近日，德国海德堡大学教授Andreas Linkermann及其团队发现了雌二醇多种功能抑制铁死亡和急性肾损伤。2025年8月13日，国际知名学术期刊《自然》发表了这一成果。

在这里，该研究组证明了在女性肾小管中被废除的铁细胞死亡繁殖。17β-雌二醇通过非基因组机制和基因组机制建立抗铁衰亡状态。其中包括羟基雌二醇衍生物对铁死亡的有效直接抑制，羟基雌二醇衍生物作为自由基捕获抗氧化剂，高浓度存在于肾小管中，当外源应用时，可以保护雄性小鼠免受AKI。在细胞中，氧化的羟基雌二醇被FSP1循环利用，但FSP1缺陷的雌性小鼠对AKI不敏感。在基因组水平上，雌性ESR1缺陷的肾小管部分失去了抗衰铁能力，与去卵巢小鼠相似。ESR1促进抗铁沉氢硫化物系统，而男性小管表达醚脂质途径的亲铁沉蛋白，这些蛋白在女性组织中被ESR1抑制直至绝经。总之，该课题组人员确定了非基因组和基因组机制，共同解释了女性小管中的铁死亡抗性，并可能作为男性和绝经后女性个体的治疗靶点。

据悉，急性肾小管坏死介导急性肾损伤（AKI）和肾单位损失，这是终末期肾脏疾病的标志。几十年来，人们都知道女性肾脏对AKI不那么敏感。急性肾小管坏死涉及沿肾小管室铁死亡的动态细胞死亡增殖。

附：英文原文

Title: Multiple oestradiol functions inhibit ferroptosis and acute kidney injury

Author: Tonnus, Wulf, Maremonti, Francesca, Gavali, Shubhangi, Schlecht, Marlena Nastassja, Gembardt, Florian, Belavgeni, Alexia, Leinung, Nadja, Flade, Karolin, Bethe, Natalie, Traikov, Sofia, Haag, Anne, Schilling, Danny, Penkov, Sider, Mallais, Melodie, Gaillet, Christine, Meyer, Claudia, Katebi, Melika, Ray, Anushka, Gerhardt, Louisa M. S., Brucker, Anne, Becker, Jorunn Naila, Tmava, Mirela, Schlicker, Lisa, Schulze, Almut, Himmerkus, Nina, Shevchenko, Andrej, Peitzsch, Mirko, Barayeu, Uladzimir, Nasi, Sonia, Putz, Juliane, Korach, Kenneth S., Neugarten, Joel, Golestaneh, Ladan, Hugo, Christian, Becker, Jan Ulrich, Weinberg, Joel M., Lorenz, Svenja, Proneth, Bettina, Conrad, Marcus, Wolf, Eckhard, Plietker, Bernd, Rodriguez, Raphal, Pratt, Derek A., Dick, Tobias P., Fedorova, Maria, Bornstein, Stefan R., Linkermann, Andreas

Issue&Volume: 2025-08-13

Abstract: Acute tubular necrosis mediates acute kidney injury (AKI) and nephron loss1, the hallmark of end-stage renal disease2,3,4. For decades, it has been known that female kidneys are less sensitive to AKI5,6. Acute tubular necrosis involves dynamic cell death propagation by ferroptosis along the tubular compartment7,8. Here we demonstrate abrogated ferroptotic cell death propagation in female kidney tubules. 17β-oestradiol establishes an anti-ferroptotic state through non-genomic and genomic mechanisms. These include the potent direct inhibition of ferroptosis by hydroxyoestradiol derivatives, which function as radical trapping antioxidants, are present at high concentrations in kidney tubules and, when exogenously applied, protect male mice from AKI. In cells, the oxidized hydroxyoestradiols are recycled by FSP19,10, but FSP1-deficient female mice were not sensitive to AKI. At the genomic level, female ESR1-deficient kidney tubules partially lose their anti-ferroptotic capacity, similar to ovariectomized mice. While ESR1 promotes the anti-ferroptotic hydropersulfide system, male tubules express pro-ferroptotic proteins of the ether lipid pathway which are suppressed by ESR1 in female tissues until menopause. In summary, we identified non-genomic and genomic mechanisms that collectively explain ferroptosis resistance in female tubules and may function as therapeutic targets for male and postmenopausal female individuals.

DOI: 10.1038/s41586-025-09389-x

Source: https://www.nature.com/articles/s41586-025-09389-x