epithelial-mesenchymal transition and fibrosis in both healthy and cancerous lung epithelial cells. Adiponectin pretreatment prevents CS-induced epithelial-mesenchymal transition and profibrotic remodeling in both cell lines; adiponectin can prevent airway remodeling and disease progression in CS conditions.