Activation of SIRT1-ERRγCo-Regulation Promotes Gastric Parietal Cell Differentiation and Offers Therapeutic Potential

Introduction: Gastric parietal cells (PCs) are critical for gastric health and acid secretion. Dysregulation in PC function leads to serious conditions, such as atrophic gastritis that can progress to adenocarcinoma. Despite their significance, the mechanisms of PC differentiation remain unclear. Our previous studies identified Estrogen-related receptor gamma ( Esrrg, ERRγ) as a pivotal factor for PC specification from progenitors yet its regulation during differentiation is unknown. Given ERRγ's role as an orphan nuclear receptor dependent on co-regulatory interactions, we hypothesized that Sirtuin 1 ( Sirt1, SIRT1) functions as a novel co-activator to enhance ERRγ activity, driving PC differentiation. Methods: We employed in vivo and in vitro models, including PCs ablation and stomach injury models (use of a high-dose tamoxifen, Atp4b-Cre + , iDTR + mice), gastric organoid culture, and lineage-traceable Sirt1 conditional knockout mice ( Fgf20-Cre + , Sirt1 fl/+ , mTmG + ; Esrrg-CreERT2 + , Sirt1 fl/+ , mTmG + ; Apt4b-Cre + , Sirt1 fl/+ , Apt4b-iDTR + , mTmG + ). Techniques involved single-cell RNA sequencing (scRNA-seq), western blotting (WB), quantitative PCR (qRT-PCR), co-immunoprecipitation (Co-IP), in vitro ESRRG-regulated reporter luciferase assay, immunofluorescence (IF), and hematoxylin and eosin staining (H&E). Resveratrol and selisistat were used to activate and inhibit SIRT1, respectively. Results: Our results showed that Sirt1 is enriched in the cluster of early PC progenitors and is co-expressed with Esrrg. We further demonstrated SIRT1's interaction with ERRγ both in vitro and in vivo within mouse gastric corpus at homeostasis, with co-localization in PCs. In vitro reporter assays indicated reduced ERRγ transactivation upon SIRT1 inhibition. Treatment with resveratrol promoted enhanced PC number in gastric organoids in PC promoting differentiation media, increased PC numbers in vivo, and upregulated ERRγ target gene expression in mouse models. This was attributed to facilitated SIRT1 nuclear localization, promoting SIRT1-ERRγ interaction. Conditional Sirt1 knockout demonstrated reduced PC numbers, decrease of ERRγ target gene expression, and delayed recovery in PC ablation models. Conclusion: Our study reveals that SIRT1 promotes ERRγ activity, fostering PC differentiation. This discovery provides a novel therapeutic strategy using FDA-approved agents such as resveratrol to treat gastritis and prevent gastric adenocarcinoma by boosting PC regeneration. It highlights a positive regulatory mechanism of ERRγ by SIRT1, potentially applicable beyond gastric biology. Further research will explore the molecular intricacies of SIRT1-ERRγ interaction and assess the clinical viability of this therapeutic approach. CPRIT RP210027 - Baylor College of Medicine Comprehensive Cancer Training Program (MD’s support); R01CA239645, R01DK105129, R01DK134531, R01CA246208 (JCM's support) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.