The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China.
Department of Anesthesiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang Province, China.
J Dig Dis. 2023 Mar;24(3):213-223. doi: 10.1111/1751-2980.13176. Epub 2023 Jun 10.
Ferroptosis is a newly discovered cell death mode that has been confirmed to occur in the intestinal epithelial cells in ulcerative colitis (UC). In this study we aimed to elucidate the mechanism of ferroptosis and its association with adenosine monophosphate-activated protein kinase (AMPK) in UC.
Gene expression profiles of colonic mucosa (GSE87473) were downloaded. Both human colonic samples and dextran sodium sulfate (DSS)-induced colitis murine model were used. The molecular markers of ferroptosis were detected using western blot and immunohistochemistry. Symptoms, iron abundance, and lipid peroxidation level of the mouse model were measured to evaluate the role of AMPK activation in ferroptosis.
Both gene and protein expressions of GPX4 and FTH1 were decreased in UC patients compared with the healthy controls. An increased iron abundance and lipid peroxidation level in colon tissues and damaged mitochondria were found in DSS-induced colitis. AMPK expression was decreased in UC patients and correlated with FTH1 and GPX4. Activation of AMPK with metformin inhibited ferroptosis in the colon, improved symptoms, and prolonged the lifespan in DSS-induced colitis mice.
Ferroptosis can be observed in colonic tissues in UC. AMPK activation inhibits ferroptosis in murine colitis model, which may act as a potential target for the treatment of colitis.
铁死亡是一种新发现的细胞死亡方式，已被证实存在于溃疡性结肠炎（UC）的肠上皮细胞中。本研究旨在阐明 UC 中铁死亡的机制及其与单磷酸腺苷激活的蛋白激酶（AMPK）的关系。
下载结肠黏膜的基因表达谱（GSE87473）。使用人结肠样本和葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型。使用 Western blot 和免疫组织化学检测铁死亡的分子标志物。测量小鼠模型的症状、铁含量和脂质过氧化水平，以评估 AMPK 激活在铁死亡中的作用。
与健康对照组相比，UC 患者的 GPX4 和 FTH1 的基因和蛋白表达均降低。在 DSS 诱导的结肠炎中，结肠组织中发现铁含量增加和脂质过氧化水平升高，且线粒体受损。UC 患者中 AMPK 的表达降低，与 FTH1 和 GPX4 相关。二甲双胍激活 AMPK 可抑制结肠中的铁死亡，改善症状，并延长 DSS 诱导的结肠炎小鼠的寿命。
在 UC 患者的结肠组织中可以观察到铁死亡。AMPK 激活抑制了小鼠结肠炎模型中的铁死亡，这可能是治疗结肠炎的潜在靶点。
