同济大学Ping Wang团队近期取得重要工作进展，他们研究提出，7-脱氢胆固醇（7-DHC）影响细胞铁死亡的敏感性。相关研究成果2024年1月31日在线发表于《自然》杂志上。
据介绍，铁死亡是一种由铁依赖性磷脂过氧化驱动的调节性细胞死亡，与多种疾病有关，包括癌症、退行性疾病和器官缺血再灌注损伤（IRI）。
使用全基因组CRISPR–Cas9筛选，研究人员发现，参与远端胆固醇生物合成的酶通过决定7-脱氢胆固醇（7-DHC）的水平在调节铁死亡中具有关键但相反的作用，7-DHC是远端胆固醇生物合成中的中间代谢产物，由甾醇C5去饱和酶（SC5D）合成，并由7-DHC还原酶（DHCR7）代谢用于胆固醇合成。研究人员发现，包括MSMO1、CYP51A1、EBP和SC5D在内的通路成分起到铁死亡潜在抑制剂的作用，而DHCR7起到促铁死亡的作用。
从机制上讲，7-DHC通过使用共轭二烯发挥其抗磷脂自氧化功能并保护血浆和线粒体膜免受磷脂自氧化的影响，来控制铁死亡的监测。重要的是，通过EBP的药理学靶向阻断内源性7-DHC的生物合成诱导铁死亡并抑制肿瘤生长，而通过抑制DHCR7增加7-DHC水平有效地促进癌症转移并减轻肾脏IRI的进展，支持该轴在体内的关键功能。
总之，这一数据揭示了7-DHC作为一种天然抗铁蛋白代谢产物的作用，并表明对7-DHC水平的药物调控是癌症和IRI的一种有前途的治疗策略。
附：英文原文
Title: 7-Dehydrocholesterol dictates ferroptosis sensitivity
Author: Li, Yaxu, Ran, Qiao, Duan, Qiuhui, Jin, Jiali, Wang, Yanjin, Yu, Lei, Wang, Chaojie, Zhu, Zhenyun, Chen, Xin, Weng, Linjun, Li, Zan, Wang, Jia, Wu, Qi, Wang, Hui, Tian, Hongling, Song, Sihui, Shan, Zezhi, Zhai, Qiwei, Qin, Huanlong, Chen, Shili, Fang, Lan, Yin, Huiyong, Zhou, Hu, Jiang, Xuejun, Wang, Ping
Issue&Volume: 2024-01-31
Abstract: Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer1,2,3, degenerative disorders4 and organ ischaemia–reperfusion injury (IRI)5,6. Here, using genome-wide CRISPR–Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)—an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1, CYP51A1, EBP and SC5D, function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI.
DOI: 10.1038/s41586-023-06983-9
Source: https://www.nature.com/articles/s41586-023-06983-9
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
