Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China.
Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, China; Institute of Stroke Research, Soochow University, Suzhou 215006, China.
Neurobiol Dis. 2024 May;194:106468. doi: 10.1016/j.nbd.2024.106468. Epub 2024 Mar 8.
Intracerebral hemorrhage (ICH) is a subtype of stroke marked by elevated mortality and disability rates. Recently, mounting evidence suggests a significant role of ferroptosis in the pathogenesis of ICH. Through a combination of bioinformatics analysis and basic experiments, our goal is to identify the primary cell types and key molecules implicated in ferroptosis post-ICH. This aims to propel the advancement of ferroptosis research, offering potential therapeutic targets for ICH treatment. Our study reveals pronounced ferroptosis in microglia and identifies the target gene, cathepsin B (Ctsb), by analyzing differentially expressed genes following ICH. Ctsb, a cysteine protease primarily located in lysosomes, becomes a focal point in our investigation. Utilizing in vitro and in vivo models, we explore the correlation between Ctsb and ferroptosis in microglia post-ICH. Results demonstrate that ICH and hemin-induced ferroptosis in microglia coincide with elevated levels and activity of Ctsb protein. Effective alleviation of ferroptosis in microglia after ICH is achieved through the inhibition of Ctsb protease activity and protein levels using inhibitors and shRNA. Additionally, a notable increase in m6A methylation levels of Ctsb mRNA post-ICH is observed, suggesting a pivotal role of m6A methylation in regulating Ctsb translation. These research insights deepen our comprehension of the molecular pathways involved in ferroptosis after ICH, underscoring the potential of Ctsb as a promising target for mitigating brain damage resulting from ICH.
脑出血（ICH）是中风的一种亚型，其死亡率和残疾率较高。最近，越来越多的证据表明铁死亡在 ICH 的发病机制中起着重要作用。通过生物信息学分析和基础实验相结合，我们的目标是确定 ICH 后铁死亡中的主要细胞类型和关键分子。这旨在推动铁死亡研究的进展，为 ICH 治疗提供潜在的治疗靶点。我们的研究表明，小胶质细胞中存在明显的铁死亡，并通过分析 ICH 后差异表达的基因，确定了靶基因组织蛋白酶 B（Ctsb）。组织蛋白酶 B 是一种主要位于溶酶体中的半胱氨酸蛋白酶，成为我们研究的焦点。我们利用体外和体内模型，探讨了 ICH 后小胶质细胞中 Ctsb 与铁死亡之间的相关性。结果表明，ICH 和血红素诱导的小胶质细胞铁死亡与 Ctsb 蛋白水平和活性的升高一致。通过抑制剂和 shRNA 抑制 Ctsb 蛋白酶活性和蛋白水平，可有效减轻 ICH 后小胶质细胞中的铁死亡。此外，还观察到 ICH 后 Ctsb mRNA 的 m6A 甲基化水平显著增加，表明 m6A 甲基化在调节 Ctsb 翻译中起着关键作用。这些研究结果加深了我们对 ICH 后铁死亡分子途径的理解，突出了 Ctsb 作为减轻 ICH 引起的脑损伤的有希望的靶点的潜力。
