铁离子过载在经典的同型半胱氨酸血症中诱导肝脏损伤的作用及机制研究

Abnormal amino acid metabolism is related a variety of human diseases. Classic homocyst(e)inemia (Hcy) is characterized by severe vascular disease and liver injury. However, how this disorder results in severe injury of liver remains a mystery. In our previous study, we observed severe iron overloaded with dramatically elevated hepatic and serum iron in Hcy murine mode which was constructed from cystathionine beta-synthase knockout mice. It is known that iron overload is toxic to cells and tissues and organs and recent studies suggest that ferroptosis may be a promising target for treating iron overload-related tissue damage. We further validated the mRNA and protein expressions of SLC7A11 which is a ferroptosis-related indicator were significantly increased in Hcy murine mode. Therefore, we hypothesize that iron overload is likely to directly induce liver injury of Hcy through SLC7A11-mediated ferroptosis. Here, we will explore the detailed roles and mechanisms of iron overload in the Hcy and evaluate the potential applications of interfering the iron overload in Hcy by using knockout animals, cell models and clinical samples of Hcy patients.This study will illuminate a novel mechanism of liver injury in Hcy via iron overload, improve the theory of iron metabolism disorder related liver injury, and may identify a new target of drug therapy for Hcy.

氨基酸代谢异常与人类多种疾病有关。经典的同型半胱氨酸血症（Hcy）患者主要表现为严重的血管疾病和肝损伤，但其中肝损伤的发生机制尚不明确。我们的前期工作发现胱硫醚β-合成酶敲除小鼠构建的Hcy小鼠模型血液和肝脏出现了严重的铁离子蓄积现象。已知铁离子过载会对细胞和组织器官产生毒害，且有研究证明铁死亡参与了铁过载相关的组织损伤。我们的研究也证实Hcy中铁死亡相关的基因SLC7A11的mRNA和蛋白表达显著增高。因此推断铁离子蓄积很有可能通过SLC7A11介导铁死亡直接诱导Hcy相关肝损伤。本项目首先利用基因敲除动物明确铁离子过载在Hcy中作用并阐明铁离子蓄积的原因，接着在Hcy细胞模型上干预铁代谢，阐明铁过载诱导肝脏损伤的机制，最后利用Hcy患者临床样本验证铁过载表型阐述临床意义。本研究将从铁过载这个新视角揭示Hcy肝损伤的全新发病机制，并完善铁代谢异常相关肝损伤理论，为Hcy的防治提供新靶标。

经典的同型半胱氨酸血症（Hcy）是由于胱硫醚β-合成酶（cystathionine β-synthase，CBS)缺乏引起的，Hcy患者主要表现为严重的血管疾病和肝损伤，但其中肝损伤的发生机制尚不明确。我们的前期工作发现胱硫醚β-合成酶敲除小鼠构建的Hcy小鼠模型血液和肝脏出现了严重的铁离子蓄积现象。已知铁离子过载会对细胞和组织器官产生毒害，且有研究证明铁死亡参与了铁过载相关的组织损伤。由此我们假设CBS敲除小鼠中铁离子蓄积很有可能通过SLC7A11介导铁死亡直接诱导了Hcy的肝损伤。. 本项目围绕这一科学假设，从CBS敲除小鼠构建的Hcy小鼠模型出现肝脏铁过载原因、铁离子过载诱导肝损伤的机制、CBS突变患者铁过载表型临床意义三个方面，深入阐述铁离子过载在经典的Hcy中诱导肝脏损伤的作用机制及临床意义。研究发现：CBS纯合敲除小鼠构建的Hcy小鼠模型机体及肝脏铁过载且导致显著的肝损伤；进一步的研究发现CBS纯合敲除小鼠肝脏Hepcidin显著增高，机制研究发现是通过IL-6/STAT3通路介导，表明其铁过载表型不是由于经典的hepcidin低表达所导致；CBS敲除小鼠构建的Hcy小鼠模型导致的肝损伤是由SLC7A11介导的铁死亡诱导的；CBS缺失后小肠FtH没有显著的变化，证实与小肠铁吸收无关，CBS缺失介导NRF2/Fpn1显著降低导致肝脏铁过载，给与NRF2的激动剂CDDO-Im可以显著的逆转CBS缺失导致Fpn1的降低及肝脏铁过载；Hcy患者CBS全外显子测序发现CBS突变患者（第12个外显子41位的碱基纯合突变）会出现血清铁蛋白异常升高。. CBS在肝癌中的作用尚不明确，研究还发现肝癌中CBS表达降低且与不良预后相关，研究证实CBS通过抑制PRRX2/IL-6/STAT3信号通路一方面促进肿瘤细胞凋亡；另一方面抑制瘤内调节性T细胞（Treg）浸润，即CBS通过双向的作用抑制肝肿瘤的进展。. 本研究揭示了CBS敲除小鼠构建的Hcy小鼠模型铁离子过载通过铁死亡诱导肝损伤，研究结果为某些病因未明的血色素沉着症患者的诊治提供了新思路。CBS可作为HCC临床免疫治疗的潜在靶点。 ...

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