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Fexuprazan safeguards the esophagus from hydrochloric acid-induced damage by suppressing NLRP1/Caspase-1/GSDMD
Seo Yeon Kim1,2, Jung-Ho Yoon1, Da Hyun Jung1
1Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.
Introduction:
Proton pump inhibitors (PPIs) and potassium-competitive acid blockers (P-CABs) are widely used to manage gastric acid-related disorders by inhibiting hydrochloric acid (HCl) secretion from parietal cells in the stomach. Although PPIs are known to have anti-inflammatory properties beyond their role in inhibiting gastric acid secretion, research on P-CABs is lacking. In this study, we aimed to investigate whether all available P-CABs exhibit anti-inflammatory effects in gastroesophageal reflux-induced esophagitis and to elucidate the underlying mechanisms.
Methods:
Het-1A cells, normal esophageal epithelial cells, were treated with HCl (pH 4) for 30 min. Esomeprazole, a representative PPI, and three currently marketed P-CABs (vonoprazan, tegoprazan, and fexuprazan) were used for pretreatment. Total RNA sequencing was performed using Het-1A cells pretreated with 1% DMSO or fexuprazan, followed by exposure to HCl. Pyroptosis was measured using lactate dehydrogenase (LDH) release and Annexin V-FITC/PI staining. Western blotting, qRT-PCR, and ELISA were used to determine the expression of the related genes.
Results:
Pretreatment with esomeprazole, vonoprazan, tegoprazan, and fexuprazan significantly inhibited the HCl-induced pro-inflammatory cytokines, including IL-6, IL-8, IL-1β, and TNF-α. Fexuprazan and vonoprazan significantly attenuated the HCl-induced pyroptosis rate, as assessed by elevated LDH release and Annexin V-FITC/PI staining, whereas esomeprazole and tegoprazan did not. RNA sequencing revealed that NOD-like receptor (NLR) family pyrin domain-containing 1 (NLRP1) was significantly reduced in Het-1A cells pretreated with fexuprazan compared to those treated with DMSO. Fexuprazan and vonoprazan markedly reduced the HCl-induced transcriptional and translational expression of genes involved in the pyroptosis pathway, including NLRP1, Caspase-1, gasdermin D, and IL-1β. Notably, fexuprazan reduced the HCl-induced increase in pyroptosis and IL-1β using siRNA, even in the presence of NLRP1 knockdown. Fexuprazan, tested on inflammatory THP-1 macrophage cells, significantly reduced NLRP1 expression and inhibited lipopolysaccharide-induced pyroptosis.
Conclusion:
Our findings reveal that all p-CABs exhibit anti-inflammatory properties, while fexuprazan inhibits inflammation and pyroptosis of esophageal cells caused by the gastric acid. Therefore, it is presumed to have additional benefits in gastroesophageal reflux disease in addition to suppressing gastric acid secretion.
Insights
All potassium-competitive acid blockers (P-CABs) show anti-inflammatory effects. Fexuprazan specifically reduces esophageal pyroptosis and inflammation caused by gastric acid, suggesting benefits for acid reflux disease.
Area of Science:
- Gastroenterology
- Cell Biology
- Pharmacology
Background:
- Proton pump inhibitors (PPIs) and potassium-competitive acid blockers (P-CABs) manage acid-related disorders by inhibiting gastric acid secretion.
- While PPIs have known anti-inflammatory properties, P-CABs' effects beyond acid suppression are less understood.
Purpose of the Study:
- To investigate if all P-CABs possess anti-inflammatory effects in acid-induced esophagitis.
- To elucidate the mechanisms underlying these anti-inflammatory actions, focusing on pyroptosis.
Main Methods:
- Esophageal epithelial cells (Het-1A) were exposed to hydrochloric acid (HCl) with or without pretreatment with PPIs (esomeprazole) or P-CABs (vonoprazan, tegoprazan, fexuprazan).
- RNA sequencing, Western blotting, qRT-PCR, ELISA, and pyroptosis assays (LDH release, Annexin V/PI staining) were employed.
- siRNA was used to investigate the role of NLRP1 in fexuprazan's effects.
Main Results:
- All tested P-CABs and esomeprazole inhibited HCl-induced pro-inflammatory cytokines (IL-6, IL-8, IL-1β, TNF-α).
- Fexuprazan and vonoprazan significantly reduced HCl-induced pyroptosis, unlike esomeprazole and tegoprazan.
- Fexuprazan decreased NLRP1 expression and pyroptosis pathway gene expression, with effects independent of NLRP1 knockdown.
Conclusions:
- All P-CABs demonstrate anti-inflammatory properties.
- Fexuprazan effectively inhibits gastric acid-induced inflammation and pyroptosis in esophageal cells.
- Fexuprazan may offer additional therapeutic benefits for gastroesophageal reflux disease beyond acid suppression.
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