Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan City, Hubei Province 430071, China; Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Disease, Wuhan City, Hubei Province 430071, China.
Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan City, Hubei Province 430071, China; Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Disease, Wuhan City, Hubei Province 430071, China.
Dig Liver Dis. 2021 Oct;53(10):1276-1285. doi: 10.1016/j.dld.2021.02.011. Epub 2021 Feb 25.
Furin is a proprotein convertase reported to have protective effects in several autoimmune diseases. However, the role of furin in ulcerative colitis (UC) remains unclear. We aimed to clarify this role.
Furin expression was measured in UC and dextran sulfate sodium (DSS)-induced colitis. Gain- and loss-of-function experiments were conducted to evaluate the effect of furin in UC using DSS-treated NCM460 cells. Several ferroptotic parameters, including cell viability, cell death rate, lipid reactive oxygen species level, mitochondrial membrane damage and glutathione peroxidase 4 (Gpx4) expression, were measured. Exogenous furin was used to treat the DSS-induced colitis in mice to confirm the results in vivo. Finally, the activation of nuclear factor erythroid 2-like 2 (Nrf2) was detected to explore the mechanism.
Furin expression was aberrant in UC. Furin overexpression attenuated DSS-induced ferroptosis-like injury and upregulated Gpx4 in NCM460 cells, whereas silencing furin had the opposite effects. Exogenous furin treatment alleviated DSS-induced colitis in mice by upregulating Gpx4. Mechanistic experiments revealed that furin activated Nrf2 both in vitro and in vivo.
Furin protects epithelial cells from DSS-induced ferroptosis-like cell injury and alleviates experimental colitis by activating the Nrf2-Gpx4 signaling pathway.
丝氨酸蛋白酶原 2（furin）是一种蛋白原转化酶，在几种自身免疫性疾病中具有保护作用。然而，furin 在溃疡性结肠炎（UC）中的作用尚不清楚。本研究旨在阐明这一作用。
检测 UC 患者和葡聚糖硫酸钠（DSS）诱导结肠炎中的 furin 表达。使用 DSS 处理的 NCM460 细胞进行 gain-和 loss-of-function 实验，评估 furin 在 UC 中的作用。测定几种铁死亡相关参数，包括细胞活力、细胞死亡率、脂质活性氧水平、线粒体膜损伤和谷胱甘肽过氧化物酶 4（Gpx4）表达。用外源性 furin 处理 DSS 诱导的结肠炎小鼠，以体内验证实验结果。最后，检测核因子红细胞 2 样 2（Nrf2）的激活情况，以探讨其作用机制。
furin 在 UC 中表达异常。在 NCM460 细胞中，furin 过表达可减轻 DSS 诱导的铁死亡样损伤并上调 Gpx4，而沉默 furin 则产生相反的效果。外源性 furin 处理可通过上调 Gpx4 缓解 DSS 诱导的结肠炎小鼠的疾病。机制实验表明，furin 可在体外和体内激活 Nrf2。
furin 通过激活 Nrf2-Gpx4 信号通路，保护上皮细胞免受 DSS 诱导的铁死亡样细胞损伤，并缓解实验性结肠炎。
