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This study aimed to explore the underlying mechanism by which genistein\u2013estrogen receptor alpha (ER\u03b1) complex targets X-inactive specific transcript (<jats:italic>Xist<\/jats:italic>) 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The effects of genistein treatment on the progression and underlying mechanism of SS were investigated using nondiabetic obese (NOD)\/LtJ mice in vivo and Interferon-\u03b3 (IFN\u03b3)-treated SGECs in vitro. Water intake and saliva flow rate were measured to evaluate the severity of xerostomia. Hematoxylin\u2013eosin 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 <jats:italic>Xist<\/jats:italic> and ACSL4. Surface plasmon resonance, molecular docking, and molecular dynamics were used to investigate the binding between genistein and ER\u03b1. Furthermore, a chromatin immunoprecipitation assay was used to analyze ER\u03b1\u2013<jats:italic>XIST<\/jats:italic> promoter interactions. The levels of malondialdehyde, glutathione, Fe<jats:sup>2+<\/jats:sup>, and mitochondrial changes were measured to evaluate ferroptosis of SGECs.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In NOD\/LtJ mice, a ferroptosis phenotype was observed in salivary glands, characterized by downregulated <jats:italic>Xist<\/jats:italic> and upregulated X chromosome inactivation gene <jats:italic>Acsl4<\/jats:italic>. Genistein significantly alleviated SS symptoms, upregulated the <jats:italic>Xist<\/jats:italic> gene, and downregulated <jats:italic>Acsl4<\/jats:italic> expression. Genistein upregulated <jats:italic>Xist<\/jats:italic> expression in the salivary gland of NOD\/LtJ mice via the ER\u03b1 signaling pathway. It downregulated <jats:italic>Acsl4<\/jats:italic> and ferroptosis in the salivary glands of NOD\/LtJ mice. IFN\u03b3-treatment induced inflammation and ferroptosis in SGECs. Genistein binding to ER\u03b1 upregulated <jats:italic>XIST<\/jats:italic>, 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-<jats:italic>XIST<\/jats:italic>-mediated ACSL4 gene silencing.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Genistein binding to ER\u03b1 targets <jats:italic>Xist<\/jats:italic>, leading to inhibiting ferroptosis by regulating ACSL4 expression in SGECs. This finding provides evidence for genistein as a treatment for SS and identifies <jats:italic>Xist<\/jats:italic> as a novel drug target for SS drug development, offering great promise for improving SS outcomes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical Abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1186\/s11658-024-00667-6","type":"journal-article","created":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T13:26:00Z","timestamp":1733145960000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Salivary gland protective and antiinflammatory effects of genistein in Sj\u00f6gren\u2019s syndrome by inhibiting Xist\/ACSL4-mediated ferroptosis following binding to estrogen receptor-alpha"],"prefix":"10.1186","volume":"29","author":[{"given":"Tianjiao","family":"Mao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqi","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiping","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoyuan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobumoto","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin H.","family":"Mayo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2974-6224","authenticated-orcid":false,"given":"Janak L.","family":"Pathak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,2]]},"reference":[{"issue":"10391","key":"667_CR1","doi-asserted-by":"publisher","first-page":"1878","DOI":"10.1016\/S0140-6736(23)00457-9","volume":"401","author":"N Conrad","year":"2023","unstructured":"Conrad N, Misra S, Verbakel JY, Verbeke G, Molenberghs G, Taylor PN, et al. 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