Pathology, research and practice最新文献_第3页

OXPHOS inhibitor IACS010759 suppresses tumor growth by modulating autophagy in esophageal squamous cell carcinoma OXPHOS抑制剂IACS010759通过调节食管鳞状细胞癌的自噬抑制肿瘤生长

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2026-03-01 Epub Date: 2026-01-14 DOI: 10.1016/j.prp.2026.156363

Xiao Han , Xueyuan Hu , Guangzhao Zhu , Yingchao Ma , Kaige Li , Hongtao Liu , Tianli Fan , Yue Xu , Wenna Guo , Yanting Zhang

Esophageal squamous cell carcinoma (ESCC) is a prevalent and highly malignant digestive tract cancer with poor prognosis. Cancer cells generally exhibit increased glycolytic activity, and it was previously believed that oxidative phosphorylation (OXPHOS) is downregulated in all cancers. However, recent studies have shown increased OXPHOS activity in some tumors, even alongside active glycolysis. This has led to the exploration of targeting elevated OXPHOS as a therapeutic strategy. Despite this, the role of OXPHOS in ESCC tumorigenesis and progression remains unclear. In this study, we found that OXPHOS-related genes are highly expressed in ESCC cell lines and tissues, and this elevated expression correlates with clinical prognosis. The OXPHOS inhibitor IACS-010759 suppressed ESCC cell proliferation, clonogenicity, and migration, while disrupting mitochondrial morphology and function. Furthermore, IACS-010759 inhibited xenograft tumor growth in nude mice. Treatment with IACS-010759 also inhibited autophagy and activated the AKT/mTOR pathway in ESCC cells. The autophagy inducer rapamycin counteracted the inhibitory effects of IACS-010759, indicating that IACS-010759 inhibits ESCC autophagy via AKT/mTOR activation, thereby exerting anti-tumor effects. Interestingly, inhibiting OXPHOS increased glycolytic activity. Combining IACS-010759 with the glycolysis inhibitor 2-DG resulted in a significant synergistic anti-tumor effect in ESCC cells and xenografts. In conclusion, our findings suggest that the OXPHOS pathway may serve as a promising therapeutic target for ESCC.

食管鳞状细胞癌（ESCC）是一种常见的消化道恶性肿瘤，预后差。癌细胞通常表现出增加的糖酵解活性，以前认为氧化磷酸化（OXPHOS）在所有癌症中都下调。然而，最近的研究表明，在一些肿瘤中，甚至与活跃的糖酵解一起，OXPHOS活性增加。这导致了针对升高的OXPHOS作为治疗策略的探索。尽管如此，OXPHOS在ESCC肿瘤发生和进展中的作用仍不清楚。在本研究中，我们发现oxphos相关基因在ESCC细胞系和组织中高表达，并且这种高表达与临床预后相关。OXPHOS抑制剂IACS-010759抑制ESCC细胞增殖、克隆原性和迁移，同时破坏线粒体形态和功能。此外，IACS-010759还能抑制裸鼠异种移植瘤的生长。IACS-010759也能抑制ESCC细胞的自噬，激活AKT/mTOR通路。自噬诱导剂雷帕霉素抵消了IACS-010759的抑制作用，表明IACS-010759通过激活AKT/mTOR抑制ESCC自噬，从而发挥抗肿瘤作用。有趣的是，抑制OXPHOS会增加糖酵解活性。IACS-010759与糖酵解抑制剂2-DG联合使用对ESCC细胞和异种移植物具有显著的协同抗肿瘤作用。总之，我们的研究结果表明，OXPHOS通路可能是ESCC的一个有希望的治疗靶点。

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引用次数: 0

Targeting FOXM1/PSAT1 axis by Brusatol inhibits lung cancer malignant progression Brusatol靶向FOXM1/PSAT1轴抑制肺癌恶性进展

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2026-03-01 Epub Date: 2026-01-15 DOI: 10.1016/j.prp.2026.156365

Siyi Ou , Xiaobo Wang , Yulan Sun , Yongfeng Liang , Jing Bai , Chuanchun Han , Jing Song

Brusatol (BRU), an extract from Brucea javanica, has been found to inhibit cancer progression. However, the downstream targets of Brusatol and its underlying mechanisms in lung cancer still not fully elucidate and warrant further investigation. Here, we identified that Brusatol significantly downregulated the mRNA and protein levels of phosphoserine aminotransferase 1 (PSAT1). Notably, overexpression of PAST1 could impair the antitumour effects of Brusatol on lung cancer cells in vitro and in vivo. Further mechanism studies revealed that FOXM1, an important transcription factor, was directly bound to the promoter of PSAT1, facilitating its transcription. Besides, FOXM1 upregulation antagonizes Brusatol’s suppression of PSAT1 and sustains tumor cell viability. Collectively, our data suggested that the FOXM1/PSAT1 axis might play an important role in the antitumour effects of Brusatol and that Brusatol may hold promise as a novel therapeutic strategy for lung cancer.

Brusatol (BRU)，一种从鸦嘴鸦属（Brucea javanica）中提取的物质，被发现可以抑制癌症的发展。然而，Brusatol的下游靶点及其在肺癌中的潜在机制尚未完全阐明，需要进一步研究。在这里，我们发现Brusatol显著下调磷酸丝氨酸转氨酶1 （PSAT1）的mRNA和蛋白水平。值得注意的是，在体外和体内实验中，过表达PAST1可能会削弱Brusatol对肺癌细胞的抗肿瘤作用。进一步的机制研究表明，FOXM1这一重要的转录因子可以直接结合到PSAT1的启动子上，促进PSAT1的转录。此外，FOXM1上调可拮抗Brusatol对PSAT1的抑制，维持肿瘤细胞活力。总之，我们的数据表明FOXM1/PSAT1轴可能在Brusatol的抗肿瘤作用中发挥重要作用，并且Brusatol可能有望成为一种新的肺癌治疗策略。

引用次数: 0

Lactylation of HK2 facilitates cisplatin resistance in NSCLC by promoting cell migration, invasion, and glycolysis HK2的乳酸化通过促进细胞迁移、侵袭和糖酵解促进非小细胞肺癌的顺铂耐药

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2026-03-01 Epub Date: 2025-12-29 DOI: 10.1016/j.prp.2025.156349

Fanrui Zeng , Wenyang Wang , Peng Liu , Qingsi Zeng

Objective

Cisplatin (DDP) resistance has markedly diminished the efficacy of DDP-based chemotherapy in non-small cell lung cancer (NSCLC). Glycolysis represents a key contributor to NSCLC progression. Lactylation, a novel epigenetic modification, directly regulates glycolysis-associated gene expression. This study aimed to investigate whether lactylation-mediated modulation of glycolytic genes contributes to DDP resistance in NSCLC.

Methods

Cell viability, migration, and invasion capacities in parental and resistant NSCLC cells were assessed using cell counting kit-8 and Transwell migration/invasion assays. RT-qPCR and Western blot analyses were employed to quantify mRNA and protein levels of glycolytic markers. A xenografted tumor model was established to evaluate in vivo tumor progression.

Results

DDP-resistant NSCLC cells exhibited elevated glycolysis activity and increased lactylation levels of hexokinase 2 (HK2). Moreover, HK2 lysine lactylation (Kla) and protein stability were enhanced in resistant cells through suppression of ubiquitination. Functional experiments demonstrated that HK2 downregulation inhibited cell viability, migration, invasion, and glycolytic metabolism in A549/DDP and H1229/DDP cells, with these effects being reversed following sodium lactate treatment. Crucially, the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) abrogated this rescue, and a K873R lactylation-deficient mutant failed to restore the malignant phenotype, confirming the specificity of the mechanism. In vivo studies further confirmed that HK2 inhibition suppressed tumor growth.

Conclusions

Lactylation at K873 stabilized HK2 by inhibiting its ubiquitination, which in turn drove glycolytic flux and promoted malignant behaviors in DDP-resistant NSCLC. This HK2 lactylation-stabilization axis represents a novel mechanism underlying chemoresistance and a promising therapeutic target for overcoming DDP resistance in NSCLC.

目的非小细胞肺癌（NSCLC）患者对铂（DDP）耐药显著降低了DDP化疗的疗效。糖酵解是NSCLC进展的关键因素。乳酸酰化是一种新的表观遗传修饰，直接调控糖酵解相关基因的表达。本研究旨在探讨乳酸化介导的糖酵解基因调节是否有助于NSCLC的DDP耐药。方法采用细胞计数试剂盒-8和Transwell迁移/侵袭试验评估亲代和耐药NSCLC细胞的细胞活力、迁移和侵袭能力。采用RT-qPCR和Western blot方法定量糖酵解标志物的mRNA和蛋白水平。建立异种移植肿瘤模型，评估肿瘤在体内的进展。结果耐药NSCLC细胞表现出糖酵解活性升高和己糖激酶2 （HK2）乳酸化水平升高。此外，通过抑制泛素化，抗性细胞中HK2赖氨酸乳酸化（Kla）和蛋白质稳定性增强。功能实验表明，HK2下调抑制了A549/DDP和H1229/DDP细胞的活力、迁移、侵袭和糖酵解代谢，乳酸钠处理后这些作用被逆转。至关重要的是，糖酵解抑制剂2-脱氧-d -葡萄糖（2-DG）消除了这种挽救作用，K873R乳酸化缺陷突变体未能恢复恶性表型，证实了其机制的特异性。体内研究进一步证实，抑制HK2抑制肿瘤生长。结论K873位点的乙酰化通过抑制其泛素化来稳定HK2，从而推动糖酵解通量，促进ddp耐药NSCLC的恶性行为。这个HK2乳酸化稳定轴代表了一种新的化疗耐药机制，也是克服非小细胞肺癌DDP耐药的一个有希望的治疗靶点。

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引用次数: 0

Endoplasmic reticulum stress and the unfolded protein response in ischemic nephropathy: Pathogenic mechanisms and emerging therapeutic strategies 缺血性肾病的内质网应激和未折叠蛋白反应：致病机制和新兴治疗策略

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2026-03-01 Epub Date: 2026-01-15 DOI: 10.1016/j.prp.2026.156367

Janavie Patel, Siddhi Bagwe Parab, Gaurav M. Doshi

One of the main causes of chronic kidney disease (CKD), ischemic nephropathy, is brought on by maladaptive cellular stress responses, specifically endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signalling, in addition to vascular insufficiency. The primary goals of UPR activation via the Protein kinase R-like ER kinase (PERK), Inositol-requiring enzyme 1 (IRE1), and Activating Transcription Factor 6 (ATF6) pathways are to support renal tubular cell survival and restore proteostasis. Prolonged or severe ER stress, on the other hand, causes the UPR to shift toward pathogenic outcomes by triggering apoptotic (C/EBP homologous protein [CHOP], caspase-12), inflammatory (c-Jun N-terminal Kinase [JNK], nuclear factor kappa B [NF-κB]), and fibrotic (transforming growth factor-beta [TGF-β]/SMAD) cascades that lead to progressive renal dysfunction, tubular atrophy, and interstitial fibrosis. Furthermore, ER-mitochondria crosstalk connects acute ischemia injury to chronic fibrosis by exacerbating mitochondrial failure, oxidative stress, and cell death. Targeting therapy requires an understanding of the UPR's dual nature, which is beneficial during brief stress but harmful during prolonged ischemia. Promising approaches to maintain kidney function include interventions that alter particular UPR branches, improve autophagy, lower oxidative damage, and restore ER equilibrium. In addition to outlining the molecular bases of ER stress and UPR in ischemic nephropathy, this review suggests innovative therapeutic strategies meant to shift the equilibrium from maladaptive to adaptive stress responses, providing novel possibilities to slow or alter the course of CKD. This review aims to critically evaluate the molecular mechanisms of ER stress and the UPR in ischemic nephropathy, with a focus on identifying potential therapeutic strategies to preserve renal function and slow CKD progression.

慢性肾脏疾病（CKD）的主要原因之一，缺血性肾病，是由不适应的细胞应激反应，特别是内质网（ER）应激和未折叠蛋白反应（UPR）信号，以及血管功能不全引起的。UPR通过蛋白激酶r -样ER激酶（PERK）、肌醇要求酶1 （IRE1）和激活转录因子6 （ATF6）途径激活的主要目的是支持肾小管细胞存活和恢复蛋白质稳态。另一方面，长期或严重的内质网应激会通过触发凋亡（C/EBP同源蛋白[CHOP]、caspase-12）、炎症（C - jun n -末端激酶[JNK]、核因子κB [NF-κB]）和纤维化（转化生长因子-β [TGF-β]/SMAD）级联反应导致进行性肾功能障碍、肾小管萎缩和间质纤维化，从而导致UPR向致病结果转变。此外，er -线粒体串扰通过加剧线粒体衰竭、氧化应激和细胞死亡将急性缺血损伤与慢性纤维化联系起来。靶向治疗需要了解UPR的双重性质，它在短暂应激时是有益的，但在长时间缺血时是有害的。维持肾功能的有希望的方法包括干预改变特定的UPR分支，改善自噬，降低氧化损伤和恢复内质网平衡。除了概述缺血性肾病中内质网应激和UPR的分子基础外，本综述还提出了创新的治疗策略，旨在将平衡从适应不良转变为适应应激反应，为减缓或改变CKD的进程提供新的可能性。这篇综述旨在批判性地评估内质网应激和UPR在缺血性肾病中的分子机制，重点是确定潜在的治疗策略，以保持肾功能和减缓CKD的进展。

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引用次数: 0

RNF6 activates JNK/c-JUN pathway in ovarian cancer by promoting K48-linked NME4 ubiquitination RNF6通过促进k48相关的NME4泛素化激活卵巢癌JNK/c-JUN通路

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2026-03-01 Epub Date: 2026-01-15 DOI: 10.1016/j.prp.2026.156366

Taoqiong Li, Fei Qian, Yumei Chen, Wei Li

Background

RING finger protein 6 (RNF6), a member of the E3 ubiquitin ligase family, has been implicated in various cancers, yet its functional significance and regulatory mechanisms in ovarian cancer (OC) are poorly understood.

Methods

RNF6 expression levels were analyzed using TCGA data and confirmed by IHC, qRT-PCR, and western blotting in OC tissues or cell lines. Functional roles of RNF6 were evaluated through CCK-8, colony formation, wound healing, Transwell, and EMT marker assays. Protein interactions and ubiquitination patterns were investigated via Co-IP, CHX chase, and ubiquitination assays. Rescue experiments were conducted by co-modulating RNF6 and NME4 expression. In vivo tumorigenesis was assessed using a nude mouse xenograft model.

Results

RNF6 was markedly overexpressed in OC and associated with poor prognosis. Silencing RNF6 suppressed cell growth, invasive behavior, and EMT, while enhancing NME4 expression. Mechanistic analyses demonstrated that RNF6 directly binds to NME4 and facilitates its K48-linked polyubiquitination, leading to proteasomal degradation. Knockdown of NME4 reversed the tumor-suppressive effects of RNF6 depletion and reinstated JNK/c-JUN pathway activation. In vivo, RNF6 silencing significantly reduced tumor burden and impaired downstream signaling events.

Conclusion

RNF6 contributed to OC malignancy by destabilizing NME4 and activating the JNK cascade. This newly identified RNF6/NME4/JNK axis provides potential targets for therapeutic intervention in OC.

dring手指蛋白6 （RNF6）是E3泛素连接酶家族的一员，与多种癌症有关，但其在卵巢癌（OC）中的功能意义和调控机制尚不清楚。方法采用TCGA数据分析srnf6在OC组织或细胞系中的表达水平，并采用免疫组化（IHC）、qRT-PCR和western blotting进行验证。通过CCK-8、菌落形成、伤口愈合、Transwell和EMT标记物检测来评估RNF6的功能作用。通过Co-IP， CHX追踪和泛素化分析研究蛋白质相互作用和泛素化模式。通过共调节RNF6和NME4的表达进行营救实验。用裸鼠异种移植模型评估体内肿瘤发生情况。结果rnf6在OC中明显过表达，与预后不良相关。沉默RNF6可抑制细胞生长、侵袭行为和EMT，同时增强NME4的表达。机制分析表明，RNF6直接结合NME4并促进其k48连锁的多泛素化，导致蛋白酶体降解。NME4的下调逆转了RNF6缺失的肿瘤抑制作用，恢复了JNK/c-JUN通路的激活。在体内，RNF6沉默可显著降低肿瘤负荷并损害下游信号事件。结论rnf6通过破坏NME4的稳定和激活JNK级联参与OC恶性肿瘤的发生。这个新发现的RNF6/NME4/JNK轴为OC的治疗干预提供了潜在的靶点。

{"title":"RNF6 activates JNK/c-JUN pathway in ovarian cancer by promoting K48-linked NME4 ubiquitination","authors":"Taoqiong Li, Fei Qian, Yumei Chen, Wei Li","doi":"10.1016/j.prp.2026.156366","DOIUrl":"10.1016/j.prp.2026.156366","url":null,"abstract":"<div><h3>Background</h3><div>RING finger protein 6 (RNF6), a member of the E3 ubiquitin ligase family, has been implicated in various cancers, yet its functional significance and regulatory mechanisms in ovarian cancer (OC) are poorly understood.</div></div><div><h3>Methods</h3><div>RNF6 expression levels were analyzed using TCGA data and confirmed by IHC, qRT-PCR, and western blotting in OC tissues or cell lines. Functional roles of RNF6 were evaluated through CCK-8, colony formation, wound healing, Transwell, and EMT marker assays. Protein interactions and ubiquitination patterns were investigated via Co-IP, CHX chase, and ubiquitination assays. Rescue experiments were conducted by co-modulating RNF6 and NME4 expression. In vivo tumorigenesis was assessed using a nude mouse xenograft model.</div></div><div><h3>Results</h3><div>RNF6 was markedly overexpressed in OC and associated with poor prognosis. Silencing RNF6 suppressed cell growth, invasive behavior, and EMT, while enhancing NME4 expression. Mechanistic analyses demonstrated that RNF6 directly binds to NME4 and facilitates its K48-linked polyubiquitination, leading to proteasomal degradation. Knockdown of NME4 reversed the tumor-suppressive effects of RNF6 depletion and reinstated JNK/c-JUN pathway activation. In vivo, RNF6 silencing significantly reduced tumor burden and impaired downstream signaling events.</div></div><div><h3>Conclusion</h3><div>RNF6 contributed to OC malignancy by destabilizing NME4 and activating the JNK cascade. This newly identified RNF6/NME4/JNK axis provides potential targets for therapeutic intervention in OC.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"279 ","pages":"Article 156366"},"PeriodicalIF":3.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

The role of CCL22 and its histamine-associated modulation in the tumor microenvironment of tongue squamous cell carcinoma CCL22及其组胺相关调控在舌鳞癌肿瘤微环境中的作用

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2026-03-01 Epub Date: 2026-01-19 DOI: 10.1016/j.prp.2026.156373

Satoshi Kimura , Shohei Shimajiri , Ayumi Nitta , Hiroaki Sato , Hirotsugu Noguchi , Toshiyuki Nakayama

Tongue squamous cell carcinoma (SCC), the most common type of oral cancer, remains a major clinical challenge due to its aggressive behavior and poor prognosis in advanced stages. Standard treatments, including surgery, radiation therapy, and chemotherapy, provide limited benefit highlighting the need for novel therapeutic strategies. Recently, immunotherapy has emerged as a promising approach, largely through its ability to reshape the tumor microenvironment (TME). Increasing evidence indicates that chemokine signaling plays a critical role in tongue SCC by orchestrating the recruitment and function of immune regulatory cells. In particular, CC chemokine ligand 22 (CCL22), mainly produced by tumor-associated macrophages and dendritic cells, promotes the accumulation of CC chemokine receptor 4 (CCR4)–expressing regulatory T cells, consequently establishing an immunosuppressive TME and facilitating tumor progression and immune evasion. Furthermore, emerging studies suggest that histamine-related pathways within the TME can induce CCL22 expression, subsequently amplifying immunosuppressive feedback loops and further modulate tumor–immune interactions, although their precise roles in tongue SCC remain incompletely understood. A deeper understanding of these intertwined networks may uncover new therapeutic targets and enhance the efficacy of existing immunotherapies, including immune checkpoint inhibitors. This review provides an updated overview of the immune landscape of tongue SCC, with special emphasis on the CCL22–CCR4 axis and its interaction with histamine signaling. A deeper understanding of CCL22- and histamine-mediated pathways may contribute to the development of more effective and personalized immunotherapy strategies for tongue SCC.

舌鳞状细胞癌（SCC）是最常见的口腔癌类型，由于其侵袭性行为和晚期预后差，仍然是一个主要的临床挑战。标准治疗，包括手术、放射治疗和化疗，提供有限的好处，强调需要新的治疗策略。最近，免疫疗法已成为一种有前途的方法，主要是通过其重塑肿瘤微环境（TME）的能力。越来越多的证据表明，趋化因子信号通过协调免疫调节细胞的募集和功能，在舌鳞状细胞癌中起着关键作用。特别是，主要由肿瘤相关巨噬细胞和树突状细胞产生的CC趋化因子配体22 （CCL22）促进表达CC趋化因子受体4 （CCR4）的调节性T细胞的积累，从而建立免疫抑制TME，促进肿瘤进展和免疫逃避。此外，新出现的研究表明，TME内的组胺相关通路可以诱导CCL22表达，随后放大免疫抑制反馈回路，并进一步调节肿瘤-免疫相互作用，尽管它们在舌SCC中的确切作用尚不完全清楚。更深入地了解这些相互交织的网络可能会发现新的治疗靶点，并提高现有免疫疗法的疗效，包括免疫检查点抑制剂。这篇综述提供了舌细胞鳞状细胞癌免疫景观的最新概述，特别强调CCL22-CCR4轴及其与组胺信号传导的相互作用。更深入地了解CCL22和组胺介导的途径可能有助于开发更有效和个性化的舌头SCC免疫治疗策略。

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引用次数: 0

Targeting the master of the replication fork—PCNA 目标是复制叉的主人- pcna。

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2026-03-01 Epub Date: 2026-01-16 DOI: 10.1016/j.prp.2026.156370

Yuanhang Gong , Weilan Hu , Min Li

Proliferating cell nuclear antigen (PCNA) orchestrates DNA replication, repair, stress responses, and cell-cycle control. Because tumors are hyperproliferative and genomically unstable, they are highly dependent on PCNA, creating a therapeutic vulnerability. Strategies under evaluation include direct inhibition of PCNA, disruption of PCNA–partner interactions that govern DNA metabolism and cell-cycle progression, and combination regimens with DNA-damaging agents to enhance chemo- and radiosensitivity. Several agents—most notably the APIM peptide ATX-101 and the allosteric small molecule AOH1996—have progressed beyond preclinical testing and are being evaluated as monotherapies or in combination with radiotherapy and genotoxic chemotherapies in early clinical studies. This review synthesizes the mechanistic rationale, therapeutic modalities, and development landscape of PCNA-targeted interventions, highlighting their potential to improve anticancer efficacy while mitigating toxicity.

增殖细胞核抗原（PCNA）协调DNA复制、修复、应激反应和细胞周期控制。由于肿瘤具有高增殖性和基因组不稳定性，它们高度依赖于PCNA，从而产生治疗脆弱性。正在评估的策略包括直接抑制PCNA，破坏控制DNA代谢和细胞周期进程的PCNA-伴侣相互作用，以及与DNA损伤剂联合用药以增强化疗和放射敏感性。一些药物——最著名的是APIM肽ATX-101和变弹性小分子aoh1996——已经超越了临床前测试，并在早期临床研究中被评估为单一疗法或与放疗和基因毒性化疗联合使用。这篇综述综合了pcna靶向干预的机制原理、治疗方式和发展前景，强调了它们在降低毒性的同时提高抗癌疗效的潜力。

引用次数: 0

RNF125 suppresses stem cell-like properties and metastasis in non-small cell lung cancer by promoting ubiquitination and degradation of DDX5 RNF125通过促进DDX5的泛素化和降解抑制非小细胞肺癌的干细胞样特性和转移

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2026-03-01 Epub Date: 2026-01-23 DOI: 10.1016/j.prp.2026.156378

Xuechun Leng , Zhongwu Hu , Mingzhi Zhang , Qiuni Chen , Keping Xu , Jun Zhao

Non-small cell lung cancer (NSCLC) is the most frequent subclass of lung cancer with a gloomy prognosis. Ring finger protein 125 (RNF125), as a ubiquitin E3 ligase, functions on the progression and development of various tumors. This study attempted to address the function and mechanism of RNF125 in NSCLC. The level of RNF125 was predicted with GEPIA2 website and verified in tumor tissues from NSCLC patients. The role of RNF125 in the malignant processes of NSCLC was determined by cell counting kit-8, the 5-ethynyl-2′-deoxyuridine (EdU) incorporation, transwell, flow cytometry and sphere‑formation experiments. The ubiquitinated role of RNF125 on DEAD-box helicase 5 (DDX5) was assessed by co-immunoprecipitation, ubiquitination and cycloheximide assays. The function of RNF125 was revealed in xenografted mice. Low RNF125 expression predicted poor prognosis in NSCLC. RNF125 inhibited the levels of indexes involved in proliferation, migration, invasion and stemness, but promoted apoptosis rate in both A549 and H1299 cells. Mechanically, RNF125 directly bound to DDX5. Overexpression of RNF125 enhanced the DDX5 ubiquitination, but knockdown of RNF125 reduced the degradation of endogenous DDX5. The inhibitory role of RNF125 overexpression in the malignant progressions of A549 cells was recovered with the upregulation of DDX5, vice versa. Besides, overexpression of RNF125 declined tumor weight and volume, the level of Ki-67 and the numbers of liver metastasis foci in vivo, vice versa. Also, RNF125 overexpression reduced the protein expressions of invasion markers and stemness markers in vivo. Collectively, low expression of RNF125 predicted poor prognosis of NSCLC patients. Upregulation of RNF125 repressed proliferation, mobility, invasion and stemness of NSCLC through the ubiquitinated degradation of DDX5.

非小细胞肺癌（NSCLC）是最常见的肺癌亚型，预后不佳。环指蛋白125 （Ring finger protein 125, RNF125）是一种泛素E3连接酶，参与多种肿瘤的发生发展。本研究试图探讨RNF125在非小细胞肺癌中的功能和机制。用GEPIA2网站预测RNF125的水平，并在NSCLC患者的肿瘤组织中进行验证。通过细胞计数试剂盒-8、5-乙基-2′-脱氧尿苷（EdU）掺入、transwell、流式细胞术和成球实验确定RNF125在NSCLC恶性过程中的作用。采用共免疫沉淀法、泛素化法和环己亚胺法评估RNF125对DEAD-box解旋酶5 （DDX5）的泛素化作用。RNF125在异种移植小鼠中的功能被揭示。低RNF125表达预示非小细胞肺癌预后不良。RNF125抑制A549和H1299细胞的增殖、迁移、侵袭和干性等指标水平，但促进细胞凋亡率。机械地，RNF125直接绑定到DDX5。过表达RNF125增强了DDX5的泛素化，而下调RNF125则降低了内源性DDX5的降解。RNF125过表达对A549细胞恶性进展的抑制作用随着DDX5的上调而恢复，反之亦然。RNF125过表达可降低肿瘤重量、体积、Ki-67水平和体内肝转移灶数量，反之亦然。此外，RNF125过表达降低了体内侵袭标志物和干性标志物的蛋白表达。综上所述，RNF125的低表达预示着NSCLC患者的不良预后。RNF125的上调通过DDX5的泛素化降解抑制NSCLC的增殖、移动性、侵袭性和干性。

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引用次数: 0

Therapeutic potential of exosomes in malignancies: From drug delivery to clinical application 外泌体在恶性肿瘤中的治疗潜力：从药物传递到临床应用

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2026-03-01 Epub Date: 2026-01-27 DOI: 10.1016/j.prp.2026.156381

Roshni Bibi, Arunika Koley, Koustav Sarkar

Background

Cancer remains one of the most pressing global health challenges, with conventional treatments such as chemotherapy and radiotherapy constrained by modest efficacy and severe long‑term adverse effects. Exosomes—nano‑sized extracellular vesicles (30–150 nm) secreted by diverse cell types—have emerged as promising candidates for cancer diagnosis and therapy due to their inherent biocompatibility, low immunogenicity, and ability to cross biological barriers.

Methods

A comprehensive review of recent literature was conducted to summarize advancements in exosome biology, isolation techniques, and engineering strategies relevant to cancer nanomedicine. Particular emphasis was placed on ESCRT (Endosomal Sorting Complex Required for Transport) dependent biogenesis mechanisms, molecular cargo profiling, and applications in targeted drug delivery.

Results

Tumor‑derived exosomes play multifaceted roles in cancer progression, including modulation of the tumor microenvironment, facilitation of metastasis, and induction of therapeutic resistance. Their molecular cargo—comprising proteins, lipids, and nucleic acids—serves as a dynamic reflection of the physiological or pathological status of the tumor cells. Technological innovations in exosome isolation, surface modification, and therapeutic payload loading have markedly improved targeted delivery and preclinical treatment outcomes. Notably, drug‑loaded exosomes demonstrate the ability to circumvent multidrug resistance.

Conclusion

Exosomes hold substantial promise for precision oncology through enhanced drug delivery and diagnostic applications. However, clinical translation requires standardized manufacturing, comprehensive safety profiling, and scalable production methods to address current limitations. Emerging strategies such as exosome mimetics and AI‑assisted production optimization poised to address these limitations, guiding the development of personalized, efficient, and targeted cancer treatments.

癌症仍然是最紧迫的全球卫生挑战之一，化疗和放疗等常规治疗受到疗效不高和严重长期副作用的限制。外泌体是由不同细胞类型分泌的纳米级细胞外囊泡（30-150 nm），由于其固有的生物相容性、低免疫原性和跨越生物屏障的能力，已成为癌症诊断和治疗的有希望的候选者。方法对近年来有关肿瘤纳米药物的外泌体生物学、分离技术和工程策略等方面的研究进展进行综述。特别强调ESCRT（运输所需的内体分选复合体）依赖的生物发生机制，分子货物分析和靶向药物递送的应用。结果肿瘤来源的外泌体在肿瘤进展中起着多方面的作用，包括调节肿瘤微环境、促进转移和诱导治疗耐药性。它们的分子货物——包括蛋白质、脂质和核酸——作为肿瘤细胞生理或病理状态的动态反映。外泌体分离、表面修饰和治疗有效载荷方面的技术创新显著改善了靶向递送和临床前治疗结果。值得注意的是，载药外泌体显示出规避多药耐药的能力。结论外泌体通过增强药物传递和诊断应用，在精确肿瘤学领域具有重要前景。然而，临床翻译需要标准化的制造、全面的安全性分析和可扩展的生产方法来解决当前的限制。外泌体模拟和人工智能辅助生产优化等新兴策略有望解决这些限制，指导个性化、高效和靶向癌症治疗的发展。

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引用次数: 0

Corrigendum to "performance of the VENTANA FOLR1 assay for folate receptor alpha: Real-world evidence from 313 Chinese participants" pathology - research and practice 279 (2026) 156359. “叶酸受体α的VENTANA FOLR1测定的性能：来自313名中国参与者的真实证据”病理学-研究与实践279(2026)156359的勘误表。

IF 3.2 4区医学 Q2 PATHOLOGY

Pathology, research and practice

Pub Date : 2026-02-26 DOI: 10.1016/j.prp.2026.156422

Xiaoyan Chen, Li Jiang, Liangyan Ruan, Teng Yu, Weiwei Rui, Yue Fan, Huafeng Wang, He Jiang, Weiwei Feng, Jing Li, Chaofu Wang

引用次数: 0