Biochimica et biophysica acta. Reviews on cancer最新文献_第2页

Protein palmitoylation and immune regulation in pancreatic ductal adenocarcinoma: Integrating insights from cross-cancer studies 胰腺导管腺癌中的蛋白棕榈酰化和免疫调节：来自交叉癌症研究的整合见解。

IF 9.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Reviews on cancer

Pub Date : 2026-01-14 DOI: 10.1016/j.bbcan.2026.189532

Xiaotong Cui , Changlei Li , Xue Zhong , Ao Sun , Yingying Lan , Zusen Wang

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunologically “cold” tumor microenvironment (TME), marked by a dense stromal barrier, impaired antigen presentation, and extensive infiltration of immunosuppressive cells. In recent years, protein S-palmitoylation, a reversible lipid modification, has emerged as a critical mechanism regulating immune signaling, receptor trafficking, and membrane localization of immune-related proteins. This review highlights the multifaceted roles of S-palmitoylation in shaping the immunological landscape of PDAC. We systematically discuss its involvement in immune checkpoint regulation, T-cell activation, antigen presentation, and the function of myeloid-derived suppressor cells (MDSCs), integrating evidence from both PDAC and other cancer types. Special attention is given to key palmitoylated molecules, including programmed death-ligand 1 (PD-L1), cluster of differentiation 80 (CD80), lymphocyte-specific protein tyrosine kinase (LCK), linker for activation of T cells (LAT), interferon-induced transmembrane proteins (IFITMs), and major histocompatibility complex class I (MHC-I), and their potential roles in the immunosuppressive network of PDAC. Moreover, we explore therapeutic strategies targeting palmitoylation, such as the use of selective palmitoyltransferase inhibitors, the design of palmitoylation-deficient CAR-T cells, and the development of nanotechnology-based delivery platforms. By incorporating cross-cancer insights, we propose that palmitoylation is a promising regulatory axis for reprogramming the PDAC immune microenvironment and overcoming resistance to immunotherapy.

胰腺导管腺癌（PDAC）以免疫“冷”肿瘤微环境（TME）为特征，其特征是间质屏障致密，抗原呈递受损，免疫抑制细胞广泛浸润。近年来，蛋白质s -棕榈酰化作为一种可逆的脂质修饰，已成为调节免疫信号、受体运输和免疫相关蛋白膜定位的关键机制。本文综述了s -棕榈酰化在形成PDAC免疫景观中的多方面作用。我们系统地讨论了它在免疫检查点调节、t细胞活化、抗原呈递和髓源性抑制细胞（MDSCs）功能中的作用，并整合了来自PDAC和其他癌症类型的证据。特别关注关键的棕榈酰化分子，包括程序性死亡配体1 （PD-L1）、分化簇80 （CD80）、淋巴细胞特异性蛋白酪氨酸激酶（LCK）、T细胞活化连接体（LAT）、干扰素诱导的跨膜蛋白（IFITMs）和主要组织相容性复合体I类（MHC-I），以及它们在PDAC免疫抑制网络中的潜在作用。此外，我们还探索了针对棕榈酰化的治疗策略，例如使用选择性棕榈酰转移酶抑制剂，设计棕榈酰化缺陷的CAR-T细胞，以及开发基于纳米技术的递送平台。通过结合交叉癌症的见解，我们提出棕榈酰化是PDAC免疫微环境重编程和克服免疫治疗耐药性的一个有希望的调控轴。

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引用次数: 0

MXene-based functional nanodrugs towards anticancer strategy and augmented sonodynamic therapy 基于mxene的功能纳米药物抗癌策略和增强声动力治疗

IF 9.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Reviews on cancer

Pub Date : 2026-01-08 DOI: 10.1016/j.bbcan.2026.189531

Xueyan Wang , Jialu Li , Ru Li, Zonghua Wang, Zhanfeng Li

MXene-based functional nanodrugs have stood out in the biomedical field owing to the attractive properties (e.g., excellent conductivity, high electromagnetic wave absorption capacity, rich surface functional groups, and easy functionalization), while sonodynamic therapy (SDT) has demonstrated excellent therapeutic efficacy because of its fast, noninvasive and deep-penetration advantages. Therefore, this review aims to summarize their cooperation in the improvements of anticancer activity. In the review, the progress of MXene-based functional nanodrugs is overviewed in the cancer treatment, where the single therapy and combinatorial therapy are described systematically. The development of MXenes as emerging sonosensitizers is narrated clearly during SDT and theranostics, focusing on various unique designs to improve the therapeutic efficacy. Moreover, we provide an in-depth analysis toward the MXene-harmonized multimodal SDT platforms, at length discussing a series of successes in the cancer treatments. Significantly, the challenges about the cooperation services of MXenes and SDT are also proposed, emphasizing more theoretical/technical innovations in the clinical antitumor applications.

基于mxene的功能纳米药物以其优异的导电性、高的电磁波吸收能力、丰富的表面官能团、易于功能化等特性在生物医学领域脱颖而出，而声动力疗法（SDT）则以其快速、无创、深穿透等优势展现出优异的治疗效果。因此，本文就它们在提高抗癌活性方面的合作进行综述。本文综述了基于mxeni的功能纳米药物在癌症治疗中的研究进展，并对其单药治疗和联合治疗进行了系统的介绍。MXenes作为新兴的超声增敏剂的发展在SDT和治疗中得到了清晰的叙述，重点介绍了各种独特的设计，以提高治疗效果。此外，我们对mxene协调的多模式SDT平台进行了深入分析，详细讨论了癌症治疗中的一系列成功案例。值得注意的是，本文还提出了MXenes与SDT合作服务面临的挑战，强调在临床抗肿瘤应用中有更多的理论/技术创新。

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引用次数: 0

Potential molecular mechanisms of malignant evolution in pulmonary nodules: From precancerous lesions to invasive adenocarcinoma 肺结节恶性演变的潜在分子机制：从癌前病变到浸润性腺癌。

IF 9.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Reviews on cancer

Pub Date : 2026-01-06 DOI: 10.1016/j.bbcan.2026.189529

Guanyu Lu, Yan Li, Xiangliang Liu, Jiuwei Cui

With the widespread implementation of lung cancer screening, the detection rate of pulmonary nodules has increased annually, and pulmonary nodules have become a global public health concern. Early identification of malignant pulmonary nodules and premalignant intervention represent important clinical challenges, requiring a deeper understanding of their evolutionary characteristics. The malignant evolution of pulmonary nodules results from multi-step, multi-factorial interactions between tumors and the host, primarily involving the evolution from precancerous lesions to invasive lung adenocarcinoma. With the continuous development of multi-omics technologies, researchers have been mapping the spatiotemporal atlas of tumor initiation and progression at the molecular level. Elucidating the molecular mechanisms of malignant evolution in pulmonary nodules involves a multi-perspective analysis of tumor cells, the microenvironment, and host factors. This integrated view facilitates the identification of key biomarkers and therapeutic targets. This review summarizes the early cellular and molecular events in the malignant evolution of pulmonary nodules, aiming to provide insights for early identification and precision treatment.

随着肺癌筛查的广泛实施，肺结节的检出率逐年上升，已成为全球关注的公共卫生问题。恶性肺结节的早期识别和癌前干预是重要的临床挑战，需要更深入地了解其进化特征。肺结节的恶性演变是肿瘤与宿主多步骤、多因素相互作用的结果，主要包括从癌前病变向浸润性肺腺癌的演变。随着多组学技术的不断发展，研究人员已经开始在分子水平上绘制肿瘤发生和发展的时空图谱。阐明肺结节恶性演变的分子机制涉及肿瘤细胞、微环境和宿主因素的多视角分析。这种整合的观点有助于关键生物标志物和治疗靶点的识别。本文综述了肺结节恶性演变的早期细胞和分子事件，旨在为早期识别和精确治疗提供参考。

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引用次数: 0

miRNA-HK2 networks in cancer metabolism: Mechanisms and dual-targeting therapeutic opportunities miRNA-HK2网络在癌症代谢中的作用：机制和双靶向治疗机会

IF 9.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Reviews on cancer

Pub Date : 2026-01-06 DOI: 10.1016/j.bbcan.2026.189530

Xinyue Jiang , Xinnan Li , Leo Tsz On Lee , Kin Yip Tam

Metabolic reprogramming, exemplified by the Warburg effect, is a hallmark of cancer. Hexokinase 2 (HK2), a key glycolytic enzyme, is frequently overexpressed in cancer, sustaining glucose metabolism and tumor progression. MicroRNAs (miRNAs) post-transcriptionally regulate HK2 by targeting its 3′untranslated region or upstream signaling pathways. While monotherapies often fail due to compensatory pathways and drug resistance, dual-targeting both HK2 and its regulatory miRNAs could achieve substantial metabolic inhibition. This review summarizes recent advances in miRNA-HK2 regulatory networks across cancers and highlights dual-targeting miRNA-HK2 as a promising therapeutic strategy to overcome metabolic plasticity and improve precision, durability, and efficacy in cancer therapy.

代谢重编程，以Warburg效应为例，是癌症的一个标志。己糖激酶2 （HK2）是一种关键的糖酵解酶，在癌症中经常过度表达，维持葡萄糖代谢和肿瘤进展。MicroRNAs （miRNAs）通过靶向HK2的3 '非翻译区或上游信号通路来调控HK2的转录后调控。由于代偿途径和耐药，单药治疗往往失败，而双重靶向HK2及其调控mirna可以实现实质性的代谢抑制。本文综述了miRNA-HK2调控网络在癌症中的最新进展，并强调了双靶向miRNA-HK2作为一种有前途的治疗策略，可以克服代谢可塑性，提高癌症治疗的准确性、持久性和有效性。

引用次数: 0

YY1 in four dimensions: From context-dependent transcription factor to spatiotemporal gene regulator 四个维度的YY1：从上下文依赖性转录因子到时空基因调控因子。

IF 9.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Reviews on cancer

Pub Date : 2026-01-03 DOI: 10.1016/j.bbcan.2025.189526

Silvia Vivarelli , Luca Falzone , Concettina Fenga , Massimo Libra

YY1 is a multifunctional transcription factor whose regulation spans transcriptional, post-transcriptional, and post-translational layers, conferring remarkable context-dependent plasticity. Several studies carried out in YY1-deficient mouse models highlight its essential roles in embryogenesis, organogenesis, and cellular homeostasis, while its deregulation in adulthood predisposes to multiple chronic diseases. In cancer, YY1 displays a bidirectional function, acting as either oncogene or tumor suppressor depending on cellular context and tumor type, and reshaping transcriptional and epigenetic networks. Emerging evidence further identifies YY1 as a clock-controlled gene and architectural regulator of circadian transcription, bridging together enhancer-promoter communication, chromatin state, and the temporal dimension of gene expression. In this context, its deregulation links circadian misalignment with oncogenic signaling, underscoring its key role as a diagnostic and prognostic biomarker, as well as a therapeutic target, thus highlighting its relevance in precision oncology.

YY1是一种多功能转录因子，其调控跨越转录层、转录后层和翻译后层，具有显著的环境依赖性可塑性。在yy1缺陷小鼠模型中进行的几项研究强调了它在胚胎发生、器官发生和细胞稳态中的重要作用，而在成年期它的失调易导致多种慢性疾病。在癌症中，YY1表现出双向功能，根据细胞背景和肿瘤类型作为癌基因或肿瘤抑制基因，并重塑转录和表观遗传网络。新出现的证据进一步确定YY1是一个生物钟控制的基因和昼夜节律转录的结构调节因子，将增强子-启动子通讯、染色质状态和基因表达的时间维度联系在一起。在这种情况下，其解除管制将昼夜节律失调与致癌信号联系起来，强调了其作为诊断和预后生物标志物以及治疗靶点的关键作用，从而突出了其在精确肿瘤学中的相关性。

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引用次数: 0

Targeting ferroptosis with flavonoids for cancer therapy: Mechanisms and opportunities 黄酮类化合物靶向铁下垂癌症治疗：机制和机遇

IF 9.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Reviews on cancer

Pub Date : 2026-01-01 DOI: 10.1016/j.bbcan.2025.189528

Guowei Gong , Zhenxia Zhang , Yuzhong Zheng

Ferroptosis, an iron-dependent regulated cell death mechanism driven by lipid peroxidation, offers a novel therapeutic approach for cancer treatment. Flavonoids, a diverse group of polyphenolic compounds, demonstrate significant anticancer potential by modulating ferroptosis pathways, including iron metabolism, GPX4 inhibition, and lipid peroxidation. This study examines flavonoid-induced ferroptosis mechanisms and their therapeutic applications. A systematic review of preclinical and clinical studies evaluated flavonoid effects (quercetin, baicalein, luteolin) on ferroptosis in cancer models. Key mechanisms analyzed included iron pool modulation, GPX4/System Xc⁻ inhibition, and lipid peroxidation enhancement. Synergistic interactions with chemotherapy, immunotherapy, and radiotherapy were assessed. Flavonoids trigger ferroptosis by (1) elevating labile iron to form redox-active complexes that can disrupt homeostasis and amplify Fenton reactions, (2) suppressing GPX4 and System Xc⁻ leading to glutathione depletion and ROS elevation, and (3) upregulating ACSL4/LOX to intensify lipid peroxidation. Preclinical data confirm efficacy in resistant cancers (triple-negative breast cancer, glioblastoma, pancreatic adenocarcinoma) and synergy with standard therapies. Challenges like poor bioavailability and tumor heterogeneity highlight the need for advanced delivery systems (nanoparticles, prodrugs). Flavonoids are promising ferroptosis inducers for apoptosis-resistant cancers, leveraging multi-target mechanisms and emerging delivery technologies. Future research should prioritize clinical translation, biomarker identification, and optimized combination regimens to enhance therapeutic outcomes.

铁下垂是一种由脂质过氧化驱动的铁依赖性调节细胞死亡机制，为癌症治疗提供了一种新的治疗方法。黄酮类化合物是一种多酚类化合物，通过调节铁代谢、GPX4抑制和脂质过氧化等铁死亡途径，显示出显著的抗癌潜力。本研究探讨黄酮类诱导的铁下垂机制及其治疗应用。一项临床前和临床研究的系统综述评估了黄酮类化合物（槲皮素、黄芩素、木犀草素）对癌症模型铁中毒的影响。分析的关键机制包括铁池调节、GPX4/System Xc -抑制和脂质过氧化增强。评估了化疗、免疫治疗和放疗的协同相互作用。黄酮类化合物通过(1)提高不稳定铁形成氧化还原活性复合物，从而破坏体内平衡并放大芬顿反应，(2)抑制GPX4和System Xc -导致谷胱甘肽消耗和ROS升高，以及(3)上调ACSL4/LOX以加强脂质过氧化。临床前数据证实了对耐药癌症（三阴性乳腺癌、胶质母细胞瘤、胰腺腺癌）的疗效以及与标准疗法的协同作用。生物利用度差和肿瘤异质性等挑战凸显了对先进给药系统（纳米颗粒、前药）的需求。黄酮类化合物利用多靶点机制和新兴的递送技术，是抗凋亡癌症的有希望的铁下垂诱导剂。未来的研究应优先考虑临床转化、生物标志物鉴定和优化联合方案，以提高治疗效果。

{"title":"Targeting ferroptosis with flavonoids for cancer therapy: Mechanisms and opportunities","authors":"Guowei Gong , Zhenxia Zhang , Yuzhong Zheng","doi":"10.1016/j.bbcan.2025.189528","DOIUrl":"10.1016/j.bbcan.2025.189528","url":null,"abstract":"<div><div>Ferroptosis, an iron-dependent regulated cell death mechanism driven by lipid peroxidation, offers a novel therapeutic approach for cancer treatment. Flavonoids, a diverse group of polyphenolic compounds, demonstrate significant anticancer potential by modulating ferroptosis pathways, including iron metabolism, GPX4 inhibition, and lipid peroxidation. This study examines flavonoid-induced ferroptosis mechanisms and their therapeutic applications. A systematic review of preclinical and clinical studies evaluated flavonoid effects (quercetin, baicalein, luteolin) on ferroptosis in cancer models. Key mechanisms analyzed included iron pool modulation, GPX4/System Xc<sup>−</sup> inhibition, and lipid peroxidation enhancement. Synergistic interactions with chemotherapy, immunotherapy, and radiotherapy were assessed. Flavonoids trigger ferroptosis by (1) elevating labile iron to form redox-active complexes that can disrupt homeostasis and amplify Fenton reactions, (2) suppressing GPX4 and System Xc<sup>−</sup> leading to glutathione depletion and ROS elevation, and (3) upregulating ACSL4/LOX to intensify lipid peroxidation. Preclinical data confirm efficacy in resistant cancers (triple-negative breast cancer, glioblastoma, pancreatic adenocarcinoma) and synergy with standard therapies. Challenges like poor bioavailability and tumor heterogeneity highlight the need for advanced delivery systems (nanoparticles, prodrugs). Flavonoids are promising ferroptosis inducers for apoptosis-resistant cancers, leveraging multi-target mechanisms and emerging delivery technologies. Future research should prioritize clinical translation, biomarker identification, and optimized combination regimens to enhance therapeutic outcomes.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1881 1","pages":"Article 189528"},"PeriodicalIF":9.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145881042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Key methylation modifications in glioma stem cells 胶质瘤干细胞中的关键甲基化修饰。

IF 9.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Reviews on cancer

Pub Date : 2025-12-31 DOI: 10.1016/j.bbcan.2025.189527

Lize Cai , Xun Sun , Rong Li , Yifang Ping , Shengqing Lv , Juxiang Chen

Glioblastoma (GBM), the most aggressive primary brain tumor in adults, is characterized by a poor prognosis with a median survival of approximately 15 months despite multimodal therapies. Its hallmark heterogeneity and cellular plasticity, driven by glioma stem cells (GSCs), which contribute to therapeutic resistance and tumor recurrence. GSCs, identified by markers such as CD133, CD15, and Nestin, exhibit self-renewal capacity, multilineage differentiation potential, and tumor-initiating ability. These cells demonstrate intrinsic resistance to radiation and chemotherapy, enhanced invasiveness, and the ability to remodel the tumor microenvironment through immune modulation and angiogenesis. Metabolic reprogramming in GSCs supports their aggressive phenotype by meeting bioenergetic demands. It also generates metabolites that drive epigenetic remodeling. Among epigenetic mechanisms, methylation of DNA, RNA, and proteins plays a critical role in regulating GSC plasticity, gene expression, and signaling pathways. This review explores the dynamics of methylation in GSCs, encompassing the latest research on DNA, RNA, and protein methylation within the field of GSCs. This review further provides insights for future research by proposing a hierarchical regulatory network of methylation in GSCs to deepen understanding of their unique characteristics. Furthermore, this review highlights the potential for developing additional methylation-related clinical markers to enhance diagnostic approaches.

胶质母细胞瘤（GBM）是成人中最具侵袭性的原发性脑肿瘤，其特点是预后差，尽管采用多种治疗方法，中位生存期约为15 个月。其标志性的异质性和细胞可塑性，由胶质瘤干细胞（GSCs）驱动，这有助于治疗抵抗和肿瘤复发。通过CD133、CD15和Nestin等标记物鉴定的GSCs表现出自我更新能力、多谱系分化潜力和肿瘤启动能力。这些细胞表现出对放疗和化疗的内在抵抗力，增强的侵袭性，以及通过免疫调节和血管生成重塑肿瘤微环境的能力。GSCs中的代谢重编程通过满足生物能量需求来支持其侵略性表型。它还产生代谢物，驱动表观遗传重塑。在表观遗传机制中，DNA、RNA和蛋白质的甲基化在调节GSC可塑性、基因表达和信号通路中起着关键作用。本文综述了GSCs中甲基化的动态，包括GSCs中DNA、RNA和蛋白质甲基化的最新研究。本综述通过提出GSCs中甲基化的分层调控网络，进一步为未来的研究提供见解，以加深对其独特特征的理解。此外，本综述强调了开发其他甲基化相关临床标志物以增强诊断方法的潜力。

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引用次数: 0

Aptamer-based strategies for glioblastoma: From SELEX to preclinical success 基于适配体的胶质母细胞瘤治疗策略：从SELEX到临床前成功。

IF 9.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Reviews on cancer

Pub Date : 2025-12-29 DOI: 10.1016/j.bbcan.2025.189524

Abdullah Tahir Bayraç

Glioblastoma presents a persistent therapeutic challenge due to extensive intratumoral heterogeneity and the blood-brain barrier. Nucleic acid aptamers offer an effective alternative to overcome these physiological obstacles where conventional modalities often have limited success. This review outlines the progression of aptamers from basic ligands to functional therapeutics, with a focus on targeting glioblastoma stem cells and engineering mechanisms for blood-brain barrier traversal. We discuss how recent biotechnological developments, including Cell-SELEX and AI-supported design, are solving earlier issues related to in vivo stability and conformational selectivity. Additionally, the article evaluates the shift toward multifunctional systems such as aptamer-drug conjugates and “drugtamers” designed for receptor-mediated transport. These advances indicate that next-generation aptamer platforms may overcome current translational limitations and enable more precise neuro-oncological treatments.

由于肿瘤内广泛的异质性和血脑屏障，胶质母细胞瘤呈现出持续的治疗挑战。核酸适体提供了一种有效的替代方法来克服这些生理障碍，而传统方法往往收效甚微。本文综述了适体从基本配体到功能治疗的进展，重点是针对胶质母细胞瘤干细胞和血脑屏障穿越的工程机制。我们讨论了最近的生物技术发展，包括Cell-SELEX和人工智能支持的设计，如何解决与体内稳定性和构象选择性相关的早期问题。此外，本文还评估了向多功能系统的转变，如适体-药物偶联物和为受体介导的运输而设计的“药物tamers”。这些进展表明，下一代适体平台可能克服目前的翻译限制，使更精确的神经肿瘤治疗成为可能。

引用次数: 0

IF 9.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Reviews on cancer

Pub Date : 2025-12-29 DOI: 10.1016/j.bbcan.2025.189525

Jagannath Pradhan, Archana Priyadarshini Samal, Uzma Khatoon, Monica Prusty, Selvakumar Elangovan

Breast cancer outcomes continue to be undermined by metastasis, relapse, and therapeutic resistance. While endocrine and targeted therapies have improved clinical outcomes, aggressive subtypes such as HER2-positive and triple-negative breast cancers remain challenging, exhibiting poor prognosis and frequent relapse. The constitutively active orphan nuclear receptor, estrogen-related receptor α (ERRα), has emerged as a key regulator of tumor energy metabolism and a crucial driver of breast cancer progression. The ERRα overexpression, frequently observed in aggressive subtypes, is strongly correlated with epithelial-mesenchymal transition, angiogenesis, invasion, metastasis, and therapy resistance. Preclinical studies demonstrate that pharmacological inhibition or gene silencing of ERRα suppresses oncogenic signaling and enhances therapeutic sensitivity. This review explores the multifaceted roles of ERRα in breast cancer and highlights its translational potential as a molecular target for treating aggressive breast cancer subtypes.

乳腺癌的预后继续受到转移、复发和治疗耐药性的影响。虽然内分泌和靶向治疗改善了临床结果，但侵袭性亚型（如her2阳性和三阴性乳腺癌）仍然具有挑战性，表现出预后差和频繁复发。组成活性的孤儿核受体雌激素相关受体α (ERRα)已成为肿瘤能量代谢的关键调节因子和乳腺癌进展的关键驱动因素。在侵袭性亚型中经常观察到的ERRα过表达与上皮-间质转化、血管生成、侵袭、转移和治疗抵抗密切相关。临床前研究表明，ERRα的药物抑制或基因沉默可抑制致癌信号传导并提高治疗敏感性。这篇综述探讨了ERRα在乳腺癌中的多方面作用，并强调了其作为治疗侵袭性乳腺癌亚型的分子靶点的翻译潜力。

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引用次数: 0

IF 9.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Reviews on cancer

Pub Date : 2025-12-26 DOI: 10.1016/j.bbcan.2025.189523

Yashfeen Munib Siddiqui , Ilma Shakeel , Gulam Mustafa Hasan , Md. Imtaiyaz Hassan

NEK2 (NIMA-Related Kinase 2), a serine/threonine kinase, is a pivotal kinase for centrosome separation and mitotic fidelity. It is increasingly recognized as a driver of oncogenesis and a contributor to therapeutic resistance. This review comprehensively discusses the structural features, expression patterns, and multilayered regulation of NEK2, along with its interactions with signaling molecules, its function, and an in-depth investigation of its roles in various diseases, specifically different types of cancers. It further highlights NEK2's involvement in signaling pathways, its contribution to chromosomal instability and tumor progression, and its potential as both a biomarker and therapeutic target in cancer. Dysregulated NEK2 causes chromosomal instability, metastatic progression, and immune evasion across diverse cancers by disrupting centrosome dynamics, rewiring oncogenic pathways (e.g., PI3K-AKT, Wnt/β-catenin), and inactivating tumor suppressors such as p53. Overexpression of NEK2 correlates with poor prognosis and chemoresistance in haematological and solid tumors, suggesting its role as a biomarker and therapeutic target. Apart from its role in cancer, dysfunction of NEK2 contributes to polycystic kidney disease, bone remodeling, and immune dysregulation, highlighting its pleiotropic roles. Recent advances in targeting NEK2 include covalent inhibitors (e.g., JH295), Hec1 disruptors (e.g., INH154), and clinical-stage compounds (e.g., T-1101), alongside emerging strategies such as PROTACs and immunotherapy. However, challenges remain in developing selective, clinically viable agents. This review provides details on the molecular architecture of NEK2, disease mechanisms, and therapeutic potential, framing it as a dual regulator and guardian of mitosis that has become a rogue oncogene and advocating its exploitation in translational medicine across cancer and non-cancer pathologies.

NEK2 （nima相关激酶2）是一种丝氨酸/苏氨酸激酶，是中心体分离和有丝分裂保真度的关键激酶。它越来越被认为是肿瘤发生的驱动因素和治疗耐药性的贡献者。本文全面讨论了NEK2的结构特征、表达模式和多层调控，以及它与信号分子的相互作用、它的功能，并深入研究了它在各种疾病，特别是不同类型的癌症中的作用。它进一步强调了NEK2参与信号通路，其对染色体不稳定性和肿瘤进展的贡献，以及其作为癌症生物标志物和治疗靶点的潜力。失调的NEK2通过破坏中心体动力学、重新连接致癌途径（如PI3K-AKT、Wnt/β-catenin）和灭活肿瘤抑制因子（如p53），导致多种癌症的染色体不稳定、转移进展和免疫逃避。NEK2的过表达与血液病和实体瘤的不良预后和化疗耐药相关，提示其作为生物标志物和治疗靶点的作用。除了在癌症中发挥作用外，NEK2的功能障碍还有助于多囊肾病、骨重塑和免疫失调，突出了它的多功能性作用。针对NEK2的最新进展包括共价抑制剂（如JH295）、Hec1干扰物（如INH154）和临床阶段化合物（如T-1101），以及新兴策略（如PROTACs和免疫疗法）。然而，在开发选择性的、临床可行的药物方面仍然存在挑战。这篇综述提供了NEK2的分子结构、疾病机制和治疗潜力的详细信息，将其定位为有丝分裂的双重调节和监护人，有丝分裂已成为一种流氓癌基因，并提倡将其用于癌症和非癌症病理的转化医学。

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引用次数: 0