ArticleCellular & molecular biology letters2024
Salivary gland protective and antiinflammatory effects of genistein in Sjögren's syndrome by inhibiting Xist/ACSL4-mediated ferroptosis following binding to estrogen receptor-alpha.
Article in Cellular & molecular biology letters, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- T Cell-Derived IFN-γ Activates Ferroptosis in Lacrimal Luminal Ductal Cells via JAK-STAT Signaling in Sjögren's Disease-Related Dry Eye.Investigative ophthalmology & visual science · 2026Article
- Decoding dry eye disease based on bioinformatics and in vitro experimental: the role of immune responses and natural product intervention.Human genomics · 2026Article
- Monocyte-Derived Macrophage Ferroptosis Amplifies Cholangitis in Primary Biliary Cholangitis via a Calpain/ACSL4 Axis.Biomedicines · 2026Article
- Molecular Insights into Oral Manifestations in Sjögren's Disease.International journal of molecular sciences · 2026Review
- The role of estrogen and its receptors in the regulation of ferroptosis and autophagy.Molecular biology reports · 2026Review
- Oridonin ameliorates the ferroptosis of chondrocyte to play a chondroprotective role in osteoarthritis.Journal of bioenergetics and biomembranes · 2026Article
- ACAA1 mediates arachidonic acid dysregulation and membrane phospholipid remodeling to promote crystal-cell adhesion and ferroptosis susceptibility in calcium oxalate kidney stone.Journal of pharmaceutical analysis · 2026Article
- Galectin-9 potentiates salivary gland damage by inducing ferroptosis in Sjogren's disease.Journal of molecular medicine (Berlin, Germany) · 2026Article
- Ferroptosis in salivary gland disorders: mechanisms, biomarkers, and therapeutic perspectives.Apoptosis : an international journal on programmed cell death · 2026Review
- Novel NDiscover oncology · 2026Article
- Multi-layered integrated shielding: engineering ferroptosis-resistant mesenchymal stem cells for precision therapy of intervertebral disc degeneration.Apoptosis : an international journal on programmed cell death · 2026Review
- Efficacy and mechanism of flavonoids in improving dry eye disease: a systematic review of animal studies.International journal of ophthalmology · 2026Review
- Genistein in autoimmune diseases: from experimental evidence to emerging clinical data.Frontiers in immunology · 2026Review
- Multidimensional targeting of ischemia-reperfusion injury by genistein: from molecular crosstalk to clinical translation.Frontiers in pharmacology · 2026Review
- Transcriptomic analysis revealed the protective role of genistein against oxidized fish oil-induced oxidative stress and inflammatory responses in turbot (Frontiers in physiology · 2026Article
- Ferroptosis and organelle roles in dry eye.iScience · 2025Review
- Ferrostatin-1 Prevents Salivary Gland Dysfunction in an Ovariectomized Rat Model by Suppressing Mitophagy-Driven Ferroptosis.Antioxidants (Basel, Switzerland) · 2025Article
- Constructing the optimal experimental autoimmune thyroiditis mouse model using porcine thyroglobulin.Frontiers in immunology · 2025Article
- Artemisinin derivatives modulate KEAP1-NRF2-xCT pathway to alleviate Sjögren's disease: insights from scRNA-seq and systems biology.Frontiers in immunology · 2025Article
- The Pathophysiological Role of Mitochondrial Oxidative Stress in Rheumatic Diseases.Journal of inflammation research · 2025Review
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Authors and funding
14 authors.
Funding
Abstract
backgroundSjögren's syndrome (SS) is an autoimmune disease with limited effective treatment options. This study aimed to explore the underlying mechanism by which genistein-estrogen receptor alpha (ERα) complex targets X-inactive specific transcript (Xist) then leads to the inhibition of ferroptosis by regulating acyl-CoA synthetase long-chain family member 4 (ACSL4) expression in salivary gland epithelial cells (SGECs) to attenuate SS.
methodsThe effects of genistein treatment on the progression and underlying mechanism of SS were investigated using nondiabetic obese (NOD)/LtJ mice in vivo and Interferon-γ (IFNγ)-treated SGECs in vitro. Water intake and saliva flow rate were measured to evaluate the severity of xerostomia. Hematoxylin-eosin staining, real-time quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay were conducted to examine the pathological lesions. Western blotting and immunohistochemistry analysis were used to evaluate the protein expression. RNA sequencing and RNA fluorescence in situ hybridization were employed to verify the relationship between Xist and ACSL4. Surface plasmon resonance, molecular docking, and molecular dynamics were used to investigate the binding between genistein and ERα. Furthermore, a chromatin immunoprecipitation assay was used to analyze ERα-XIST promoter interactions. The levels of malondialdehyde, glutathione, Fe
resultsIn NOD/LtJ mice, a ferroptosis phenotype was observed in salivary glands, characterized by downregulated Xist and upregulated X chromosome inactivation gene Acsl4. Genistein significantly alleviated SS symptoms, upregulated the Xist gene, and downregulated Acsl4 expression. Genistein upregulated Xist expression in the salivary gland of NOD/LtJ mice via the ERα signaling pathway. It downregulated Acsl4 and ferroptosis in the salivary glands of NOD/LtJ mice. IFNγ-treatment induced inflammation and ferroptosis in SGECs. Genistein binding to ERα upregulated XIST, and aquaporin 5 expression, downregulated ACSL4, and SS antigen B expression, and reversed ferroptosis in SGECs. Genistein mitigated inflammation and ferroptosis in SGECs by upregulated-XIST-mediated ACSL4 gene silencing.
conclusionsGenistein binding to ERα targets Xist, leading to inhibiting ferroptosis by regulating ACSL4 expression in SGECs. This finding provides evidence for genistein as a treatment for SS and identifies Xist as a novel drug target for SS drug development, offering great promise for improving SS outcomes.
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