Cancer letters最新文献_第9页

Integrated multi-omics analyses identified the H3K18la-based spatiotemporal characteristics and risk-stratified treatment strategy in lung adenocarcinoma 综合多组学分析确定了基于h3k18la的肺腺癌时空特征和风险分层治疗策略。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-11-20 DOI: 10.1016/j.canlet.2025.218158

Ao Shen , Sufei Zheng , Xiaoya Tang , Yuxin Yao , Enzhi Yin , Nan Sun , Jie He

Lung adenocarcinoma (LUAD) is the most common histological type of lung cancer, characterized by high mortality, recurrence, and metastasis. Despite advancements in therapies such as surgery, targeted treatment and immunotherapy, therapeutic resistance and immune evasion remain significant challenges. In our study, we integrated multi-omics data, including spatial transcriptomics, single-cell RNA sequencing, H3K18la ChIP-seq, CRISPR data and bulk transcriptomics, to explore the metabolic heterogeneity of LUAD, particularly focusing on glycolysis and histone H3K18 lactylation (H3K18la). Our findings revealed significant intra- and inter-tumoral metabolic heterogeneities, with glycolysis and H3K18la-related genes being more active in tumor regions. We also identified H3K18la-related gene activities as a marker of LUAD progression, demonstrating its strong correlation with glycolysis and tumor cell phenotypes. Based on these insights, we developed a machine learning-based prognostic model (termed as “Kla.Sig”) that predicts patient survival and immunotherapy response, with validation across multiple cohorts. The model highlighted the immunosuppressive tumor microenvironment in high-risk score patients, with lower immune cell infiltration and higher immune evasion ability. In addition, we developed an online R shiny application “LUAD-Kla.Sig” to facilitate users’ estimation of survival based on Kla.Sig model. In-silico drug screening suggests that targeting Polo-like kinase 1 (PLK1) with BI-2536 could be an effective strategy for high-risk LUAD patients. This study offers a deeper understanding of LUAD metabolism and immune evasion at single-cell and spatial resolution, proposing potential therapeutic targets and a risk-stratified treatment strategy for precision medicine.

肺腺癌（LUAD）是最常见的肺癌组织学类型，具有高死亡率、高复发和转移的特点。尽管手术、靶向治疗和免疫治疗等治疗方法取得了进展，但治疗耐药性和免疫逃避仍然是重大挑战。在我们的研究中，我们整合了多组学数据，包括空间转录组学、单细胞RNA测序、H3K18la ChIP-seq、CRISPR数据和大量转录组学，来探索LUAD的代谢异质性，特别是关注糖酵解和组蛋白H3K18乳酸化（H3K18la）。我们的研究结果揭示了显著的肿瘤内和肿瘤间代谢异质性，糖酵解和h3k18la相关基因在肿瘤区域更活跃。我们还发现h3k18la相关基因活性是LUAD进展的标志，表明其与糖酵解和肿瘤细胞表型有很强的相关性。基于这些见解，我们开发了一种基于机器学习的预后模型（称为“Kla.Sig”），可以预测患者的生存和免疫治疗反应，并在多个队列中进行了验证。该模型突出了高危评分患者肿瘤微环境免疫抑制，免疫细胞浸润较低，免疫逃避能力较高。此外，我们开发了一个在线R shiny应用程序“LUAD-Kla.Sig”，方便用户基于Kla.Sig模型进行生存估计。计算机药物筛选表明，用BI-2536靶向polo样激酶1 （PLK1）可能是治疗高风险LUAD患者的有效策略。该研究在单细胞和空间分辨率上对LUAD代谢和免疫逃避有了更深入的了解，为精准医疗提供了潜在的治疗靶点和风险分层治疗策略。

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引用次数: 0

HOXC8-activated TRIM22/NF-κB pathway promotes stemness in colorectal cancer hoxc8激活的TRIM22/NF-κB通路促进结直肠癌的干性。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-11-19 DOI: 10.1016/j.canlet.2025.218156

Song Tan , Yifan Chen , Yizhen Chen , Shaolin Liu , Changshun Yang , Yulong Mi , Xiaojun Lin , Houqiang Li , Hengrui Liu , Weihua Li , Shengtao Lin

Colorectal cancer (CRC) remains a significant global health challenge and is characterized by high incidence and mortality rates. Although the homeobox gene family has been implicated in oncogenic processes, the precise functional role of HOXC8 in regulating CRC proliferation and stemness remains poorly defined. Cancer cells with stem-related properties, a distinct cellular subpopulation endowed with self-renewal and differentiation capacities, play pivotal roles in tumor initiation, metastasis, and therapeutic resistance. In this study, we demonstrate that HOXC8 overexpression promotes CRC cell proliferation, enhances stemness properties, and confers chemoresistance. Mechanistically, HOXC8 transcriptionally activates TRIM22, leading to the ubiquitination and degradation of IκBα, which subsequently potentiates NF-κB signaling to drive stemness maintenance in CRC cells. These findings delineate a previously unrecognized HOXC8/TRIM22/NF-κB signaling axis that critically regulates tumor progression, offering a promising molecular target for therapeutic intervention in CRC.

结直肠癌（CRC）仍然是一个重大的全球健康挑战，其特点是高发病率和死亡率。尽管同源盒基因家族与致癌过程有关，但HOXC8在调节结直肠癌增殖和干性中的确切功能作用仍不清楚。具有干细胞相关特性的癌细胞是一个独特的细胞亚群，具有自我更新和分化能力，在肿瘤的发生、转移和治疗抵抗中起着关键作用。在这项研究中，我们证明HOXC8过表达促进结直肠癌细胞增殖，增强干细胞特性，并赋予化学耐药。在机制上，HOXC8转录激活TRIM22，导致i -κB α的泛素化和降解，随后增强NF-κB信号传导，驱动CRC细胞的干细胞维持。这些发现揭示了先前未被识别的HOXC8/TRIM22/NF-κB信号轴对肿瘤进展的关键调控，为CRC的治疗干预提供了一个有希望的分子靶点。

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引用次数: 0

Corrigendum to “Gobal crotonylome reveals that HNRNPC and its crotonylation promote p53-deficient tumor growth by stabilizing CCND1 and MCM3 mRNAs” [Cancer Lett. 628 (2025) 217854] “global crotonyome揭示HNRNPC及其crotonylation通过稳定CCND1和MCM3 mrna促进p53缺陷肿瘤生长”的更正[Cancer Lett]. 628(2025) 217854。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-11-17 DOI: 10.1016/j.canlet.2025.218042

Liangjie Sun , Xiaolei Gao , Meng Wang , Yixin Zhang , Ruiqing Sun , Yang Chen , Yan Bai , Yi Li , Lan Luo , Chong Ding , Yixiang Wang

引用次数: 0

ANGPTL3 promotes colorectal carcinoma progression and metastasis through regulating COL1A2 transcription via interacting with integrin αVβ3 ANGPTL3通过与整合素αVβ3相互作用调控COL1A2转录，促进结直肠癌的进展和转移。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-11-17 DOI: 10.1016/j.canlet.2025.218150

Zhiping Chen , Zhenxing Liang , Tanxing Cai , Xin Yang , Haiqing Jie , Wei Xiao , Xiaobin Zheng , Huashan Liu , Liang Huang , Li Xiong , Guolin Li , Liang Kang

Distant metastasis constitutes the predominant determinant of adverse prognosis and mortality in colorectal cancer (CRC), with hepatic dissemination representing the most prevalent metastatic pattern and primary contributor to CRC-related deaths. The pathogenesis of colorectal liver metastases (CRLM) involves a multistep cascade modulated by intricate tumor-host interactions, yet the molecular drivers remain incompletely elucidated. Through comparative transcriptomic profiling of matched primary tumors (PT) and liver metastases (LM) in CRC patients, we identified angiopoietin-like protein 3 (ANGPTL3) as a metastasis-associated molecular signature showing significant upregulation in LM tissues correlating with aggressive clinicopathological features. Functional characterization revealed that ANGPTL3 overexpression orchestrated pro-metastatic reprogramming, potentiating in vitro proliferation, migration, and invasion capacities, while concurrently driving subcutaneous tumorigenesis and hepatic colonization in vivo. Conversely, ANGPTL3 silencing markedly attenuated these malignant phenotypes. Mechanistic investigations revealed that ANGPTL3 binds to integrin αVβ3 via its FLD domain, inducing ITGB3 phosphorylation at Y773 and activating the downstream FAK/Src-JAK2/STAT3 axis. This cascade culminates in the transcriptional upregulation of the core extracellular matrix (ECM) component COL1A2, resulting in aberrant collagen deposition and ECM remodeling. The remodeled microenvironment in turn facilitates epithelial-mesenchymal transition (EMT) and angiogenesis, thereby promoting CRC progression and metastasis. Our findings thus delineate the ANGPTL3-integrin αVβ3-STAT3-COL1A2 axis as a central driver of CRC metastasis, nominating ANGPTL3 as both prognostic biomarker for metastatic risk stratification and therapeutic target amenable to molecular intervention in CRC management.

远处转移是结直肠癌（CRC）不良预后和死亡率的主要决定因素，肝脏播散是最普遍的转移方式，也是CRC相关死亡的主要原因。结直肠肝转移（CRLM）的发病机制涉及由复杂的肿瘤-宿主相互作用调节的多步骤级联，但分子驱动因素仍未完全阐明。通过比较CRC患者匹配原发肿瘤（PT）和肝转移瘤（LM）的转录组学分析，我们发现血管生成素样蛋白3 （ANGPTL3）是转移相关的分子标记，在肝癌组织中显示显著上调，与侵袭性临床病理特征相关。功能表征显示，ANGPTL3过表达介导了促转移重编程，增强了体外增殖、迁移和侵袭能力，同时在体内驱动皮下肿瘤发生和肝脏定植。相反，ANGPTL3沉默可显著减轻这些恶性表型。机制研究表明，ANGPTL3通过其FLD结构域与整合素αVβ3结合，诱导ITGB3在Y773位点磷酸化，激活下游FAK/Src-JAK2/STAT3轴。这一级联反应最终导致核心细胞外基质（ECM）成分COL1A2的转录上调，导致异常的胶原沉积和ECM重塑。重塑的微环境反过来促进上皮-间质转化（EMT）和血管生成，从而促进结直肠癌的进展和转移。因此，我们的研究结果表明，ANGPTL3-整合素αVβ3-STAT3-COL1A2轴是结直肠癌转移的主要驱动因素，并将ANGPTL3列为结直肠癌转移风险分层的预后生物标志物和适合分子干预的治疗靶点。

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引用次数: 0

SB225002 enhances radiosensitivity in cervical cancer via direct neutrophil inhibition and tumor cell suppression SB225002通过直接中性粒细胞抑制和肿瘤细胞抑制增强宫颈癌的放射敏感性。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-11-17 DOI: 10.1016/j.canlet.2025.218153

Yanghong Ni , Xiaoting Zhou , Yan Tang , Wenyan Ren , Xiao Liang , Yi Lin , Houhui Shi , Furong Qing , Aqu Alu , Ruyu Pi , Jian Liu , Xia Zhao , Min Luo , Xiawei Wei

Radiotherapy resistance is a major contributor to therapeutic failure in cervical cancer, largely due to the immunosuppressive tumor microenvironment (TME). Increasing clinical and experimental evidence underscores the role of neutrophils infiltration in reducing the efficacy of radiation therapy. Additionally, the CXCR2/CXCL signaling axis has been identified as a key regulator of neutrophils recruitment.

Our study demonstrates that radiotherapy significantly enhances neutrophils infiltration by activating CXCR2-CXCL signaling and drives their polarization toward a pro-tumor N2-like phenotype through TGF-β signaling in cervical cancer. Further investigation revealed that CXCR2 antagonist SB225002 exerts a synergistic effect with radiotherapy and concurrent chemoradiotherapy in cervical cancer, primarily via inhibiting neutrophils infiltration and alleviating the immunosuppressive TME. Meanwhile, SB225002 exerts direct antitumor activity and enhances the radiosensitivity of cervical cancer cells by facilitating DNA double-strand breaks, promoting G2/M phase cell cycle arrest, and inducing apoptosis.

In summary, our findings highlight neutrophils inhibition via CXCR2 antagonist as a promising therapeutic strategy to enhance cervical cancer responsiveness to radiotherapy.

放疗抵抗是宫颈癌治疗失败的主要原因，主要是由于免疫抑制肿瘤微环境（TME）。越来越多的临床和实验证据强调中性粒细胞浸润在降低放射治疗疗效中的作用。此外，CXCR2/CXCL信号轴已被确定为中性粒细胞募集的关键调节因子。我们的研究表明，在宫颈癌中，放疗通过激活CXCR2-CXCL信号显著增强中性粒细胞的浸润，并通过TGF-β信号驱动其向促肿瘤的n2样表型极化。进一步研究发现，CXCR2拮抗剂SB225002主要通过抑制中性粒细胞浸润和减轻免疫抑制性TME，与宫颈癌放疗及同步放化疗发挥协同作用。同时，SB225002通过促进DNA双链断裂、促进G2/M期细胞周期阻滞、诱导凋亡等方式直接发挥抗肿瘤活性，增强宫颈癌细胞的放射敏感性。总之，我们的研究结果强调通过CXCR2拮抗剂抑制中性粒细胞是一种有希望的治疗策略，可以增强宫颈癌对放疗的反应性。

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引用次数: 0

Manganese mediates nucleoplasm distribution of cGAS to enhance systemic antitumor immunity and drive abscopal effect 锰介导cGAS核质分布，增强全身抗肿瘤免疫，驱动体外效应。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-11-17 DOI: 10.1016/j.canlet.2025.218154

Tiance Wang , Zijian Lv , Runjia Fan , Jiejie Liu , Yan Zhang , Chunmeng Wang , Qianyi Ming , Meixia Chen , Yulin Jia , Qingming Yang , Zhengfan Jiang , Qian Mei , Weidong Han

Abscopal effect remains rare and clinically unpredictable because of immunosuppressive mechanisms and inadequate immune activation. This phenomenon may stem from cyclic GMP-AMP synthase (cGAS) sequestration within the nucleus, where high-affinity nucleosome-DNA interactions potently suppress cGAS activation. Our study elucidates the capacity of manganese (Mn²⁺) to overcome this limitation through cytoplasmic relocalization and potentiation of cGAS activity, thereby enabling abscopal responses. We demonstrated that Mn²⁺ disrupts nucleosomal constraints on cGAS, permitting robust double-stranded DNA (dsDNA) sensing and activation. This molecular reprogramming amplifies cytosolic cGAS-STING signaling cascades and IFN-I production in irradiated tumors, potentiating systemic antitumor immunity. Notably, Mn²⁺ exerts direct immunostimulatory effects on adaptive immunity by activating T cells, creating synergistic therapeutic benefits. Preliminary clinical observations in advanced metastatic malignancies have demonstrated that Mn²⁺ augments abscopal responses during radiotherapy. These findings mechanistically delineate the dual role of Mn²⁺ in modulating tumor-intrinsic cGAS-STING activation and immune effector functions, supporting its therapeutic application in combination with radioimmunotherapy regimens to overcome tumor microenvironment immunosuppression and induce abscopal effect.

由于免疫抑制机制和免疫激活不足，体外效应仍然罕见且临床不可预测。这种现象可能源于细胞核内环GMP-AMP合成酶（cGAS）的隔离，其中高亲和力核小体- dna相互作用可有效抑制cGAS的激活。我们的研究阐明了锰（Mn2+）通过细胞质再定位和增强cGAS活性来克服这一限制的能力，从而实现了体外反应。我们证明了Mn2+破坏核小体对cGAS的限制，允许强大的双链DNA （dsDNA）传感和激活。这种分子重编程放大了细胞内cGAS-STING信号级联和辐照肿瘤中IFN-I的产生，增强了全身抗肿瘤免疫。值得注意的是，Mn2+通过激活T细胞对适应性免疫产生直接的免疫刺激作用，从而产生协同治疗效果。晚期转移性恶性肿瘤的初步临床观察表明，Mn2+增强放射治疗期间的体外反应。这些发现从机制上描述了Mn2+在调节肿瘤固有的cGAS-STING激活和免疫效应功能中的双重作用，支持其与放射免疫治疗方案联合应用以克服肿瘤微环境免疫抑制并诱导体外效应。

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引用次数: 0

Cancer metastasis mediated by circadian rhythm disruption: Molecular mechanisms to clinical significance and implications 由昼夜节律紊乱介导的癌症转移：分子机制的临床意义和意义。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-11-17 DOI: 10.1016/j.canlet.2025.218155

Guoqing Li , Yuxuan Wan , Gaoyuan Cui , Ke Jiang , Jiaoao Su , Saili Duan , Shi Chang

Circadian rhythm, a biological clock-regulated physiological phenomenon with a periodicity of approximately 24 h, is controlled by multiple core molecules, including BMAL1, CLOCK, PERs, and CRYs. Multiple lines of evidence demonstrates that circadian rhythm disruption can influence the metastatic cascade by modulating epithelial-mesenchymal transition, cancer stem cells, circulating tumor cells, the tumor microenvironment, and immune surveillance. Mechanistically, clock dysregulation drives extracellular matrix remodeling and alters matrix stiffness, fostering a pro-metastatic niche. It also disrupts immune homeostasis by inducing T cell exhaustion, promoting NK cell senescence, and reprogramming macrophage polarization toward tumor-supportive phenotypes. Therapeutically, targeting core circadian molecules and implementing chronotherapy have shown significant clinical potential. This review highlights the role of circadian rhythm disruption in promoting various stages of the metastatic cascade across cancers and explores the therapeutic potential of circadian-targeted agents and chronotherapy in controlling cancer metastasis. By synthesizing current evidence, we propose a novel conceptual framework that positions circadian rhythm disruption as a temporal gatekeeper of metastatic plasticity, offering a pan-cancer unifying model and new insights into the development of chronotherapeutic strategies aimed at controlling metastasis.

昼夜节律是由BMAL1、CLOCK、PERs、CRYs等多个核心分子控制的生理现象，其周期约为24小时。多种证据表明，昼夜节律中断可以通过调节上皮-间质转化、癌症干细胞、循环肿瘤细胞、肿瘤微环境和免疫监视来影响转移级联反应。从机制上讲，生物钟失调驱动细胞外基质重塑和改变基质硬度，促进转移生态位。它还通过诱导T细胞衰竭、促进NK细胞衰老和巨噬细胞极化向肿瘤支持表型重编程来破坏免疫稳态。在治疗方面，针对核心昼夜节律分子和实施时间疗法已显示出显著的临床潜力。这篇综述强调了昼夜节律破坏在促进癌症转移级联的各个阶段中的作用，并探讨了昼夜节律靶向药物和时间疗法在控制癌症转移方面的治疗潜力。通过综合目前的证据，我们提出了一个新的概念框架，将昼夜节律破坏定位为转移可塑性的时间看门人，提供了一个泛癌症统一模型，并为旨在控制转移的时间治疗策略的发展提供了新的见解。

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引用次数: 0

Fibrillarin-dependent 2′-O-methylation modulates RPS28 ribosome incorporation and oncogenic translation 纤维蛋白依赖的2'- o -甲基化调节RPS28核糖体整合和致癌翻译。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-11-17 DOI: 10.1016/j.canlet.2025.218124

Paula Groza , Kanchan Kumari , Margalida Esteva-Socias , Johanna Schott , Devi Prasad Bhattarai , Joanna J. Sajkowska , Rubin Dasgupta , Carlos Peula , Eliana Destefanis , Chloe Williams , Virginie Marchand , Pernilla Wikström , Rebecca Wiberg , Ana Bosch Campos , Jonathan D. Gilthorpe , Bogdan Pop , Andre Mateus , Yuri Motorin , Erik Dassi , Katja Petzold , Francesca Aguilo

Fibrillarin (FBL), a core component of the C/D box small nucleolar ribonucleoprotein (snoRNP) complex, catalyzes the 2′-O-methylation (Nm) of the ribose 2′-hydroxyl moiety in ribosomal RNA (rRNA). Distinct Nm patterns contribute to ribosome heterogeneity, which is linked to selective translation of oncogenes. FBL dysregulation generates an aberrant Nm signature in triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype. This study investigated the role of FBL in TNBC via translation-driven mechanisms. Our findings show that FBL knockdown impairs oncogenic traits, triggers metabolic stress, and reduces the translation efficiency of oncogenes, such as metastasis-associated protein 1 (MTA1), interleukin-1 receptor-associated kinase 1 (IRAK1), and thymosin beta 10 (TMSB10). RiboMethSeq confirmed that the rRNA Nm sites exhibited differential sensitivity to FBL depletion. Additionally, FBL knockdown led to alterations in 18S ribosome structure confirmed by SHAPE and specifically reduced RPS28 incorporation into ribosomes. Notably, silencing RPS28 also disrupted both the oncogenic phenotype and downregulated MTA1, IRAK1, and TMSB10 expression. These findings reveal a complex interplay between FBL, rRNA Nm modifications, and RPS28 in shaping oncogenic protein pools and ribosomal composition in TNBC, offering promising insights into therapeutic approaches targeting this aggressive cancer subtype.

纤原蛋白（fibrarin， FBL）是C/D盒小核核核糖核蛋白（snoRNP）复合物的核心组分，可催化核糖体RNA （rRNA）中核糖2′-羟基部分的2′- o -甲基化（Nm）。不同的Nm模式有助于核糖体的异质性，这与癌基因的选择性翻译有关。FBL失调在三阴性乳腺癌（TNBC）中产生异常的Nm信号，TNBC是最具侵略性的乳腺癌亚型。本研究通过翻译驱动机制探讨了FBL在TNBC中的作用。我们的研究结果表明，FBL敲低会损害致癌性状，引发代谢应激，并降低癌基因的翻译效率，如转移相关蛋白1 （MTA1）、白细胞介素-1受体相关激酶1 （IRAK1）和胸腺酶β 10 （TMSB10）。RiboMethSeq证实，rRNA Nm位点对FBL缺失表现出不同的敏感性。此外，FBL敲低导致SHAPE证实的18S核糖体结构改变，并特异性减少RPS28与核糖体的结合。值得注意的是，沉默RPS28也破坏了致癌表型，下调了MTA1、IRAK1和TMSB10的表达。这些发现揭示了FBL、rRNA纳米修饰和RPS28在TNBC中形成致癌蛋白池和核糖体组成的复杂相互作用，为针对这种侵袭性癌症亚型的治疗方法提供了有希望的见解。

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引用次数: 0

CD40 drives tumor growth in non-small cell lung cancer via non-canonical immune-independent mechanisms CD40通过非典型免疫非依赖性机制驱动非小细胞肺癌的肿瘤生长

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-11-17 DOI: 10.1016/j.canlet.2025.218151

Yujie Liu , Chandra Bhushan Prasad , Zhaojun Qiu , Deepika Singh , Nicholas Bean , Shravya Honne , Xiaoli Zhang , Chunhong Yan , Zaibo Li , Baek Kim , Qi-En Wang , Junran Zhang

引用次数: 0

Corrigendum to “Synergistic targeting of FASN and HMGCS1 by cerulenin enhances tumor cell ferroptosis sensitivity through rewiring lipid metabolism and blocking GPX4 biosynthesis” [Cancer Lett. (2025) 633 217992] “蓝核蛋白协同靶向FASN和HMGCS1，通过脂质代谢重组和阻断GPX4生物合成增强肿瘤细胞铁凋亡敏感性”[Cancer Lett]的更正。（2025） 633 217992]。

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters

Pub Date : 2025-11-16 DOI: 10.1016/j.canlet.2025.218149

Chaoyi Xia , Xue Sun , Yang Wang , Jingshu Min , Wenxia Zhang , Chong Wei , Lianchao Gao , Feiyang Zhao , Abdur Raheem Aleem , Wanting Peng , Yiren Hu , Qiang Zhang , Caiyun Fu

引用次数: 0