Acid exposure induces pyroptosis in esophageal epithelial cells.
6 affiliations
- 1Inner Mongolia Institute of Digestive Diseases, 30 Hudemulin Rd, Baotou, 014030, China.
- 2The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, 30 Hudemulin Rd, Baotou, Inner Mongolia, 014030, China.
- 3Inner Mongolia Institute of Digestive Diseases, 30 Hudemulin Rd, Baotou, 014030, China. [email protected].
- 4The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, 30 Hudemulin Rd, Baotou, Inner Mongolia, 014030, China. [email protected].
- 5Inner Mongolia Institute of Digestive Diseases, 30 Hudemulin Rd, Baotou, 014030, China. [email protected].
- 6The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, 30 Hudemulin Rd, Baotou, Inner Mongolia, 014030, China. [email protected].
Abstract
Background: Gastroesophageal reflux disease (GERD) is a common digestive disorder featuring epithelial hyperplasia and may lead to esophageal malignancy. Acid reflux associated with GERD has been blamed for this consequence. Thus, acid suppression has been a primary clinical strategy for treating GERD. Is acid the real cause of esophageal hyperplasia?
Methods: This study dissected the role of acid in esophageal cell proliferation versus cell death by in vitro experimentation using esophageal epithelial cell lines. Cells were exposed to pH 4.5 medium either acutely or chronically, and then assessed for cell viability, expression and localization of proliferating cell nuclear antigen (PCNA), p21, caspase 1/3/4/7, Gasdermin-D (GSDMD), interleukin-1β/18 (IL-1β/18), and mixed lineage kinase domain-like (MLKL) by Western blotting, immunoprecipitation, enzyme-linked immunosorbent assay, and immunofluorescence.
Results: Although PCNA was upregulated in both nuclei and cytoplasm of esophageal epithelial cells, acid alone mainly induced cytoplasmic PCNA accumulation. Moreover, acid was found to induce pyroptotic cell death, rather than cell proliferation or other types of cell death such as apoptosis and necroptosis, characterized by CASP1/GSDMD cleavage rather than CASP3/7 cleavage, IL-1β/18 activation and release, and GSDMD rather than MLKL membrane localization. Inhibition of pyroptosis by either blocking CASP1 activation with Z-YVAD-FMK or knockdown of GSDMD reversed the antiproliferative effect of acid, rescued cells from death by 22.2% and 51.5% after acute and chronic acid exposure, respectively, while inhibition of apoptosis with Z-IETD-FMK or Z-LEHD-FMK or necroptosis with Necrosulfonamide did not.
Conclusion: Altogether, this study demonstrated that acid exposure induces pyroptotic cell death rather than cell proliferation in esophageal epithelial cells, suggesting that the cause of esophageal epithelial hyperplasia in GERD may be more complex than just acid exposure.
Graphical Abstract: It has long been thought that acid reflux promotes esophageal epithelial proliferation, resulting in esophageal hyperplasia, a common characteristic of GERD. This study demonstrates, in vitro, that acid exposure induces pyroptotic cell death, thereby promoting esophageal inflammation rather than cell proliferation. Thus, GERD-induced esophageal hyperplasia must be due to factors other than acid reflux alone.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12885-026-16646-3.
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BibTeX
@article{meng2026acid,
title = {{Acid exposure induces pyroptosis in esophageal epithelial cells.}},
author = {Zhiyi Meng and Wei Hou and Yuanyuan Nian and Bofu Tang and Tong Dang and Xianmei Meng and Jianyuan Chai},
journal = {BMC cancer},
year = {2026},
month = jul,
doi = {10.1186/s12885-026-16646-3},
url = {https://europepmc.org/article/MED/42958125},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Acid exposure induces pyroptosis in esophageal epithelial cells.
AU - Zhiyi Meng
AU - Wei Hou
AU - Yuanyuan Nian
AU - Bofu Tang
AU - Tong Dang
AU - Xianmei Meng
AU - Jianyuan Chai
PY - 2026
DA - 2026/07/29
JO - BMC cancer
DO - 10.1186/s12885-026-16646-3
UR - https://europepmc.org/article/MED/42958125
AB - Background: Gastroesophageal reflux disease (GERD) is a common digestive disorder featuring epithelial hyperplasia and may lead to esophageal malignancy. Acid reflux associated with GERD has been blamed for this consequence. Thus, acid suppression has been a primary clinical strategy for treating GERD. Is acid the real cause of esophageal hyperplasia? Methods: This study dissected the role of acid in esophageal cell proliferation versus cell death by in vitro experimentation using esophageal epithelial cell lines. Cells were exposed to pH 4.5 medium either acutely or chronically, and then assessed for cell viability, expression and localization of proliferating cell nuclear antigen (PCNA), p21, caspase 1/3/4/7, Gasdermin-D (GSDMD), interleukin-1β/18 (IL-1β/18), and mixed lineage kinase domain-like (MLKL) by Western blotting, immunoprecipitation, enzyme-linked immunosorbent assay, and immunofluorescence. Results: Although PCNA was upregulated in both nuclei and cytoplasm of esophageal epithelial cells, acid alone mainly induced cytoplasmic PCNA accumulation. Moreover, acid was found to induce pyroptotic cell death, rather than cell proliferation or other types of cell death such as apoptosis and necroptosis, characterized by CASP1/GSDMD cleavage rather than CASP3/7 cleavage, IL-1β/18 activation and release, and GSDMD rather than MLKL membrane localization. Inhibition of pyroptosis by either blocking CASP1 activation with Z-YVAD-FMK or knockdown of GSDMD reversed the antiproliferative effect of acid, rescued cells from death by 22.2% and 51.5% after acute and chronic acid exposure, respectively, while inhibition of apoptosis with Z-IETD-FMK or Z-LEHD-FMK or necroptosis with Necrosulfonamide did not. Conclusion: Altogether, this study demonstrated that acid exposure induces pyroptotic cell death rather than cell proliferation in esophageal epithelial cells, suggesting that the cause of esophageal epithelial hyperplasia in GERD may be more complex than just acid exposure. Graphical Abstract: It has long been thought that acid reflux promotes esophageal epithelial proliferation, resulting in esophageal hyperplasia, a common characteristic of GERD. This study demonstrates, in vitro, that acid exposure induces pyroptotic cell death, thereby promoting esophageal inflammation rather than cell proliferation. Thus, GERD-induced esophageal hyperplasia must be due to factors other than acid reflux alone. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12885-026-16646-3.
SN - 1471-2407
ER -