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Esomeprazole alleviates fibrosis in systemic sclerosis by modulating AhR/Smad2/3 signaling
Jiani Liu1, Zixin Pi1, Yangfan Xiao2
1Department of Dermatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Hunan Key Laboratory of Medical Epigenetics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Abstract:
Systemic sclerosis (SSc) is a connective tissue disease with the involvement of complex signaling pathways, such as TGF-β/Smad2/3. SSc can lead to severe multiple organ fibrosis, but no effective therapy is currently available because of its unclear pathogenesis. Exploring new treatments is the focus of recent research on SSc. Recent studies have implied a potential antifibrotic role of esomeprazole (ESO), but with currently unidentified mechanisms. Signaling of AhR, a ligand-dependent transcription factor, has been described as a key controller of fibrosis, tumorigenesis, and immune balance. Recently, it has been reported that ESO may be an exogenous agonist of AhR signaling, while no previous study has revealed the effects of ESO on SSc and its underlying mechanisms. In this study, we demonstrate that ESO suppresses the migration of SSc dermal fibroblasts, downregulates profibrotic markers, including COLIA1, α-SMA CTGF and MMP1, and limits collagen production potentially via the activation of AhR signaling. More importantly, ESO could block Smad2/3 phosphorylation concurrently with the reduction in collagen via AhR signaling. Moreover, our results from the bleomycin (BLM)-induced SSc model in skin and lung shows that ESO ameliorates fibrosis in vivo, which in keeping with our in vitro results. We conclude that ESO is a potential therapeutic drug for SSc fibrosis.
Insights
Systemic sclerosis (SSc) treatment may be improved by esomeprazole (ESO). ESO shows potential antifibrotic effects by activating the AhR pathway, reducing fibrosis in skin and lung models.
Area of Science:
- Connective tissue diseases
- Fibrosis research
- Drug discovery
Background:
- Systemic sclerosis (SSc) is a fibrotic disease with no effective treatments.
- The exact pathogenesis of SSc and its complex signaling pathways, like TGF-β/Smad2/3, remain unclear.
- Esomeprazole (ESO) has shown potential antifibrotic properties, but its mechanisms in SSc are unknown.
Purpose of the Study:
- To investigate the antifibrotic effects of esomeprazole (ESO) in systemic sclerosis (SSc).
- To explore the underlying mechanisms of ESO's action, particularly its potential role in activating the Aryl hydrocarbon receptor (AhR) signaling pathway.
- To evaluate ESO's efficacy in both in vitro SSc models and in vivo SSc models.
Main Methods:
- Investigated the effect of ESO on SSc dermal fibroblast migration and profibrotic marker expression (COLIA1, α-SMA, CTGF, MMP1).
- Assessed collagen production and Smad2/3 phosphorylation in response to ESO.
- Utilized a bleomycin (BLM)-induced SSc mouse model to evaluate ESO's in vivo efficacy in skin and lung fibrosis.
Main Results:
- Esomeprazole (ESO) suppressed SSc dermal fibroblast migration and reduced profibrotic markers and collagen production.
- ESO's antifibrotic effects were linked to the activation of the Aryl hydrocarbon receptor (AhR) signaling pathway.
- ESO inhibited Smad2/3 phosphorylation and ameliorated skin and lung fibrosis in a bleomycin-induced SSc mouse model.
Conclusions:
- Esomeprazole (ESO) demonstrates significant antifibrotic activity in systemic sclerosis (SSc) models.
- Activation of AhR signaling by ESO is a key mechanism underlying its therapeutic potential in SSc.
- ESO represents a promising therapeutic candidate for treating SSc fibrosis.
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