Apigenin alleviates Sjögren's syndrome-induced salivary gland epithelial cell ferroptosis via ERα signaling-mediated regulation of the ATF3/SLC7A1l axis.

Autor: Liu Q; School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Medical University, Guangzhou 510140, China., Mao T; School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Medical University, Guangzhou 510140, China., Liu F; School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Medical University, Guangzhou 510140, China., Chen B; School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Medical University, Guangzhou 510140, China., Liu Z; School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Medical University, Guangzhou 510140, China., Pathak JL; School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Medical University, Guangzhou 510140, China. Electronic address: J.pathak@gzhmu.edu.cn., Li J; School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Medical University, Guangzhou 510140, China. Electronic address: ljiang@gzhmu.edu.cn.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2024 Dec 25; Vol. 143 (Pt 2), pp. 113409. Date of Electronic Publication: 2024 Oct 18.
DOI: 10.1016/j.intimp.2024.113409
Abstrakt: Background: In Sjögren's syndrome (SS)-an autoimmune disease characterized by dry mouth and eyes-salivary gland epithelial cells (SGECs) undergo ferroptosis, which disrupts their integrity and impairs saliva secretion. Apigenin, a phytoestrogen, is known to activate estrogen signalling and alleviate xerostomia in ovariectomized mice; however, its effect on SGEC survival and function in SS remains unclear. We hypothesized that apigenin alleviates SS symptoms and progression by inhibiting ferroptosis in SGECs and aimed to elucidate the underlying mechanism.
Methods: Apigenin (50 mg/kg) was orally gavaged to non-obese diabetic (NOD)/LtJ female mice (SS model); changes in SS functional indicators were analyzed using mRNA sequencing and bioinformatic analyses of submandibular glands. Interferon-gamma (IFN-γ)-stimulated SGECs were used to model SS in vitro; SGEC activity and aquaporin 5 (AQP5) expression were analyzed. Immunohistochemical staining, transmission electron microscopy, RT-qPCR, western blotting and other methods were used to verify the mechanisms.
Results: Apigenin significantly increased salivary secretion and AQP5 expression while inhibiting ferroptosis and immune infiltration in NOD mouse submandibular glands. The oxidative stress gene ATF3 was upregulated and GPX4 was downregulated in NOD mice compared to that in control group (ICR mice); however, apigenin reversed this effect. IFN-γ treatment downregulated AQP5, SLC7A11, and GPX4 expression while promoting ATF3 expression and ferroptosis, which was mitigated by apigenin. ATF3 knockdown increased SLC7A11 and GPX4 expression, inhibiting SS and ferroptosis. Furthermore, apigenin inhibited ferroptosis in SGECs through ESR1 binding to ATF3.
Conclusion: Apigenin alleviates SS by regulating SGEC ferroptosis via the ERα-regulated ATF3/SLC7A11 axis, highlighting its therapeutic potential in SS.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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