# Hydrogen Sulfide Inhibits H. pylori-Induced Gastric Fibroblast Activation: Implications for Cancer Prevention

## TL;DR

Hydrogen sulfide may help prevent cancer by reducing harmful effects of H. pylori on stomach cells.

## Contribution

This study shows hydrogen sulfide inhibits H. pylori-induced fibroblast activation and supports its potential as a cancer prevention strategy.

## Key findings

- Hydrogen sulfide donor NaHS reduces H. pylori-induced fibroblast activation and pro-tumorigenic markers.
- NaHS modulates sulfur metabolism without disrupting enzyme homeostasis and increases metronidazole sensitivity.
- High-dose NaHS limits H. pylori adhesion and reinfection-induced activation.

## Abstract

What are the main findings?
Hp (cagA+vacA+)-induced inflammation reduces gastric fibroblast proliferation/viability and reprograms these cells toward a CAF-like phenotype (Twist upregulation/nuclear localization, increased FAP/FSP, enhanced IL-6/IL-8/HGF expression), upregulation of NF-κB/STAT3 activation and induction of the sulfur-metabolizing enzymes CBS, MPST and TST.The fast-releasing H2S donor NaHS (50–400 µM) attenuates Hp-induced fibroblast activation markers/secretome, reduces Twist and NF-κB/STAT3 activation, and modulates the sulfur/H2S-metabolizing enzyme network without disrupting basal enzyme homeostasis.

Hp (cagA+vacA+)-induced inflammation reduces gastric fibroblast proliferation/viability and reprograms these cells toward a CAF-like phenotype (Twist upregulation/nuclear localization, increased FAP/FSP, enhanced IL-6/IL-8/HGF expression), upregulation of NF-κB/STAT3 activation and induction of the sulfur-metabolizing enzymes CBS, MPST and TST.

The fast-releasing H2S donor NaHS (50–400 µM) attenuates Hp-induced fibroblast activation markers/secretome, reduces Twist and NF-κB/STAT3 activation, and modulates the sulfur/H2S-metabolizing enzyme network without disrupting basal enzyme homeostasis.

What is the implication of the main finding?
Based on our data, modulation of H2S signaling may be considered as a possible approach to attenuate Hp-dependent fibroblast activation and to help maintain fibroblast homeostasis and, at higher NaHS doses, can additionally reduce Hp adhesion and increase metronidazole sensitivity.Preliminary experiments with the slow-releasing donor GYY4137 (50–100 µM) support follow-up studies using slow-release H2S donors to better approximate physiological H2S signaling.

Based on our data, modulation of H2S signaling may be considered as a possible approach to attenuate Hp-dependent fibroblast activation and to help maintain fibroblast homeostasis and, at higher NaHS doses, can additionally reduce Hp adhesion and increase metronidazole sensitivity.

Preliminary experiments with the slow-releasing donor GYY4137 (50–100 µM) support follow-up studies using slow-release H2S donors to better approximate physiological H2S signaling.

Early prevention of pathological changes underlying gastric cancer (GC) development is a critical strategy, offering the most effective opportunity to limit malignant progression and improve patient outcomes. We have previously demonstrated that Helicobacter pylori (Hp) (cagA+vacA+) contributes to GC development by activating gastric fibroblasts toward CAF-like phenotype, eliciting aggressive, cancer stem cells (CSCs)-related malignant transformation of LGR5+ normal epithelial cells. A key mediator of these processes appears to be the NF-κB/STAT3 axis. Therefore, our aim was to investigate the protective role of hydrogen sulfide (H2S) as a potential novel strategy for counteracting Hp-induced fibroblast reprogramming. Human fibroblasts were infected with Hp (cagA+vacA+) for 120 h. The fast-releasing H2S donor NaHS (50, 100, 200 and 400 µM) was added every 24 h. Activation markers, corresponding signaling pathways, H2S release and activities of H2S-metabolizing enzymes were determined. NaHS reduced Hp-induced fibroblast activation and their pro-inflammatory, pro-tumorigenic markers, which was associated with the inhibition of NF-κB/STAT3 axis and Twist expression. Additionally, it modulated sulfur metabolism while preserving sulfur-enzyme homeostasis. NaHS limited Hp adhesion (high doses), reduced reinfection-induced activation and increased sensitivity of Hp to metronidazole. These findings suggest that H2S signaling may represent a modulatory factor of NF-κB/STAT3-driven inflammatory responses during Hp infection and warrant further investigation.