7-Dehydrocholesterol dictates ferroptosis sensitivity
文献类型：期刊论文
| 作者 | Li, Yaxu7,8; Ran, Qiao7,8; Duan, Qiuhui7,8; Jin, Jiali7,8; Wang, Yanjin7,8; Yu, Lei7,8; Wang, Chaojie7,8; Zhu, Zhenyun6; Chen, Xin5; Weng, Linjun7,8 |
| 刊名 | NATURE
 |
| 出版日期 | 2024-02-08 |
| 卷号 | 626期号:7998页码:29 |
| ISSN号 | 0028-0836 |
| DOI | 10.1038/s41586-023-06983-9 |
| 通讯作者 | Wang, Ping(wangp@tongji.edu.cn) |
| 英文摘要 | Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer1-3, 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. 7-Dehydrocholesterol (7-DHC) is a natural anti-ferroptotic metabolite and pharmacological manipulation of 7-DHC levels shows promise as a therapeutic strategy for cancer and ischaemia-reperfusion injury. |
| WOS关键词 | POLYUNSATURATED FATTY-ACIDS ; LEMLI-OPITZ-SYNDROME ; CELL-DEATH ; RATE CONSTANTS ; CANCER-CELLS ; PEROXIDATION ; MECHANISMS ; STEROLS ; IDENTIFICATION ; PATHOGENESIS |
| 资助项目 | National Key Research and Development Program of China[2022YFC3401500] ; National Key Research and Development Program of China[2021YFA1302200] ; National Key Research and Development Program of China[2020YFA0803201] ; National Natural Science Foundation of China[31830053] ; National Natural Science Foundation of China[31920103007] ; National Natural Science Foundation of China[82341028] ; National Natural Science Foundation of China[82122056] ; National Natural Science Foundation of China[82073155] ; National Natural Science Foundation of China[82073153] ; National Natural Science Foundation of China[32030053] ; National Natural Science Foundation of China[22207084] ; National Natural Science Foundation of China[32150710522] ; Shanghai Sailing Program[22YF1433500] ; Shanghai Municipal Health Commission[20204Y0033] ; Fundamental Research Funds for the Central Universities[22120220616] ; Fundamental Research Funds for the Central Universities[PA2023000692] ; City University of Hong Kong[9380154] ; City University of Hong Kong[7006046] ; Shanghai Rising-Star Program[23QA1407500] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| 出版者 | NATURE PORTFOLIO |
| WOS记录号 | WOS:001159144100020 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309940]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Wang, Ping |
| 作者单位 | 1.Mem Sloan Kettering Canc Ctr, Cell Biol Program, New York, NY USA 2.City Univ Hong Kong, Dept Biomed Sci, Hong Kong, Peoples R China 3.Shanghai Jiao Tong Univ, Xinhua Hosp, Dept Gen Surg, Sch Med,Shanghai Key Lab Biliary Tract Dis Res, Shanghai, Peoples R China 4.Chinese Acad Sci, Univ Chinese Acad Sci, CAS Ctr Excellence Mol Cell Sci, CAS Key Lab Nutr Metab & Food Safety,Shanghai Inst, Shanghai, Peoples R China 5.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Nutr & Hlth, CAS Key Lab Nutr Metab & Food Safety, Shanghai, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, State Key Lab Drug Res, Shanghai, Peoples R China 7.Tongji Univ, Shanghai Frontiers Sci Ctr Nanocatalyt Med, Sch Med, Shanghai, Peoples R China 8.Tongji Univ, Shanghai Peoples Hosp 10, Canc Ctr, Sch Med, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Yaxu,Ran, Qiao,Duan, Qiuhui,et al. 7-Dehydrocholesterol dictates ferroptosis sensitivity[J]. NATURE,2024,626(7998):29. |
| APA | Li, Yaxu.,Ran, Qiao.,Duan, Qiuhui.,Jin, Jiali.,Wang, Yanjin.,...&Wang, Ping.(2024).7-Dehydrocholesterol dictates ferroptosis sensitivity.NATURE,626(7998),29. |
| MLA | Li, Yaxu,et al."7-Dehydrocholesterol dictates ferroptosis sensitivity".NATURE 626.7998(2024):29. |
入库方式： OAI收割
来源：上海药物研究所
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