Synthesis and functional evaluation of low-molecular-weight dextran sulfate as an inhibitor of TGF-β1-induced epithelial-to-mesenchymal transition in A549 cells

doi:10.5246/jcps.2025.03.016

Abstract

Abstract:

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by excessive fibrotic remodeling, for which effective therapeutic options remain severely limited. Among the pathogenic mechanisms implicated in IPF, epithelial-to-mesenchymal transition (EMT) is recognized as a pivotal driver of fibroblast activation and extracellular matrix deposition. In this study, we aimed to develop low-molecular-weight dextran sulfate sodium (LMW-DSS) derivatives and assess their capacity to interfere with EMT, thereby offering novel therapeutic avenues for IPF management. Starting with dextran (2 kDa) as a precursor, we successfully synthesized two sulfated derivatives, DSS-LS and DSS-HS, via distinct sulfonation processes. Using a TGF-β1-stimulated A549 alveolar epithelial cell model, we demonstrated that LMW-DSS compounds exhibited no cytotoxicity, as validated by CCK-8 viability assays. Importantly, Transwell migration assays revealed that LMW-DSS markedly attenuated TGF-β1-induced A549 cell migration, indicating a potent anti-fibrotic effect. Moreover, qPCR and Western blotting analyses confirmed that LMW-DSS significantly suppressed the expression and secretion of key pro-fibrotic mediators, including TGF-β1 and VEGF-A, and downregulated critical EMT-associated markers such as Snail and vimentin. Notably, reduced α-SMA expression following LMW-DSS treatment further substantiated its role in hindering EMT progression. Collectively, these findings highlighted the capacity of LMW-DSS to effectively impede EMT and fibrotic processes, thereby delaying the progression of pulmonary fibrosis. This work not only underscored the therapeutic potential of LMW-DSS in IPF but also provided compelling experimental evidence to support its development as a promising anti-fibrotic agent for clinical application.

Key words: Idiopathic pulmonary fibrosis, Epithelial to mesenchymal transition, Dextran sulfate sodium, Transforming growth factor-β1, A549

Supporting:

Guohao Song, Linbo Fu, Yidian Mo, Tongtong Geng, Ximin Lv, Xiangbao Meng, Heng Wang, Zhongtang Li, Zhongjun Li. Synthesis and functional evaluation of low-molecular-weight dextran sulfate as an inhibitor of TGF-β1-induced epithelial-to-mesenchymal transition in A549 cells[J]. Journal of Chinese Pharmaceutical Sciences, 2025, 34(3): 210-222.

Figures/Tables 7

References 37

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