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更新于：2025-05-07

NCOA4

更新于：2025-05-07

基本信息

别名

70 kDa androgen receptor coactivator、70 kDa AR-activator、Androgen receptor coactivator 70 kDa protein

+ [10]

简介

Cargo receptor for the autophagic turnover of the iron-binding ferritin complex, playing a central role in iron homeostasis (PubMed:25327288, PubMed:26436293). Acts as an adapter for delivery of ferritin to lysosomes and autophagic degradation of ferritin, a process named ferritinophagy (PubMed:25327288, PubMed:26436293). Targets the iron-binding ferritin complex to autolysosomes following starvation or iron depletion (PubMed:25327288). Ensures efficient erythropoiesis, possibly by regulating hemin-induced erythroid differentiation (PubMed:26436293). In some studies, has been shown to enhance the androgen receptor AR transcriptional activity as well as acting as ligand-independent coactivator of the peroxisome proliferator-activated receptor (PPAR) gamma (PubMed:10347167, PubMed:8643607). Another study shows only weak behavior as a coactivator for the androgen receptor and no alteration of the ligand responsiveness of the AR (PubMed:10517667). Binds to DNA replication origins, binding is not restricted to sites of active transcription and may likely be independent from the nuclear receptor transcriptional coactivator function (PubMed:24910095). May inhibit activation of DNA replication origins, possibly by obstructing DNA unwinding via interaction with the MCM2-7 complex (PubMed:24910095).

关联

项与 NCOA4 相关的药物

Selenium nanoparticles(SeNPs)

靶点

NCOA4 x XBP1

作用机制

NCOA4 modulators [+1]

在研机构

广东医科大学附属医院 [+1]

原研机构-

在研适应症

缺血性肾病 [+2]

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

NCOA4 antagonists(China Pharmaceutical University)

靶点

NCOA4

作用机制

NCOA4 antagonists

在研机构

中国药科大学

原研机构

中国药科大学

在研适应症

肝损伤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 NCOA4 相关的临床结果

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100 项与 NCOA4 相关的转化医学

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0 项与 NCOA4 相关的专利（医药）

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1,015

项与 NCOA4 相关的文献（医药）

2025-08-01·Tissue and Cell

Gastrodin promotes ferroptosis in CRC cells by inhibiting SKP2 to reduce NCOA4 ubiquitination

Article

作者: Xu, Zhijie ; Yan, Shengyu ; Xie, Yafeng ; Liu, Wanying ; Ding, Yating ; Cheng, Zhidong ; Zhang, Qiao

BACKGROUNDGastrodin, an important component of traditional Chinese medicine, is gaining interest because of its anti-tumor effects. Ferroptosis is a new mode of cell death, which has emerged as a promising target for colorectal cancer (CRC) treatment. This research investigates the action mechanism of gastrodin on the process of CRC by inducing ferroptosis.METHODSThe mRNA and protein levels were measured via qRT-PCR and western blot. Cell viability was assessed by CCK-8 assay. The cell proliferation was examined using colony formation assay. Live-Dead cell staining was evaluated by Calcein-AM/PI staining. The effect of ferroptosis was evaluated by detecting the levels of reactive oxygen species (ROS), intracellular total iron, ferrous iron (Fe^2 +), malondialdehyde (MDA), glutathione (GSH) by kits, as well as the expressions of subunit solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), ferritin light chain (FTL) and acyl-CoA synthetase long chain family member 4 (ACSL4) by western blot. Co-immunoprecipitation (Co-IP) assay was applied to analyze the binding relationship between S-phase kinase-associated protein 2 (SKP2) and nuclear receptor coactivator 4 (NCOA4).RESULTSGastrodin could induce ferroptosis in CRC cells. SKP2 ameliorated gastrodin induced ferroptosis in CRC cells. Besides, SKP2 mediated NCOA4 degradation by ubiquitination. SKP2 was involved in ferroptosis of CRC cells by regulating NCOA4. Gastrodin induced ferroptosis in CRC cells via SKP2/NCOA4 axis.CONCLUSIONGastrodin repressed SKP2 expression, deactivated NCOA4 ubiquitination thus elevated NCOA4 expression, and promoted ferroptosis in CRC cells.

2025-06-01·Biochemical Pharmacology

A novel way of regression of pregnant corpus luteum during parturition in mice: The ferroptosis associated with NCOA4-mediated ferritinophagy

Article

作者: Zhu, Jun ; Kuang, Haibin ; Li, Yue ; Zhao, Hongru ; Yang, Bei ; Li, Fei ; Cheng, Yanmin ; Zhang, Yulu ; Yin, Jiting ; Song, Jiahao

Numerous studies have shown that inappropriate regression of corpus luteum would lead to adverse pregnancy outcomes during gestation. However, the detailed mechanisms and types of programmed cell death involved in the regression of pregnant corpus luteum are largely unknown. Here, we investigated whether ferroptosis and ferritinophagy were involved in luteal regression during parturition in mice and related mechanisms. The results showed that ferroptosis and ferritinophagy were both involved in luteal regression during mice peri-parturition in vivo. Erastin (ferroptosis agonist) treatment significantly accelerated luteal regression and induced premature labor in pregnant mice. PGF2α treatment induced the ferroptosis and ferritinophagy of luteal cells in vitro. Nevertheless, inhibition or promotion of ferroptosis significantly altered the states of PGF2α-induced luteal cell viability and ferroptosis. Furthermore, inhibition of autophagy (3-methyladenine co-treatment) alleviated PGF2α-induced ferritinophagy and ferroptosis of luteal cells, and knockdown of NCOA4 reduced the degradation of FTH1 and the level of ferroptosis of luteal cells induced by PGF2α. In summary, our current data demonstrated that the ferroptosis associated with NCOA4-mediated ferritinophagy was a novel way of luteal regression during peri-parturition in mice. Targeting ferroptosis in the corpus luteum may be a therapeutic strategy for preventing luteal insufficiency in the future.

2025-06-01·Fish & Shellfish Immunology

Eucommia ulmoides leaf extracts combined with Astragalus polysaccharides: Effects on growth, antioxidant capacity, and intestinal inflammation in juvenile large yellow croaker (Larimichthys crocea)

Article

作者: Qi, Qiong ; Zhang, Jiaonan ; Li, Changhui ; Shao, Jianchun ; Chen, Xiaojuan ; Lv, Huiyuan ; Chen, Xinhua ; Wang, Xuexi ; Liu, Qianqian

Eucommia ulmoides leaf extract (ELE) and Astragalus polysaccharides (APS) have been widely used as immunopotentiators in aquaculture. Our prior research on large yellow croaker (Larimichthys crocea) demonstrated that dietary 1 g/kg APS bolstered fish immunity and antioxidant defense. However, the combined effect of ELE and APS in juvenile large yellow croaker remains unknown. Hence, this study aimed to investigate the synergistic effect of ELE and APS on the growth, antioxidant capacity, and intestinal inflammation in large yellow croaker. A total of 1200 fish were divided into five groups and fed diets with 1 g/kg APS and varying ELE levels: 0 g/kg (ELE0), 0.25 g/kg (ELE0.25), 0.5 g/kg (ELE0.5), 1 g/kg (ELE1), and 2 g/kg (ELE2). After an 8-week feeding period, the ELE0.5 and ELE1 groups showed superior weight gain rate, specific growth rate, and feed efficiency compared to other groups. The ELE1 group also had elevated trypsin and lipase activities in the intestine, whereas α-amylase activity was not influenced by ELE addition. Antioxidant enzyme activities, such as hepatopancreas superoxide dismutase (SOD) and glutathione peroxidase (GPX) in the ELE1 group were significantly enhanced, while malondialdehyde (MDA) levels decreased with increasing ELE. Intestinal morphology revealed the highest villi height in proximal and distal intestines of ELE1 group, with no significant change in mucosal thickness. In terms of cytokines, the ELE1 group showed significant down-regulation of pro-inflammatory (tnf-α, il-1β and il-6) and up-regulation of anti-inflammatory (il-4/13a, il-10 and tgf-β) markers, modulated by MAPK and mTOR signaling. In conclusion, this study indicates that supplementing diets with 1 g/kg ELE alongside 1 g/kg APS in juvenile large yellow croaker offers the best synergistic effect on fish immunity, including enhanced growth, antioxidant capacity, and relieved intestinal inflammation through MAPK and mTOR signaling.

项与 NCOA4 相关的新闻（医药）

2025-04-05

·ioncology

例例在望 | PD-L1突然入局是“神来之笔”还是“迷魂阵”——RET基因融合伴PD-L1高表达的肺腺癌病例分享

点击蓝字关注我们例例在望微专辑扫描二维码可查看更多内容刘文静，马锐丨辽宁省肿瘤医院胸内二科2012年RET基因重排被定义为非小细胞肺癌的驱动因素之一。RET基因重排在肺腺癌的发生率为1%-2% 主要包括RET基因融合（KIF5B exon15-RET exon12融合，CCDC6-RET融合，TRIM33-RET融合，NCOA4-RET融合），RET基因突变等。RET基因融合的非小细胞肺癌临床特点多为不吸烟（或少吸烟）、较年轻（<60岁）的患者。ARROW和LIBRETTO-431研究评估了选择性RET抑制剂普拉塞替尼和塞普替尼在晚期非小细胞肺癌的疗效，两种抑制剂的客观有效率均达60%以上。I/II期临床研究ARROW显示在既往接受治疗的RET融合阳性非小细胞肺癌患者，接受普拉提尼治疗的中位PFS为16.6个月，中位OS达44.3个月。III期研究LIBRETTO-431揭示了赛普替尼一线治疗PFS为 24.8个月，较化疗联合免疫组显著延长13.6个月，进一步明确了靶向治疗作为RET融合阳性的非小细胞肺癌标准治疗的一线推荐，改写了RET融合阳性晚期非小细胞肺癌的治疗指南。PD-L1表达可改变存在基因突变的非小细胞肺癌患者的生存预后。研究发现，EGFR突变阳性的肺腺癌，若其携带PD-L1高表达，接受靶向治疗时获益有限。而对于KRAS突变的非小细胞肺癌患者，若伴有 PD-L1 高表达，免疫治疗带来的获益则更为显著。那么，PD-L1表达对RET基因融合患者的治疗会产生怎样的影响呢？本文报道2例RET基因融合伴PD-L1高表达的晚期肺腺癌一线应用选择性RET抑制剂治疗的病例，旨在探讨PD-L1高表达对RET融合阳性患者治疗的影响。马锐教授辽宁省肿瘤医院胸内二科主任，肿瘤学博士中国医科大学、大连医科大学硕士研究生导师学术兼职：中国临床肿瘤学会理事会理事，中国老年学学会老年肿瘤专业委员执行委员，中国老年学学会老年肿瘤专业委员肺癌分委会常务委员，中国医药教育协会肺部肿瘤专委会常务委员，辽宁省生命科学学会常务理事，中国抗癌协会肺癌专业委员会委员，辽宁省抗癌协会理事会理事，辽宁省生命科学学会肺癌专业委员会主任委员，辽宁省抗癌协会肿瘤转移专业委员会主任委员，辽宁省抗癌协会肿瘤标志物专业委员会副主任委员，辽宁省医学会内科学分会委员会常务委员，辽宁省生命科学学会老年肿瘤专业委员会常务委员中国肿瘤生物治疗杂志、中国实用内科、医学与哲学，沈阳医学院学报等多家杂志编委及审稿专家。主持省部级、市级课题9项，获辽宁省科技进步三等奖2项、沈阳市科技进步二等奖1项，第一及通讯作者发表论文40余篇。刘文静医学博士，主任医师，中国医科大学硕士研究生导师社会兼职：中国中医药信息学会中西医外科智能诊疗分会常务理事,中国医药教育协会中医药慢病防治工程委员会委员,辽宁省免疫学会肿瘤营养与免疫分会委员,北京医学奖励基金会肺癌医学青年专家委员会委员,辽宁省中西医结合学会盆底康复专业委员会委员，沈阳市劳动能力鉴定委员会专家参与国家自然基金1项，主持省级、市级课题3项，发表I区等SCI及核心期刊论文8篇。获ESMO ASIA 2018青年旅行基金，2017年良医汇“35under35最具潜力青年肿瘤医生”全国100强。病例153岁男性，无吸烟饮酒史，脑血栓病史。2024年7月胸部CT：右肺下叶见一团块状软组织密度影，范围约10.8×9.0cm，边界不清，周围并见斑片状磨玻璃密度影，右肺下叶前底段支气管阻塞。纵隔及右肺门见肿大淋巴结影。考虑右肺下叶支气管肺癌。伴纵隔及右肺门淋巴结转移瘤，右下肺静脉瘤栓。2024.7.23行肺穿刺取病理:（肺）腺癌伴有神经内分泌分化。NGS基因检测：RET KIF5B exon15-RET exon12 融合。PD-L1（克隆号28-8）TPS=90%。临床诊断：右肺下叶恶性肿瘤 cT4N2aM1a IVA期，肺门淋巴结继发恶性肿瘤，纵隔淋巴结继发恶性肿瘤，胸腔积液，大脑中动脉取栓术后。治疗经过：2024.08开始口服赛普替尼（160mg，bid）。2024.09复查胸CT评效PR。2025.1复查胸CT：右肺下叶外基底段见一不规则形实性肿块，大小约94mm×87mm，边缘呈分叶状，其内密度不匀。右侧胸腔见少许水样密度影。评效PD，PFS=5个月。患者未同意再次组织活检，目前应用卡博替尼治疗，仍在随访中。治疗期间未出现毒性反应。2024.082024.09 评效PR2025.01 评效PD病例255岁男性，无吸烟史，有饮酒嗜好。2024年11月常规体检胸CT：左肺上叶占位性病变，大小约2.7×2.4cm，恶性可能大；左肺、左侧叶间胸膜及胸膜下多发微小结节，转移待除外。左侧胸腔积液，部分骨质改变。2024年12月初肺穿刺活检，病理：(肺)腺癌。NGS基因检测: CCDC6-RET（exon1-exon12）融合突变阳性(丰度:13.21%)。PD-L1表达阳性(TPS=35%，CPS=45)。临床诊断：左肺上叶恶性肿瘤cT1cN2bM1a IVA期，肺门继发恶性肿瘤，纵隔继发恶性肿瘤，胸膜继发恶性肿瘤，胸腔积液。治疗经过：2025.01开始口服普拉替尼（400mg，qd）。2025.03复查胸CT：左肺上叶、右肺上叶、左肺斜裂见多发实性结节影，长径范围约3-17mm，较大者大小约17mm×12mm，位于左肺上叶下舌段，可见分叶、毛刺、胸膜凹陷、棘状突起征象。纵隔内小淋巴结。评效PR，随访中。治疗期间未出现毒性反应。2024.122025.03 评效PR病例讨论普拉替尼和塞普替尼均是新一代RET靶点选择性抑制剂，两者均能有效抑制RETV804L/M耐药突变体。相对于卡博替尼、凡德他尼等多靶点抑制剂，普拉替尼和塞普替尼对RET基因融合具有更高的选择性。本文分享的两个病例，均为RET融合突变伴PD-L1高表达的晚期肺腺癌患者一线应用选择性RET-TKIs且均快速起效，其中一例治疗有效持续时间仅5个月，另一例处于随访状态。对于RET融合阳性的NSCLC患者，一线选择RET-TKIs毋庸置疑。但是，同时伴有PD-L1高表达者，治疗又将何去何从？PD-L1是否成为RET-TKIs治疗路上的“绊脚石”？目前发现的选择性RET酪氨酸激酶抑制剂（TKIs）的耐药机制包括RETV804L/M突变体、RET G810R 溶剂前沿突变体、RETG810C/S/R突变，RETG810C突变。此外，PTEN缺失性功能异常、PIK3CA突变、KRAS突变、BRAF突变、MET扩增等也参与了RET-TKIs耐药。然而，PD-L1高表达对RET-TKIs疗效的影响及其机制尚不清楚。回顾既往研究，EGFR敏感突变并伴随PD-L1高表达时，靶向治疗获益有限，且预后可能更差。PD-L1高表达已经成为EGFR敏感突变的非小细胞肺癌靶向治疗耐药的机制之一。机制研究发现，PI3C信号通路突变（PI3CA和PTEN突变）的存在可能导致这组患者对EGFR-TKIs产生原发耐药。此外，PD-L1/BAG-1信号通路可通过上调TGF-Smad通路及YAP1表达，持续激活细胞外调节的ERK通路，诱导EGFR-TKIs耐药。因此，我们推测PD-L1可能通过耐药相关的信号通路影响RET-TKIs敏感性。研究报道，13%-50%RET基因融合的患者可同时存在PD-L1高表达。RET基因融合伴PD-L1高表达的患者，能否获益于免疫治疗？Hegde等收集了70例RET阳性的恶性肿瘤患者，其中非小细胞肺癌29例（41%）。共18例患者经免疫组确认了PD-L1表达状态，15例为非小细胞肺癌。18例患者中，4例（22.2%）PD-L1表达强阳性（≥50%），4例（22.2%）PD-L1中度表达（1% ~ 49%），10例（55.6%）PD-L1无表达（<1%）。15例非小细胞肺癌中，8例（53.3%）PD-L1表达强阳性或中度表达，7例（46.7%）PD-L1无表达。18例患者中，3例PD-L1强阳性患者接受了免疫治疗，2例因疾病进展治疗持续时间不到2个月，另1例因免疫联合化疗的毒性反应，于治疗后0.7个月停止治疗。1例PD-L1中度表达的患者接受了免疫联合化疗，分析时已经治疗了1.4个月，疾病尚无进展。Michael等收集了74例RET基因重排的肺癌患者，26例确认了PD-L1表达状态。6例（23%）PD-L1表达在1% ~ 49%，5例（19%）PD-L1表达为50%或更高。PD-L1表达为50%和30%的患者接受免疫治疗，无进展生存时间仅为1.3个月、2.5个月。同样，高TMB患者（5.27和3.51个突变/Mb）接受免疫治疗后，PFS仅为3.1和1.3个月。从这些小样本研究可以看出，RET基因融合伴PD-L1高表达的患者接受免疫治疗的疗效并不理想。这种免疫治疗的低应答率可能包含以下原因。首先，驱动基因突变的肿瘤中，PD-L1表达并非与PD-L1/PD-L1抑制剂的疗效相关。肿瘤细胞PD-L1高表达可能反映了细胞通过PD-L1途径被激活导致靶向治疗的耐药，而不是免疫反应的标志。其次，单一驱动基因突变的肺癌免疫微环境被视为“cold，non-inflamed”，肿瘤组织内缺少免疫细胞浸润或炎症迹象。也就是说，PD-L1高表达很少伴随高水平CD8+肿瘤浸润淋巴细胞，而后者被认为是PD-L1/PD-L1抑制剂的主要效应产物。结论新一代RET选择性抑制剂是RET基因融合突变的一线优选。RET融合阳性且伴PD-L1高表达的晚期非小细胞肺癌患者，依据指南推荐，我们选择了“有靶打靶”的治疗原则，两例患者均快速起效，但其中一例出现了短期耐药。研究表明，PD-L1“突然入局”似乎并未给RET基因融合阳性的非小细胞肺癌患者带来免疫治疗的惊喜。耐药后的治疗模式该走向何方，是PD-1/PD-L1联合抗血管靶向治疗及化疗的四药模式，还是VEGF/PD-1结合的特异性抗体与化疗的三药联合，或是抗体偶联药物的挑战，期待新的临床数据为患者提供更加有效的治疗策略。对于上述病例的耐药后的基因状态我们也会持续关注，耐药后病理组织的基因检测，更有助于多维度解析耐药机制。参考文献（上下滑动可查看）1.Takahashi, M., J. 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Am Soc Clin Oncol Educ Book, 2020. 40: p. 372-384.https://doi-org.libproxy1.nus.edu.sg/10.1200/edbk_28079519.Dudnik, E., E. Bshara, A. Grubstein, L. Fridel, T. Shochat, L.C. Roisman, M. Ilouze, A.B. Rozenblum, S. Geva, A. Zer, O. Rotem, A.M. Allen, and N. Peled, Rare targetable drivers (RTDs) in non-small cell lung cancer (NSCLC): Outcomes with immune check-point inhibitors (ICPi). Lung Cancer, 2018. 124: p. 117-124.https://doi-org.libproxy1.nus.edu.sg/10.1016/j.lungcan.2018.07.04420.Schoenfeld, A.J., H. Rizvi, C. Bandlamudi, J.L. Sauter, W.D. Travis, N. Rekhtman, A.J. Plodkowski, R. Perez-Johnston, P. Sawan, A. Beras, J.V. Egger, M. Ladanyi, K.C. Arbour, C.M. Rudin, G.J. Riely, B.S. Taylor, M.T.A. Donoghue, and M.D. Hellmann, Clinical and molecular correlates of PD-L1 expression in patients with lung adenocarcinomas. Ann Oncol, 2020. 31(5): p. 599-608.https://doi-org.libproxy1.nus.edu.sg/10.1016/j.annonc.2020.01.06521.Negrao, M.V., F. Skoulidis, M. Montesion, K. Schulze, I. Bara, V. Shen, H. Xu, S. Hu, D. Sui, Y.Y. Elamin, X. Le, M.E. Goldberg, K. Murugesan, C.J. Wu, J. Zhang, D.S. Barreto, J.P. Robichaux, A. Reuben, T. Cascone, C.M. Gay, K.G. Mitchell, L. Hong, W. Rinsurongkawong, J.A. Roth, S.G. Swisher, J. Lee, A. Tsao, V. Papadimitrakopoulou, D.L. Gibbons, B.S. Glisson, G. Singal, V.A. Miller, B. Alexander, G. Frampton, L.A. Albacker, D. Shames, J. Zhang, and J.V. Heymach, Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer. J Immunother Cancer, 2021. 9(8).https://doi-org.libproxy1.nus.edu.sg/10.1136/jitc-2021-002891（来源：《肿瘤瞭望》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

免疫疗法临床3期临床2期临床结果

2025-02-23

·精准药物

FIC！四川大学欧阳亮课题组报道选择性ERK1/2-ERK5抑制剂，对耐药三阴性乳腺癌有效

近日，四川大学华西医院生物治疗全国重点实验室孙秋/欧阳亮科研团队在《Signal Transduction and Targeted Therapy》（IF=40.80）杂志发表研究成果，成功设计并合成了一种新型ERK1/2 - ERK5代偿机制抑制剂 SKLB-D18，在三阴乳腺癌小分子治疗研究方面取得进展。三阴乳腺癌是一种治疗难度较大的癌症亚型，目前针对它的激酶靶向治疗面临着诸多挑战，其中癌细胞对 KRAS、MEK 等靶点药物产生的获得性耐药问题尤为突出。细胞外调节蛋白激酶 1/2（ERK1/2）处于相关信号通路的末端，是一个重要的治疗靶点，但针对它的单药治疗在临床试验中效果有限，主要原因在于疗效欠佳和容易出现耐药性。此外，抑制 ERK1/2 会导致 ERK5 的代偿性激活，这也限制了相关治疗的效果。该科研团队经过深入研究，发现多靶点协同靶向可能是克服耐药问题的有效策略。于是，他们运用计算机辅助药物设计，结合优势骨架拼接和药效团融合原理，设计并合成了同时针对 ERK1/2 和 ERK5 的选择性抑制剂 SKLB-D18。研究数据显示，SKLB-D18 对 ERK1/2 和 ERK5 具有纳摩尔级别的抑制活性，具备高亲和力和激酶选择性。在体外实验中，能有效抑制三阴乳腺癌细胞的增殖和转移。体内实验结果表明，口服 SKLB-D18 能显著抑制肿瘤生长，抑瘤效果优于现有的临床 ERK1/2 抑制剂 BVD-523，也超过了 BVD-523 与 ERK5 抑制剂 XMD8-92 的联合用药方案，且未观察到明显毒性反应，显示出良好的耐受性。研究团队利用 X 射线晶体学技术解析了 SKLB-D18 与 ERK2 和 ERK5 的共晶结构，清晰展示了其与靶点的结合模式，为理解其选择性和作用机理提供了重要依据。进一步研究表明，SKLB-D18作为自噬激动剂，可通过调控mTOR/p70S6K信号轴和NCOA4介导的铁自噬途径，在克服三阴性乳腺癌多药耐药中发挥关键作用。此次研究揭示了三阴乳腺癌中 ERK1/2 - ERK5 的代偿机制，为三阴乳腺癌的治疗提供了新的方向。不过，研究团队也指出，SKLB-D18 在长期使用过程中是否会诱导新的耐药机制，以及其在体内复杂环境中的代谢途径等问题，还需要进一步研究。后续，团队将围绕这些问题展开探索，同时也会研究 SKLB-D18 与其他抗癌药物联合治疗的策略，以及评估它在不同类型肿瘤中的治疗效果，推动该成果向临床应用转化。声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

临床结果临床2期临床1期

2025-01-14

·生物世界

Cell子刊：上海中医药大学栾鑫/张卫东/张莉君团队开发基于铁死亡的乳腺癌治疗新策略

撰文丨王聪编辑丨王多鱼排版丨水成文乳腺癌占全球所有新发癌症病例的 11.7%，是全球最常见的癌症之一。其中，三阴性乳腺癌（TNBC）因其侵袭性强、预后差和高转移潜力，成为最凶险的乳腺癌亚型，5 年生存率仅为11%。由于缺乏其他乳腺癌亚型的特异性分子靶点，传统化疗和靶向治疗在 TNBC 中的疗效明显有限。因此，迫切需要开发有效的治疗策略和药物来改善 TNBC 患者的生存结局，降低死亡率。 2025年1月13日，上海中医药大学栾鑫、张卫东、张莉君等人在 Cell 子刊 Cell Reports Medicine 上发表了题为：Dual ferroptosis induction in N2-TANs and TNBC cells via FTH1 targeting: A therapeutic strategy for triple-negative breast cancer 的研究论文。该研究发现了隐丹参酮（CTS）的一种衍生物小分子——CT-1，通过靶向 FTH1，诱导N2 型肿瘤相关中性粒细胞（N2 型 TAN）和三阴性乳腺癌（TNBC）细胞的双重铁死亡，从而为三阴性乳腺癌（TNBC）的治疗带来了新策略。中性粒细胞作为具有抗炎功能的关键免疫细胞，在三阴性乳腺癌（TNBC）的发展、转移和预后中发挥重要作用。肿瘤相关中性粒细胞（TAN）与 TNBC 的不良预后密切相关，其可分为两种亚型：抗肿瘤 N1 型、促肿瘤 N2 型。在 TNBC 的早期阶段，N1 型 TAN 主要通过分泌 I 型干扰素（IFN-α）和通过白细胞介素-18（IL-18）激活自然杀伤（NK）细胞来抑制肿瘤生长。但随着 TNBC 的进展，N2 型 TAN 占比增加。这些 N2 型 TAN 通过释放中性粒细胞弹性蛋白酶（NE）和上调增殖诱导配体（APRIL）促进 TNBC 细胞增殖。此外，它们还通过分泌趋化因子、血管内皮生长因子（VEGF）和基质金属蛋白酶-9（MMP-9）促进肿瘤血管生成。它们与循环肿瘤细胞（CTC）的相互作用也导致中性粒细胞胞外诱捕网（NET）的释放，促进血行转移，增加肺转移的风险。虽然阻断或消除中性粒细胞浸润肿瘤可在一定程度上抑制 TNBC 的生长和转移，但中性粒细胞是体内最丰富的免疫细胞，完全阻碍其迁移会损害整体免疫防御。因此，对 N2 型 TAN 的精准靶向和选择性清除，成为 TNBC 治疗方案开发中的一个重要焦点。铁死亡（Ferroptosis）是一种受控的非凋亡细胞死亡新形式，以多不饱和磷脂的过度过氧化为特征，与多种生物学过程密切相关，包括铁代谢、氨基酸代谢、脂质代谢以及谷胱甘肽、还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）、磷脂和辅酶Q10的生物合成。在这些过程中，多不饱和脂质含量是铁死亡易感性的关键决定因素。最近的单细胞转录组和全转录组分析揭示了 TAN 中参与铁死亡调控的基因的富集和上调。脂质积累在乳腺癌肿瘤组织中的 N2 型 TAN 中更为明显，这些储存的脂质被转移到肿瘤细胞，为其生长和转移提供燃料。这提示了我们，N2 型 TAN 可能特别容易发生铁死亡。 TNBC 还表现出与铁死亡相关的异常基因表达模式，包括铁代谢相关的转铁蛋白受体和脂代谢相关的 ACSL4 表达上调，以及铁输出转运蛋白的表达下调。这些失调的基因表达，特别是在铁和脂质代谢方面，为TNBC提供了大量的铁和脂质，使癌细胞特别容易受到铁死亡诱导药物的影响。因此，确定一个能够同时诱导 N2 型 TAN 和 TNBC 细胞发生铁死亡的精准靶点，具有重要的治疗意义。在这项最新研究中，研究团队发现了一种小分子——CT-1，它是隐丹参酮（CTS）的衍生物，能够有效抑制三阴性乳腺癌（TNBC）的生长，同时显著降低肿瘤组织中 N2 型肿瘤相关中性粒细胞（N2 型 TAN）的比例。此外，CT-1 在体外和体内均能诱导 N2 型 TAN 和 TNBC 细胞同时发生铁蛋白自噬诱导的铁死亡，其作用机制是通过靶向铁蛋白重链-1（FTH1）并促进 NCOA4 与铁蛋白的相互作用来实现的。这些发现表明，CT-1 作为一种有前景的治疗剂，能够诱导 N2 型肿瘤相关中性粒细胞（N2 型 TAN）和三阴性乳腺癌（TNBC）细胞发生铁死亡，为通过靶向 FTH1 治疗三阴性乳腺癌提供了新策略。论文链接： https://www-cell-com.libproxy1.nus.edu.sg/cell-reports-medicine/fulltext/S2666-3791(24)00686-4 设置星标，不错过精彩推文开放转载欢迎转发到朋友圈和微信群微信加群为促进前沿研究的传播和交流，我们组建了多个专业交流群，长按下方二维码，即可添加小编微信进群，由于申请人数较多，添加微信时请备注：学校/专业/姓名，如果是PI/教授，还请注明。点在看，传递你的品味

临床研究临床终止