Salivary gland protective and antiinflammatory effects of genistein in Sjögren’s syndrome by inhibiting Xist/ACSL4-mediated ferroptosis following binding to estrogen receptor-alpha

作者：Tianjiao Mao, Wei Wei, Bo Chen, Yixin Chen, Shuqi Liang, Guiping Chen, Zhuoyuan Liu, Xiaodan Wu, Lihong Wu, Xiaomeng Li, Nobumoto Watanabe, Kevin H. Mayo, Janak Lal Pathak, Jiang Li · 发表于：Cellular & Molecular Biology Letters · 年份：2024 · DOI：10.1186/s11658-024-00667-6 · 被引用次数：26 · 研究领域：Ferroptosis and cancer prognosis、Salivary Gland Disorders and Functions、Immune cells in cancer

Abstract Background Sjögren’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. Methods 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-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 2+ , and mitochondrial changes were measured to evaluate ferroptosis of SGECs. Re...