更新于：2024-11-01

SLC7A11

更新于：2024-11-01

基本信息

别名

Amino acid transport system xc-、Calcium channel blocker resistance protein CCBR1、Cystine/glutamate transporter

+ [4]

简介

Heterodimer with SLC3A2, that functions as an antiporter by mediating the exchange of extracellular anionic L-cystine and intracellular L-glutamate across the cellular plasma membrane (PubMed:15151999, PubMed:34880232, PubMed:35352032, PubMed:35245456, PubMed:11417227, PubMed:14722095, PubMed:11133847). Provides L-cystine for the maintenance of the redox balance between extracellular L-cystine and L-cysteine and for the maintenance of the intracellular levels of glutathione that is essential for cells protection from oxidative stress (By similarity). The transport is sodium-independent, electroneutral with a stoichiometry of 1:1, and is drove by the high intracellular concentration of L-glutamate and the intracellular reduction of L-cystine (PubMed:11417227, PubMed:11133847). In addition, mediates the import of L-kynurenine leading to anti-ferroptotic signaling propagation required to maintain L-cystine and glutathione homeostasis (PubMed:35245456). Moreover, mediates N-acetyl-L-cysteine uptake into the placenta leading to subsequently down-regulation of pathways associated with oxidative stress, inflammation and apoptosis (PubMed:34120018). In vitro can also transport L-aspartate (PubMed:11417227). May participate in astrocyte and meningeal cell proliferation during development and can provide neuroprotection by promoting glutathione synthesis and delivery from non-neuronal cells such as astrocytes and meningeal cells to immature neurons (By similarity). Controls the production of pheomelanin pigment directly (By similarity).

关联

项与 SLC7A11 相关的药物

BAY-94-9392

靶点

SLC7A11

作用机制

SLC7A11抑制剂 [+1]

在研机构

The University of Texas MD Anderson Cancer Center [+6]

原研机构

Piramal Pharma Limited

在研适应症

同种异体移植排斥反应 [+12]

非在研适应症

晚期三阴性乳腺癌 [+18]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

SXC-2023

靶点

SLC7A11

作用机制

SLC7A11刺激剂

在研机构

Promentis Pharmaceuticals, Inc.

原研机构

Promentis Pharmaceuticals, Inc.

在研适应症

可卡因相关疾病

非在研适应症

破坏性、冲动控制及品行障碍 [+1]

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

FC-003

靶点

SLC7A11

作用机制

SLC7A11抑制剂

在研机构

FerroptoCure KK

原研机构

FerroptoCure KK

在研适应症

实体瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 SLC7A11 相关的临床试验

NCT06343532 / Not yet recruiting临床1期IIT

Phase 1, Double-Blind, Placebo-Controlled, Parallel Group Study to Assess Potential Interactions Between Intravenous Cocaine and Oral SXC-2023

The goal of this clinical trial is to determine whether there are any interactions between the study drug and cocaine. Researchers will compare a treatment group and a placebo group to see if they experience any effects when administered cocaine after taking the treatment/placebo.

开始日期2024-06-01

申办/合作机构

National Institute on Drug Abuse

[+3]

NCT05322135 / Active, not recruiting早期临床1期IIT

A Pilot Study of Glutamine PET Imaging of Head and Neck Squamous Cell Carcinoma

We propose a focused, prospective pilot clinical imaging trial to evaluate 11C-Gln PET/CT followed by 18F-FSPG PET/CT in 20 HNSCC patients. Imaging metrics that are common to PET (e.g. SUVmax, peak or mean) will be determined.
This study will also allow the acquisition of additional safety and biodistribution data, as, to date, only a limited number of patients have been evaluated with 11C-Gln as a direct PET imaging biomarker of Gln uptake. To date, no adverse side effects have been observed. We do not anticipate any toxicity since this tracer is a naturally-occurring essential amino acid in high abundance and is administered at sub-pharmacologic doses.
A long-term goal of these preliminary studies is to validate the utility of Gln PET imaging metrics for HNSCC and to expand this imaging technique to additional patients in prospective cohorts of patients with HNSCC.

开始日期2022-09-14

申办/合作机构

The University of Texas MD Anderson Cancer Center

NCT02379377 / Recruiting临床1期IIT

PET Imaging of Hepatocellular Carcinoma With 18F-FSPG

This clinical trial studies fluorine F 18 L-glutamate derivative BAY94-9392 (18F-FSPG) positron emission tomography (PET) in imaging patients with liver cancer before undergoing surgery or transplant. Diagnostic procedures, such as 18F-FSPG PET, may help find and diagnose liver cancer and find out how far the disease has spread.

开始日期2022-02-15

申办/合作机构

The University of Texas MD Anderson Cancer Center

[+1]

100 项与 SLC7A11 相关的临床结果

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100 项与 SLC7A11 相关的转化医学

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0 项与 SLC7A11 相关的专利（医药）

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2,707

项与 SLC7A11 相关的文献（医药）

2025-01-01·Journal of Ethnopharmacology

Ethyl acetate fraction of Thesium chinense Turcz. alleviates chronic obstructive pulmonary disease through inhibition of ferroptosis mediated by activating Nrf2/SLC7A11/GPX4 axis

Article

作者: Wang, Ying-Yue ; Guan, Yue-Qin ; Liu, Ming-Jie ; Wang, Xiao-Ning ; Wen, Xue-Sen ; Shen, Tao ; Li, Guo-Hui ; Xu, Zhen-Peng

ETHNOPHARMACOLOGICAL RELEVANCEThesium chinense Turcz., a traditional Chinese herbal medicine, displays good therapeutic efficiency against respiratory diseases (e.g. pneumonia, pharyngitis) in clinical applications, however, its effects on COPD and the mechanism of action are still unclear.AIM OF THE STUDYThis study aims to investigate the therapeutic effect of the ethyl acetate fraction of Thesium chinense Turcz. (TCEA) on COPD and reveal the underlying mechanism.MATERIALS AND METHODSA cigarette smoke (CS)-induced mouse COPD model was established, and the efficacy of TCEA was evaluated using peripheral blood testing, HE and Masson staining, qRT-PCR and ELISA assays. TCEA was analyzed for chemical composition by LC-MS/MS and HPLC. Prediction of major signaling pathways and potential targets was performed by network pharmacology. The molecular mechanism of TCEA was explored by immunoblotting, immunofluorescence staining, flow cytometry, and ubiquitination assay. Finally, potential active small molecules in TCEA were identified by molecular virtual screening.RESULTSTCEA treatment significantly inhibited the secretion of pro-inflammatory factors and attenuated pathological emphysema. The main chemical constituents of TCEA were identified as flavonoids by UPLC-MS/MS. Network pharmacology analysis enriched the Nrf2 signaling pathway closely related to oxidative stress. Our results suggested that TCEA inhibited ferroptosis by activating Nrf2/SLC7A11/GPX4 axis and inhibiting lipid metabolism-related proteins, ACSL4, ALOX5 and COX2 in vivo and in vitro. Noteworthily, the beneficial impact of TCEA on regulation of SLC7A11 and GPX4 vanished after silencing Nrf2. Moreover, Nrf2 ubiquitination was inhibited by TCEA treatment. Finally, several flavonoids modulating Nrf2 were identified by molecular virtual screening.CONCLUSIONSTCEA significantly alleviated COPD progression by inhibiting ferroptosis primarily through activation of Nrf2/SLC7A11/GPX4 signaling. Flavonoids are the main active components that exert their effects. These findings shed light on the mechanism of action of TCEA and its potential active components, providing a feasible approach for the treatment of COPD.

2025-01-01·Gene

ZC3H13 may participate in the ferroptosis process of sepsis-induced cardiomyopathy by regulating the expression of Pnn and Rbm25

Article

作者: Chang, Jing ; Huang, Yan ; Lin, Wenji ; Li, Haihong

BACKGROUNDN6 methyladenosine (m6A) regulates the ferroptosis in different diseases. However, there is no report about the role of the m6A regulator in the ferroptosis process of septic cardiomyopathy (SCM). This study aims to find the potential m6A regulator that participates in the ferroptosis process of SCM.METHODSGenes related to m6A were identified through bioinformatics analysis in GSE142615. Then, the expression of Rrp8, Trmt6, Trmt61a, Ythdf1, and ZC3H13 was detected in lipopolysaccharide (LPS)-treated HL-1 cells using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). After overexpression or interference with ZC3H13, Cell Counting Kit-8 measured cell proliferation, flow cytometry detected apoptosis and reactive oxygen species (ROS) accumulation was observed. Then, we identified the potential downstream genes of ZC3H13 through further bioinformatics analysis followed by qRT-PCR and western blotting validation.RESULTSThere were five differentially expressed genes related to m6A, including Rrp8, Trmt6, Trmt61a, Ythdf1, and ZC3H13. The expression of Rrp8, Trmt6, Trmt61a, Ythdf1, and ZC3H13 mRNA was significantly up-regulated in the LPS-treated HL-1 cells, with ZC3H13 having the highest expression. Furthermore, overexpression of ZC3H13 inhibited the proliferation of HL-1 cells and promoted apoptosis and ROS accumulation. While, interfering with ZC3H13 promoted the proliferation of LPS-treated HL-1 cells, and reduced apoptosis and ROS accumulation. Additionally, si-ZC3H13 promoted the expression of Pnn, GPX4, and SLC7A11; while inhibiting the expression of Rbm25 and Caspase 3.CONCLUSIONSIn a word, the silence of ZC3H13 increased the proliferation and ferroptosis-related protein expression, decreased apoptosis and ROS accumulation, as well as maybe by regulating Pnn and Rbm25 expression.

2025-01-01·Cellular Signalling

The SIRT6/BAP1/xCT signaling axis mediates ferroptosis in cisplatin-induced AKI

Article

作者: Zhou, Xiangjun ; Yang, Songyuan ; Ye, Zehua ; Chen, Lijia ; Li, Wei ; Cheng, Fan ; Din, Shikuan

BACKGROUNDCisplatin is extensively utilized in clinical settings for treating solid tumors; However, its use is restricted because of the kidney damage caused by side effects. Moreover, currently, no effective medications have been approved to prevent or treat acute kidney injury induced by cisplatin. Our research indicates that sirtuin 6 (SIRT6) can inhibit ferroptosis induced by cisplatin, and the use of SIRT6 agonists can alleviate acute kidney injury caused by cisplatin.METHODSAn animal model of cisplatin-induced acute kidney injury (AKI) was established, followed by RNA sequencing to identify potential differentially expressed genes (DEGs) and associated pathways. To explore the role of SIRT6 in this model, SIRT6 knockout mice were generated, and recombinant adeno-associated virus was employed to achieve SIRT6 overexpression in the mice. In vitro, cells were cultured in a cisplatin-containing medium to establish a cisplatin-induced cell model. The function of SIRT6 was further investigated by overexpressing or knocking down the gene using lentiviral plasmids. To elucidate the underlying molecular mechanisms, we employed RNA sequencing, performed bioinformatics analyses, and conducted chromatin immunoprecipitation assays.RESULTSRNA sequencing and Western blot analyses revealed a significant reduction in SIRT6 expression in mice with cisplatin-induced acute kidney injury (AKI). Enhancing SIRT6 expression improved renal function, reduced ferroptosis, and mitigated kidney damage, whereas SIRT6 knockout exacerbated kidney injury and heightened ferroptosis. Mechanistically, RNA sequencing, bioinformatics analysis, and chromatin immunoprecipitation assays demonstrated that SIRT6 inhibits ferroptosis by reducing the acetylation of histone H4K9ac at the BAP1 promoter. Furthermore, in vitro studies demonstrated that the SIRT6 agonist UBCS039 can alleviate cisplatin-induced acute kidney injury, highlighting its potential therapeutic role in mitigating cisplatin's damaging effects. However, further research is needed to fully elucidate the underlying mechanisms and to validate these findings in vivo.CONCLUSIONOur findings underscore the critical role of the SIRT6/BAP1/xCT axis in regulating ferroptosis, particularly via the downregulation of SIRT6, in the context of cisplatin-induced acute kidney injury (AKI). This suggests that SIRT6 could be a promising therapeutic target for treating cisplatin-induced AKI. However, additional research is required to explore the specific mechanisms and fully assess the therapeutic potential of SIRT6 in this context.

项与 SLC7A11 相关的新闻（医药）

2024-10-23

·今日头条

【Lancet子刊】瑞金医院刘炳亚团队发现SLC7A9抑制剂如何精准打击胃癌，开辟化疗新天地

【导读】 SLC7A9负责二元氨基酸和胱氨酸（内流）与中性氨基酸（外排）的交换。胱氨酸/半胱氨酸转运与铁死亡有关。 2024年10月21日，上海交通大学医学院附属瑞金医院刘炳亚团队在期刊《eBioMedicine》上发表了题为“SLC7A9 suppression increases chemosensitivity by inducing ferroptosis via the inhibition of cystine transport in gastric cancer”的研究论文。研究结果表明， SLC7A9作为铁死亡抑制剂，独立于SLC7A11。因此，针对SLC7A9的治疗干预有望使胃癌细胞对铁死亡和化疗治疗敏感，并最终改善胃癌患者的预后。 https://www-thelancet-com.libproxy1.nus.edu.sg/journals/ebiom/article/PIIS2352-3964(24)00411-0/fulltext 铁死亡与癌症 01 SLC7A11在铁死亡和癌症发展中起着关键作用。许多研究都集中在SLC7A9与慢性肾病之间的关系上，已发现SLC7A9突变可导致各种类型的胱氨酸尿症。此外，研究人员已经确定了SLC7A9表达水平与细胞内GSH水平之间的关系。这些发现表明，SLC7A9可能在铁死亡的调节中发挥作用。在团队之前对胃癌的差异调节网络（DRN）分析中，SLC7A9被确定为胃癌与癌旁组织之间最重要的差异调节基因（DRG）。在这项研究中，团队证明SLC7A9表达在TP53缺陷型胃癌中上调，并且，SLC7A9的上调通过抑制铁死亡诱导化疗耐药，与SLC7A1无关，表明SLC7A9充当铁死亡抑制因子。 SLC7A9抑制铁死亡并在PDO和PDX模型中，抵抗erastin的作用 02 PDO模型是使用胃癌组织建立的。为了进一步证实SLC7A9在人胃癌中的致癌作用，团队用erastin处理细胞并评估类器官的生长。PDO的生长速率表明，erastin抑制P2类器官（低SLC7A9表达水平）的活力，比P5类器官（高SLC7A9表达水平）更有效；SLC7A9表达水平较高的PDO，显示出更高的IC50erastin的值。erastin比P5/shNC类器官更有效地抑制P5/shSLC7A9类器官的活力，而erastin的抗肿瘤作用在P2/oeSLC7A9类器官中减弱。团队发现，SLC7A9敲低或erastin治疗抑制肿瘤生长，双重治疗显示出最大的治疗效果。IHC分析显示，shSLC7A9和erastin治疗的肿瘤中ki67阳性细胞的数量少于对照肿瘤，ki67阳性细胞在shSLC7A9+erastin治疗的肿瘤中最少。GPX4阳性细胞，表现出与ki67阳性细胞相同的趋势。这些发现证实， SLC7A9驱动铁死亡耐药，SLC7A9敲除使胃癌细胞在体内对铁死亡敏感。 SLC7A9在PDO和PDX模型中逆转了erastin的肿瘤杀伤作用，shSLC7A9在体内使erastin致敏。总结 03 1. SLC7A9的作用： SLC7A9通过促进胱氨酸的转运，增加GSH的产生，并促进GPX4蛋白的合成，从而抑制脂质过氧化物的积累和铁死亡。 2. SLC7A9与胃癌： SLC7A9的表达水平在TP53突变的胃癌中升高，且p53可以转录抑制SLC7A9。SLC7A9在胃癌中的作用，可能比SLC7A11更重要。 3. 铁死亡与化疗耐药性：铁死亡有助于癌细胞克服对化疗的耐药性，并可能逆转对放疗、免疫疗法和靶向治疗的耐药性。 4. SLC7A9作为治疗靶点： SLC7A9的表达介导了细胞对化疗的耐药性，敲低SLC7A9可以使胃癌细胞对化疗药物敏感。 5. 研究的未来方向：未来的研究方向包括设计siRNA药物和探索靶向SLC7A9的化合物。参考资料： 1.Sung, H. ∙ Ferlay, J. ∙ Siegel, R.L. ∙ et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin. 2021; 71:209-249 2.Joshi, S.S. ∙ Badgwell, B.D. Current treatment and recent progress in gastric cancer CA A Cancer J Clin. 2021; 71:264-279 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 上海｜11月15日-16日 ▶ 2024第一届中国类器官转化医学大会 🕓 上海｜11月21日-24日 ▶ 第七届上海国际肿瘤内科学论坛 🕓 全国｜2024年12月-2025年03月 ▶ 中国转化医学产业大会 🕓 上海｜2025年02月28日-03月01日 ▶ 第四届长三角单细胞组学技术应用论坛暨空间组学前沿论坛点击对应文字查看详情

临床结果临床研究临床终止

2024-10-08

·生物制品圈

免疫逃逸新机制！中国药科大学合作发文：改善肿瘤治疗效果的新策略

【导读】尽管免疫检查点阻断疗法（ICB）已广泛应用于黑色素瘤治疗，但其临床响应率仍然较低。环状非编码RNA（circRNAs）在癌症进展中起着关键作用，可能是限制ICB治疗效果的关键因素。 9月28日，中国药科大学与南京医科大学研究人员合作在期刊《Molecular Cancer》上发表了题为“Circular RNA-encoded oncogenic PIAS1 variant blocks immunogenic ferroptosis by modulating the balance between SUMOylation and phosphorylation of STAT1”的研究论文，本研究中，与仅接受PD-1抑制剂治疗的对照组相比，联合治疗组中circPIAS1的表达显著下调，并显示出更高的蛋白质编码潜力。circPIAS1主要定位于细胞核中，在肿瘤组织中的表达明显高于相邻组织，在促进癌细胞增殖方面发挥着关键作用。该circRNA可以通过编码一种独特的108个氨基酸组成的多肽来发挥其促进癌症的功能，并阻碍ICB疗法的效果。机制上，circPIAS1-108aa通过招募SUMO E3连接酶Ranbp2来增强STAT1的SUMO化，从而激活SLC7A11/GPX4信号通路的转导，并限制IFNγ诱导的免疫原性细胞坏死。此外，ASO-circPIAS1与PD-1抑制剂的联合使用能够有效抑制黑色素瘤的生长，并在体内显著增强免疫药物的疗效。总之，本研究揭示了一种独特的机制，即由circPIAS1在黑色素瘤中编码的108aa肽通过调节STAT1的SUMO化和磷酸化之间的平衡，显著阻碍了ICB疗法诱导的免疫原性铁死亡，从而实现免疫逃避。这项工作揭示了circPIAS1-108aa是限制黑色素瘤免疫治疗效果的关键因素，并提出了改善ICB治疗效果的有希望的策略。 https://molecular-cancer-biomedcentral-com.libproxy1.nus.edu.sg/articles/10.1186/s12943-024-02124-6 背景知识 01 黑色素瘤起源于黑色素细胞的癌变，具有高度侵袭性、转移性和致命性。近年来，就发病率而言，它已成为增长最快的癌症类型之一，对全球个体构成严重威胁。目前，ICB疗法是治疗黑色素瘤的主要方法，如靶向PD-1/PD-L1的抑制剂，可破坏癌细胞对T细胞的保护作用，激活CD8+ T细胞并释放IFNγ，增强STAT1磷酸化，抑制SLC7A11/GPX4轴的下游转导，最终触发癌细胞免疫原性铁死亡。尽管取得了这些进展，但仍有超过一半的患者未能从ICB治疗中获得显著益处，甚至对治疗无响应。黑色素瘤中是否存在维持肿瘤进展并阻碍免疫检查点抑制剂起效的关键因素尚不清楚且迫在眉睫。环状非编码RNA（circRNA）是一种由前体mRNA反向剪接形成环状共价闭合结构的调节性非编码RNA。这些circRNA对RNA酶具有抵抗力，并在体内保持稳定的功能。circRNA在疾病发展中经常扮演关键角色，尤其是在癌症中，它们作为关键调节因子发挥作用。据报道，circRNA可以通过多种途径影响癌症进展。此外，在KRAS突变肿瘤细胞中上调circATXN7转录物，它可以直接与p65亚基结合阻断其核定位，导致免疫疗法抵抗。同样地，circYBX1在高度侵袭性的肝细胞癌组织中也极为丰富，通过与YBX1相互作用，引发YBX1的液-液相分离，进而招募HnRNP家族降解TPM4 mRNA，加速肝癌转移。最近的研究表明，尽管circRNAs通常被归类为非编码RNA，但其中一部分具有编码蛋白质的能力。这些肽已被确定为影响肿瘤进展的关键因素。之前的研究发现，circ-E-cadherin是促进胶质母细胞瘤进展的关键因素。可是，其作用机制并不涉及miRNA sponge，而是依赖于多轮的翻译过程生成一个含有254个氨基酸的肽。该肽与EGFR的CR2结构域相互作用，最终重新激活下游EGFR通路，抵消EGFR抑制剂的作用。抑制circPIAS1能增强PD-1抑制剂的抗黑色素瘤效果 02 为了研究circPIAS1在黑色素瘤中的作用及其作为治疗靶点的潜力，研究人员在C57BL/6J小鼠中建立了黑色素瘤皮下接种模型，并给予不同的治疗。研究人员设计了特异性的ASO来靶向并敲低circPIAS1的连接位点。使用PD-1抑制剂和IgG阴性对照来评估了ASO-circPIAS1对体内免疫疗法的影响。动物实验结果表明，包括体重和组织在内的小鼠健康状况未受治疗影响。此外，在单独给予ASO-circPIAS1或PD-1抑制剂后，肿瘤体积降低。联合治疗显示出最明显的抑制作用。这些发现表明，抑制circPIAS1与PD-1抑制剂的结合显著增强了免疫疗法的疗效，凸显了circPIAS1在限制免疫检查点抑制剂的抗肿瘤作用方面的作用。靶向circPIAS1可显著增强免疫检查点抑制剂的抗黑色素瘤效果为了探究circPIAS1是否可以通过抑制STAT1磷酸化过程来减轻免疫介导的铁死亡，研究人员对肿瘤组织进行了IHC染色分析。ASO-circPIAS1与PD-1抑制剂的联合治疗导致P-STAT1水平显著升高，而GPX4水平则呈相反趋势。此外，研究人员通过蛋白质免疫印迹试验观察了小鼠肿瘤组织中上述蛋白质的水平变化，这些结果与IHC结果一致。先前的研究表明，发生铁死亡的癌细胞可以调节免疫微环境并增强肿瘤免疫浸润。因此，研究人员评估了肿瘤组织中的铁死亡和免疫微环境。结果显示，癌细胞中的铁死亡显著增加，联合治疗后免疫环境中CD8+T细胞和IFNγ水平显著升高。这些发现表明，circPIAS1敲低可以增强免疫检查点抑制剂的疗效，为改善临床黑色素瘤免疫治疗提供了一种新的方法。研究小结 03 总之，本研究发现了一种独特的108个氨基酸长的肽（circPIAS1-108aa），由circPIAS1在人和小鼠黑色素瘤细胞中编码，它会削弱IFNγ的抗癌作用。此外，本研究揭示了黑色素瘤免疫逃逸的一种新机制，其中circPIAS1-108aa通过招募SUMO E3连接酶Ranbp2来增强STAT1(Tyr701)的SUMO化，从而抑制STAT1的磷酸化。这一过程激活了SLC7A11/GPX4信号通路，阻碍了IFNγ诱导的免疫原性细胞坏死，最终降低了ICB疗法在黑色素瘤中的有效性。【参考资料】https://molecular-cancer-biomedcentral-com.libproxy1.nus.edu.sg/articles/10.1186/s12943-024-02124-6 识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所转载文章系出于天坛生物，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

免疫疗法临床结果

2024-09-27

·生物探索

Mol Cell | OPA1协调线粒体ROS和整合应激反应调控细胞铁死亡

引言铁死亡是一种铁依赖的非凋亡性细胞死亡形式，这种细胞死亡形式与传统的细胞凋亡、坏死等形式不同，主要由细胞内铁的积累以及脂质过氧化引发【1, 2】。细胞内存在抗氧化机制试图抑制这些氧化物的积累，其中谷胱甘肽过氧化物酶4（GPx4）是抵御铁死亡的主要防御机制之一，它是一种PL氢过氧化物酶，利用谷胱甘肽（GSH）作为辅助因子催化氧化脂质的还原【3, 4】。GSH的生成依赖于半胱氨酸的供应，而半胱氨酸通过细胞膜上的转运体导入细胞，一旦GSH耗尽，GPx4无法正常发挥功能，细胞将变得易于发生铁死亡【5】。线粒体是活性氧（ROS）生成的主要场所，高水平的ROS会导致细胞的氧化性死亡，而抑制线粒体ROS特别是脂质ROS可以减轻铁死亡，说明线粒体在直接促进脂质过氧化中起到的关键作用。但是，关于线粒体如何调控铁死亡的具体仍然未知。近日，来自美国阿尔伯特-爱因斯坦医学院的Richard N. Kitsis在Molecular Cell上发表了论文OPA1 promotes ferroptosis by augmenting mitochondrial ROS and suppressing an integrated stress response。在本研究中，作者探究了线粒体蛋白OPA1在调控铁死亡中的作用，研究发现OPA1能通过调节线粒体ROS和整合应激反应来调控细胞对铁死亡的敏感性。 OPA1是一种线粒体动力蛋白样GTP酶，负责线粒体形态发生、融合和能量动力学。鉴于OPA1在控制线粒体结构和能量方面的作用，作者推测OPA1可能是通过线粒体依赖机制来调节铁死亡的关键节点。为了研究OPA1在铁死亡中的作用，作者使用了小鼠胚胎成纤维细胞（MEFs）和人类U2OS骨肉瘤细胞，并在这两种细胞中分别敲除Opa1，通过三种方法（半胱氨酸剥夺、小分子抑制剂诱导和脂质过氧化检测）诱导铁死亡。研究发现，OPA1的缺失可以显著减少脂质过氧化和由多种铁死亡诱导剂引起的细胞死亡。这表明OPA1可能是铁死亡的一个正调控因子，在铁死亡中起到促进作用。此外，OPA1的GTPase活性在这个过程中十分重要，GTPase功能缺陷突变体（K301A）不能拯救Opa1缺失导致的铁死亡抑制。研究人员进一步的机制研究发现，OPA1促进铁死亡的能力与其促进线粒体融合的能力无关，因为在缺失Opa1的细胞中表达L-OPA1（具有促进线粒体融合能力）和S-OPA1（不具有促进线粒体融合能力）两种异构体时，所有细胞的死亡率相似，脂质过氧化水平也无显著差异。除了介导线粒体融合外，OPA1还调控线粒体嵴的超微结构、电子传递链复合物（ETC）的组装以及氧化磷酸化。因此，缺失Opa1导致线粒体嵴的结构混乱和ETC I、III、IV和V的组装受损，但不影响复合物II的组装。有趣的是，OPA1在通过半胱氨酸剥夺和xGT抑制剂（erastin）导致的线粒体ROS和脂质ROS积累中发挥作用，而在通过GPx4抑制剂（RSL3）引发的ROS积累中不发挥作用。这种差异性解释了为什么Opa1缺失的MEFs对erastin诱导的铁死亡比对RSL3更具抗性。为了理解OPA1缺失如何赋予细胞对铁死亡的抗性，研究人员接下来探究了OPA1缺失是否影响xCT-GSH-GPx4通路。研究发现，OPA1的缺失上调了xCT基因的转录和活性，进而GSH水平也得到提升。更加重要的是，OPA1缺失细胞表现出更高的GPx4蛋白水平，并在erastin和RSL3处理期间GPx4水平并没有很快的下降，这与细胞对铁死亡的抗性一致。敲低xCT基因使得OPA1缺失细胞对铁死亡的抗性消失，细胞重新变得对铁死亡敏感。这些结果表明，OPA1缺失通过上调xCT-GSH-GPx4通路赋予细胞对铁死亡的抗性。研究人员随后通过RNA-seq分析发现，ATF4转录因子是整合应激反应的关键转录激活因子，能够上调一些铁死亡抗性相关基因（如xCT基因）的表达，OPA1的缺失导致ATF4表达上调以及整合应激反应的激活。文章的最后，作者还探究了OPA1对脂质代谢的影响。通过脂质组学分析，磷脂、溶血磷脂、甘油酯、游离脂肪酸和鞘脂在OPA1缺失的细胞中表现出显著变化。其中，多不饱和脂肪酸的某些种类表现出减少的现象，大多数单不饱和脂肪酸则显著富集。多不饱和脂肪酸在铁死亡过程中特别容易发生过氧化，而单不饱和脂肪酸可以减少细胞膜上脂质过氧化的积累，这表明单不饱和脂肪酸的积累可能在抑制铁死亡中发挥了潜在作用。模式图（Credit: Molecular Cell）参考文献 https://www-nature-com.libproxy1.nus.edu.sg/articles/d41591-024-00013-5 1. Dixon, S.J., Lemberg, K.M., Lamprecht, M.R., Skouta, R., Zaitsev, E.M., Gleason, C.E., Patel, D.N., Bauer, A.J., Cantley, A.M., Yang, W.S., et al. (2012). Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072. 2. Dixon, S.J., and Stockwell, B.R. (2019). The hallmarks of ferroptosis. Annu. Rev. Cancer Biol. 3, 35–54. 3. Yang, W.S., SriRamaratnam, R., Welsch, M.E., Shimada, K., Skouta, R., Viswanathan, V.S., Cheah, J.H., Clemons, P.A., Shamji, A.F., Clish, C.B., et al. (2014). Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331. 4. Seiler, A., Schneider, M., Fo ̈ rster, H., Roth, S., Wirth, E.K., Culmsee, C., Plesnila, N., Kremmer, E., Ra ̊ dmark, O., Wurst, W., et al. (2008). Glutathione peroxidase 4 senses and translates oxidative stress into 12/ 15-lipoxygenase dependent- and AIF-mediated cell death. Cell Metab. 8, 237–248 5. Poltorack, C.D., and Dixon, S.J. (2022). Understanding the role of cysteine in ferroptosis: progress & paradoxes. FEBS Journal 289, 374–385. https://doi-org.libproxy1.nus.edu.sg/10.1016/j.molcel.2024.07.020 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述