Journal of Advanced Research最新文献_第10页

Fibrinogen exacerbates α-synuclein aggregation and mitochondrial dysfunction via alpha5beta3 integrin in Parkinson’s disease 纤维蛋白原通过α 5beta3整合素加重帕金森病患者α-突触核蛋白聚集和线粒体功能障碍

IF 13 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2026-03-01 Epub Date: 2025-05-25 DOI: 10.1016/j.jare.2025.05.050

Zifeng Huang , Jialing Zheng , Feilan Yuan , Hui Zhong , Ruoyang Yu , Yuqi Luo , Muwei Zhang , Shuhan Chen , Bibiao Shen , Zhenchao Xie , Wanlin Yang , Shuzhen Zhu , Rongfang Que , Fen Xie , Huanzhu Liu , Weili Yang , Lu Zhang , Wenhua Zheng , Kunlin Jin , Chao Deng , Qing Wang

Introduction

Blood–brain barrier(BBB) disruption promotes the influx of the fibrinogen(FG); however, it remains unknown whether FG deposit contributes to neurodegeneration in Parkinson’s disease(PD).

Objectives

We aimed to examine the pathophysiologic link among FG, mitochondrial dysfunction and α-synuclein(α-syn) abnormality in PD.

Methods

First, plasma FG levels were measured in 60 healthy controls and 60 PD patients. Second, to determine whether FG contributes to PD pathogenesis, FG was injected into the substantia nigra pars compacta(SNpc) of healthy and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-treated PD mice. Meanwhile, intraperitoneal injections of batroxobin were used to deplete FG in the brain of PD mice. Mitochondrial ultrastructure in mouse models was observed by transmission electron microscopy(TEM), and mitochondrial functions in SH-SY5Y cells were examined by different assay kits and flow cytometry. The mechanisms underlying FG-induced α-syn abnormality and mitochondrial dysfunction were observed by RNA sequencing and validated in various experiments including western blot and immunostaining. Last, the endocytosis of FG in primary neurons were detected by confocal microscopy, and α-syn aggregation after FG co-incubation were evaluated by western blot, ThT-binding assay and TEM.

Results

PD patients exhibited elevated levels of FG in peripheral blood compared to HCs, and there was a positive correlation between the plasma FG and PD clinical severity. Excessive FG in the SNpc of MPTP-treated mice promoted poly (ADP-ribose) (PAR) polymerase-1(PARP1) elevation, mediated by the α_vβ₃ integrin receptor. FG exacerbated α-syn abnormalities and mitochondrial dysfunctions via PARP1 activation. Moreover, FG entered neurons by α_vβ₃ integrin mediation, potentially enhancing α-syn fibrillation and toxicity. FG facilitated α-syn aggregation subsequently reduced ATP-dependent Clp protease(ClpP) level, impairing neuronal mitochondrial unfolded response and increasing mitochondrial ROS. Pharmacological depletion of FG by batroxobin ameliorated neurodegeneration in MPTP-treated mice.

Conclusion

Our study indicate that FG plays an essential pathological role in α-syn abnormality. FG-targeting therapy can be a promising strategy against neurodegeneration in PD.

血脑屏障（BBB）破坏促进纤维蛋白原（FG）的流入；然而，FG沉积是否与帕金森病（PD）的神经退行性变有关尚不清楚。目的探讨PD患者FG、线粒体功能障碍和α-突触核蛋白（α-syn）异常之间的病理生理联系。方法首先测定60例健康人与60例帕金森病患者血浆FG水平。其次，为了确定FG是否参与PD的发病机制，将FG注射到健康和1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）治疗的PD小鼠的黑质致密部（SNpc）中。同时，通过腹腔注射巴曲酶蛋白来消耗PD小鼠脑内的FG。透射电镜观察小鼠线粒体超微结构，流式细胞术检测SH-SY5Y细胞线粒体功能。通过RNA测序观察fg诱导的α-syn异常和线粒体功能障碍的机制，并通过western blot和免疫染色等多种实验进行验证。最后，用共聚焦显微镜检测原代神经元中FG的内吞作用，用western blot、t -结合实验和透射电镜观察FG共孵育后α-syn聚集情况。结果spd患者外周血FG水平高于hc患者，血浆FG水平与PD临床严重程度呈正相关。mptp处理小鼠SNpc中过量的FG促进了αvβ3整合素受体介导的聚adp核糖（PAR）聚合酶-1（PARP1）的升高。FG通过激活PARP1加剧α-syn异常和线粒体功能障碍。此外，FG通过αvβ3整合素介导进入神经元，可能增强α-syn纤颤和毒性。FG促进α-syn聚集，随后降低atp依赖性Clp蛋白酶（ClpP）水平，损害神经元线粒体未折叠反应，增加线粒体ROS。用巴曲霉素消耗FG可改善mptp处理小鼠的神经退行性变。结论FG在α-syn异常中起重要病理作用。fg靶向治疗是一种很有前途的治疗PD神经退行性疾病的方法。

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引用次数: 0

Basophilic exosomes promote SLE development via exacerbating B cell activation through the lncRNA ENST00000537616/miR-330-5p/KRAS axis 嗜碱性外泌体通过lncRNA ENST00000537616/miR-330-5p/KRAS轴加剧B细胞活化，从而促进SLE的发展

IF 13 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2026-03-01 Epub Date: 2025-05-31 DOI: 10.1016/j.jare.2025.05.056

Jiaxuan Chen , Shuxian Chen , Kangyuan Shen , Shuting Wang , Xiaoxian Liu , Jiaqi Lun , Xiaowei Xu , Lu Lu , Tingting Li , Jiahui Lu , Lawei Yang , Fengbiao Guo , Liuyong You , Haiyan Xiao , Hua-Feng Liu , Qingjun Pan

Introduction

Uncontrolled B-cell activation in systemic lupus erythematosus (SLE) induces autoantibody production and inflammation and causes tissue damage. Basophils have been shown to promote B cell activation in SLE; however, the molecular mechanisms involved remain nebulous.

Objective

To elucidate the role of basophilic exosomes in B-cell activation and explore the associated molecular mechanisms in SLE.

Methods

We employed a multifaceted approach combining human cell studies and animal models and assessed the effects of human basophil-derived exosomes on B cell activation in SLE patients by evaluating activation markers following exosome uptake. Furthermore, we used a basophil-depleted lupus mouse model to examine the impact of basophilic exosomes on disease progression and conducted transcriptomic analysis of basophilic exosomes to identify key molecular regulators. Finally, we explored the therapeutic potential of targeting lncRNA ENST00000537616 by intervening in its expression in humanized SLE mouse models.

Results

Human-activated basophil-derived exosomes significantly enhanced the activation of B cells from SLE patients in vitro. In the basophil-depleted lupus mouse model, activated basophilic exosomes induced excessive splenic immune cell proliferation and exacerbated renal dysfunction. Transcriptomic analysis revealed lncRNA ENST00000537616 as a key regulator released by activated basophilic exosomes, promoting B cell activation. LncRNA ENST00000537616 inhibition in a humanized SLE mouse model significantly attenuated immune hyperactivation and improved renal function, mirroring the effects of activated basophilic exosome inhibition. Mechanistically, activated basophilic exosomes facilitated B cell activation via the lncRNA ENST00000537616/miR-330-5p/KRAS axis.

Conclusions

This study provides novel insights into the pathogenesis of SLE by elucidating the role of basophilic exosomes and the lncRNA ENST00000537616/miR-330-5p/KRAS axis in B cell activation.

系统性红斑狼疮（SLE）不受控制的b细胞激活诱导自身抗体产生和炎症并导致组织损伤。嗜碱性粒细胞已被证明在SLE中促进B细胞活化；然而，所涉及的分子机制仍然模糊不清。目的阐明嗜碱性外泌体在SLE b细胞活化中的作用，探讨其分子机制。方法采用多方面的方法，结合人细胞研究和动物模型，通过评估外泌体摄取后的增殖和激活标记物，评估人嗜碱性粒细胞来源的外泌体对SLE患者B细胞活化的影响。此外，我们使用嗜碱性粒细胞缺失狼疮小鼠模型来检查嗜碱性外泌体对疾病进展的影响，并对嗜碱性外泌体进行转录组学分析以确定关键的分子调节因子。最后，我们通过干预lncRNA ENST00000537616在人源化SLE小鼠模型中的表达，探索其治疗潜力。结果人类激活的嗜碱性粒细胞来源的外泌体在体外显著增强SLE患者B细胞的激活，增殖和激活标记物增加。在嗜碱性粒细胞缺失的狼疮小鼠模型中，激活的嗜碱性外泌体诱导脾免疫细胞过度增殖，加重肾功能。转录组学分析显示lncRNA ENST00000537616是激活的嗜碱性外泌体释放的关键调节因子，促进B细胞增殖和活化。在人源化SLE小鼠模型中，lncRNA ENST00000537616抑制显著减轻免疫过度激活和改善肾功能，反映了活化的嗜碱性外泌体抑制的作用。在机制上，活化的嗜碱性外泌体通过lncRNA ENST00000537616/miR-330-5p/KRAS轴促进B细胞增殖和活化，其中lncRNA竞争性地结合miR-330-5p，减轻KRAS抑制。本研究通过阐明嗜碱性外泌体和lncRNA ENST00000537616/miR-330-5p/KRAS轴在B细胞活化中的作用，为SLE的发病机制提供了新的见解。

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引用次数: 0

S100B induces angiogenesis via the clathrin/FOXO1/β-catenin signaling pathway and contributes to Bevacizumab resistance in epithelial ovarian cancer S100B通过clathrin/FOXO1/β-catenin信号通路诱导血管生成，并参与上皮性卵巢癌的贝伐单抗耐药

IF 13 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2026-03-01 Epub Date: 2025-05-31 DOI: 10.1016/j.jare.2025.05.060

Haoya Xu, Wenzhi Li, Huiran Yue, Yang Bai, Jun Li, Xin Lu, Jieyu Wang

Introduction

Bevacizumab (BEV), the most common antiangiogenic agent for treating ovarian cancer, prolongs progression-free survival (PFS) but does not significantly improve overall survival (OS). Improving the limited clinical benefit of BEV remains a major challenge in ovarian cancer treatment. Although several studies have explored the mechanisms underlying tumor resistance to BEV, the clinical translation of these findings to overcome BEV resistance has been limited.

Objectives

To identify the key molecules and mechanisms that modulate ovarian cancer sensitivity to BEV.

Methods

RNA sequencing was conducted on BEV-sensitive and BEV-resistant mouse ovarian cancer tissue to identify differentially expressed genes (DEGs). A prognostic assessment was performed and a risk signature was constructed using these DEGs and the BEV-related sequencing datasets. S100B was identified and assessed in angiogenesis using tube formation, 3D fibrin bead sprouting, wound healing, and migration assays. Downstream targets and signaling pathways of S100B in HUVECs were identified by proteomics and validated by western blot. The effect of S100B inhibitors on BEV efficacy was evaluated using in vivo experiments.

Results

A BEV-related prognostic signature comprising 11 genes was constructed. Of these, S100B expression significantly increased in BEV-resistant mouse ovarian cancer tissue and significantly correlated with poor PFS and OS of ovarian cancer patients treated with a BEV combination chemotherapy. HUVECs co-cultured with S100B-overexpressing ovarian cancer cells promoted tube formation, sprouting, and migration. Exogenous S100B entered HUVECs via clathrin-mediated endocytosis, downregulated FOXO1 expression, and promoted β-catenin nuclear translocation and transcriptional activity, ultimately enhancing tube formation. The S100B inhibitor pentamidine significantly increased BEV responsiveness and prolonged survival in ovarian tumor-bearing mice.

Conclusion

S100B is a key molecule regulating ovarian cancer sensitivity to BEV. Paracrine S100B secreted by ovarian cancer cells acts on HUVECs, promoting angiogenesis through the FOXO1/β-catenin pathway. Pentamidine combined with BEV holds potential for overcoming BEV resistance in clinical use.

贝伐单抗（bevizumab， BEV）是治疗卵巢癌最常用的抗血管生成药物，可延长无进展生存期（PFS），但不能显著提高总生存期（OS）。提高BEV有限的临床疗效仍然是卵巢癌治疗的主要挑战。尽管一些研究已经探索了肿瘤对BEV耐药的机制，但这些发现在克服BEV耐药方面的临床翻译仍然有限。目的探讨卵巢癌对BEV敏感的关键分子及其调控机制。方法对bev敏感和bev耐药小鼠卵巢癌组织进行srna测序，鉴定差异表达基因（DEGs）。使用这些deg和bev相关测序数据集进行预后评估并构建风险特征。S100B通过血管生成、3D纤维蛋白珠发芽、伤口愈合和迁移试验进行鉴定和评估。S100B在HUVECs中的下游靶点和信号通路通过蛋白质组学鉴定和western blot验证。通过体内实验评价S100B抑制剂对BEV的影响。结果构建了包含11个基因的bev相关预后特征。其中，S100B表达在BEV耐药小鼠卵巢癌组织中显著升高，并与BEV联合化疗的卵巢癌患者PFS和OS差显著相关。huvec与过表达s100b的卵巢癌细胞共培养，促进了试管的形成、发芽和迁移。外源S100B通过网格蛋白介导的内噬作用进入HUVECs，下调FOXO1表达，促进β-catenin核易位和转录活性，最终促进管的形成。S100B抑制剂喷他脒显著提高卵巢荷瘤小鼠的BEV反应性，延长生存期。结论s100b是调控卵巢癌对BEV敏感性的关键分子。卵巢癌细胞分泌的旁分泌S100B作用于HUVECs，通过FOXO1/β-catenin通路促进血管生成。喷他脒联合BEV在临床应用中具有克服BEV耐药性的潜力。

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引用次数: 0

OsCPK9-mediated Thr105 phosphorylation activates OsCATC to enhance drought tolerance in rice oscpk9介导的Thr105磷酸化激活OsCATC增强水稻抗旱性

IF 13 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2026-03-01 Epub Date: 2025-06-05 DOI: 10.1016/j.jare.2025.06.004

Fu Shi , Li Li , Yaqiong Wang , Yanbin Guan , Ya’Nan Wu , Qian Zhang , Junli Chang , Mingjie Chen , Yuesheng Wang , Sanhe Li , Xuebin Zhang , Guangyuan He , Yin Li , Guangxiao Yang

Introduction

Drought poses a significant environmental challenge, disrupting plant growth and reducing crop productivity. As sensors and effectors in calcium signaling, calcium-dependent protein kinases (CPKs) regulate plant development and environmental adaptation. However, the specific roles and molecular networks of many OsCPKs in rice adaptation to abiotic stress remain to be elucidated.

Objectives

Drought-tolerant rice holds significant potential for enhancing yield stability and global food security. The study aimed to isolate drought-responsive OsCPKs and explore their molecular mechanisms.

Methods

To elucidate the mechanisms underlying OsCPK9-mediated drought tolerance, we integrated assays of Co-immunoprecipitation, yeast two-hybrid, GST pull-down and bimolecular fluorescence complementation to validate the OsCPK9-interacting proteins. In vitro protein phosphorylation analysis was conducted to identify phosphorylated substrates and sites. Rice yield performance was evaluated through three-year field trials.

Results

OsCPK9 overexpressing plants enhanced drought tolerance in rice, accompanied by lower H₂O₂ content and higher catalase activity than wild-type (WT) plants. Conversely, OsCPK9 knockout plants exhibited sensitive to drought stress compared with WT plants. Myristoylation and palmitoylation contributed to plasma membrane localization of OsCPK9, which is required for drought tolerance. OsCPK9 interacts with and phosphorylates Catalase C (OsCATC) at the plasma membrane. Phosphorylation of OsCATC at the highly conserved Thr105 enhanced its self-interaction, promoting oligomer formation and thereby increasing catalytic activity. OsCATC overexpressing plants showed higher catalase activity and improved drought tolerance compared to WT plants. Moreover, OsCPK9 overexpressing plants mitigated a 17.6% average yield loss per plant relative to WT plants.

Conclusion

This study reveals that myristoylation and palmitoylation of OsCPK9 contribute to its plasma membrane localization and drought tolerance. The post-translational regulatory mechanism mediated by OsCPK9 enhances environmental adaptability and provides a promising strategy to improve rice grain yield under drought stress conditions.

干旱造成了重大的环境挑战，破坏了植物生长并降低了作物产量。钙依赖性蛋白激酶（CPKs）作为钙信号传导的传感器和效应器，调控着植物的发育和环境适应。然而，许多OsCPKs在水稻适应非生物胁迫中的具体作用和分子网络仍有待阐明。目的抗旱水稻在提高产量稳定和全球粮食安全方面具有重要潜力。本研究旨在分离干旱响应型OsCPKs并探讨其分子机制。方法利用共免疫沉淀、酵母双杂交、GST下拉和双分子荧光互补等方法验证oscpk9相互作用蛋白，阐明oscpk9介导的抗旱机制。体外蛋白磷酸化分析鉴定磷酸化底物和位点。通过三年田间试验对水稻产量进行了评价。结果soscpk9过表达植株抗旱性增强，H2O2含量降低，过氧化氢酶活性高于野生型（WT）植株。相反，OsCPK9基因敲除植株对干旱胁迫表现出敏感性。肉豆蔻酰化和棕榈酰化有助于OsCPK9的质膜定位，这是耐旱性所必需的。OsCPK9与质膜上的过氧化氢酶C （OsCATC）相互作用并磷酸化。OsCATC高度保守的Thr105位点的磷酸化增强了其自相互作用，促进了低聚物的形成，从而提高了催化活性。OsCATC过表达植株的过氧化氢酶活性和抗旱性均高于WT植株。此外，与WT植株相比，OsCPK9过表达植株的单株平均产量损失减轻了17.6%。结论OsCPK9的肉豆蔻酰化和棕榈酰化参与了其质膜定位和耐旱性。OsCPK9介导的翻译后调控机制增强了水稻在干旱胁迫条件下的环境适应性，为提高水稻产量提供了一种有希望的策略。

{"title":"OsCPK9-mediated Thr105 phosphorylation activates OsCATC to enhance drought tolerance in rice","authors":"Fu Shi , Li Li , Yaqiong Wang , Yanbin Guan , Ya’Nan Wu , Qian Zhang , Junli Chang , Mingjie Chen , Yuesheng Wang , Sanhe Li , Xuebin Zhang , Guangyuan He , Yin Li , Guangxiao Yang","doi":"10.1016/j.jare.2025.06.004","DOIUrl":"10.1016/j.jare.2025.06.004","url":null,"abstract":"<div><h3>Introduction</h3><div>Drought poses a significant environmental challenge, disrupting plant growth and reducing crop productivity. As sensors and effectors in calcium signaling, calcium-dependent protein kinases (CPKs) regulate plant development and environmental adaptation. However, the specific roles and molecular networks of many OsCPKs in rice adaptation to abiotic stress remain to be elucidated.</div></div><div><h3>Objectives</h3><div>Drought-tolerant rice holds significant potential for enhancing yield stability and global food security. The study aimed to isolate drought-responsive <em>OsCPK</em>s and explore their molecular mechanisms.</div></div><div><h3>Methods</h3><div>To elucidate the mechanisms underlying OsCPK9-mediated drought tolerance, we integrated assays of Co-immunoprecipitation, yeast two-hybrid, GST pull-down and bimolecular fluorescence complementation to validate the OsCPK9-interacting proteins. <em>In vitro</em> protein phosphorylation analysis was conducted to identify phosphorylated substrates and sites. Rice yield performance was evaluated through three-year field trials.</div></div><div><h3>Results</h3><div><em>OsCPK9</em> overexpressing plants enhanced drought tolerance in rice, accompanied by lower H<sub>2</sub>O<sub>2</sub> content and higher catalase activity than wild-type (WT) plants. Conversely, <em>OsCPK9</em> knockout plants exhibited sensitive to drought stress compared with WT plants. Myristoylation and palmitoylation contributed to plasma membrane localization of OsCPK9, which is required for drought tolerance. OsCPK9 interacts with and phosphorylates Catalase C (OsCATC) at the plasma membrane. Phosphorylation of OsCATC at the highly conserved Thr105 enhanced its self-interaction, promoting oligomer formation and thereby increasing catalytic activity. <em>OsCATC</em> overexpressing plants showed higher catalase activity and improved drought tolerance compared to WT plants. Moreover, <em>OsCPK9</em> overexpressing plants mitigated a 17.6% average yield loss per plant relative to WT plants.</div></div><div><h3>Conclusion</h3><div>This study reveals that myristoylation and palmitoylation of OsCPK9 contribute to its plasma membrane localization and drought tolerance. The post-translational regulatory mechanism mediated by OsCPK9 enhances environmental adaptability and provides a promising strategy to improve rice grain yield under drought stress conditions.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 57-73"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144228718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Preclinical evidence of adenosine for early intervention in Bungarus multicinctus envenomation 腺苷对多爪兔中毒早期干预的临床前证据

IF 13 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2026-03-01 Epub Date: 2025-06-09 DOI: 10.1016/j.jare.2025.06.012

Jing Huang , Yue Qin , Haiyu Chen , Fangkun Liu

Introduction

Snakebites, one of the world’s deadliest neglected tropical diseases, predominantly affect impoverished rural communities in tropical and subtropical regions. The clinical management of snakebite envenomation currently relies heavily on antivenom serum, which is often inaccessible and expensive in these areas. Thus, effective and cost-efficient therapies for treating snakebite envenomation are urgently needed. Pimpinella diversifolia DC, a herb widely distributed across Asia, has long been used in traditional medicine for the treatment of snake venom poisoning.

Objectives

To investigate the efficacy of P. diversifolia in counteracting venom-induced lethality caused by various neurotoxic venoms in mouse models and in vitro experiments.

Methods

The protective effects of P. diversifolia against various neurotoxic venoms were evaluated in C57BL/6 mice by intraperitoneal administration of the aqueous extract immediately after injection of snake venom. The primary components of P. diversifolia were identified using liquid chromatography-mass spectrometry, and the compounds were subsequently assessed for their ability to protect against neurotoxicity. Additionally, the neurotoxic effects of Bungarus multicinctus venom and efficacy of the drug against venom-induced neurotoxicity were examined in chick biventer cervicis (BC) and mouse phrenic nerve-diaphragm (PND) preparations.

Results

P. diversifolia partially prevented lethality in some of the mice injected with various snake venoms. Adenosine, one of the most abundant compounds in the extract, significantly prevented lethality in mice caused by B. multicinctus venom, with 100% survival observed within 48 h. Adenosine markedly attenuated the neurotoxic effects of B. multicinctus venom in BC and PND preparations, and prevented the inhibition of muscular contractions induced by exogenous acetylcholine and carbamylcholine.

Conclusion

Adenosine may have a protective role against B. multicinctus venom-induced neurotoxicity in preclinical models, warranting further investigation into its mechanisms and clinical applicability.

蛇咬伤是世界上最致命的被忽视的热带病之一，主要影响热带和亚热带地区的贫困农村社区。蛇咬伤中毒的临床治疗目前严重依赖抗蛇毒血清，而抗蛇毒血清在这些地区往往难以获得且价格昂贵。因此，迫切需要有效和经济有效的治疗蛇咬伤中毒的方法。细叶松是一种广泛分布于亚洲的草本植物，长期以来在传统医学中被用于治疗蛇毒中毒。目的通过小鼠模型和体外实验，探讨何首乌对多种神经毒性毒液致毒的拮抗作用。方法以C57BL/6小鼠为实验对象，在注射蛇毒后立即给药，观察其水提物对多种神经毒性毒液的保护作用。采用液相色谱-质谱联用技术鉴定了金合欢的主要成分，并对其抗神经毒性的能力进行了评估。此外，我们还研究了黄颡鱼毒液对鸡颈（BC）和小鼠膈神经隔膜（PND）的神经毒性作用及抗毒作用。在一些注射了各种蛇毒的老鼠身上，百叶散部分地阻止了它们的死亡。腺苷是提取物中最丰富的化合物之一，可显著预防多inctus b毒液引起的小鼠死亡，在48 h内观察到100%的存活率。腺苷能明显减弱BC和PND制剂中多刺牛毒的神经毒性作用，并能阻止外源性乙酰胆碱和氨甲酰胆碱对肌肉收缩的抑制作用。结论在临床前模型中，腺苷可能对多纹夜蛾毒液引起的神经毒性具有保护作用，其机制和临床适用性有待进一步研究。

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引用次数: 0

Development and characterization of endolysosomal trafficking targeting chimera degraders of α1A-adrenergic receptor 靶向α 1a -肾上腺素能受体嵌合体降解物的内溶酶体运输的研制与表征

IF 13 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2026-03-01 Epub Date: 2025-06-07 DOI: 10.1016/j.jare.2025.06.014

Jiwei Chen , Shuo Wang , Tong Li , Wenhua Li , Xuechun Ke , Zhao Ma , Lupei Du , Minyong Li

Introduction

Despite the booming targeted protein degradation technologies, degrading cell membrane proteins remains an enormous challenge. In particular, only a limited approach is appropriate for the degradation of the G protein-coupled receptor (GPCR) superfamily. It is encouraging that accelerating GPCRs’ endocytosis and switching their post-endocytic fate from recycling to lysosomal degradation would represent a promising strategy for developing chemical degraders of GPCRs.

Objectives

This study aimed to elucidate the mechanism underlying post-endocytic sorting of internalized α_1A-adrenergic receptor (α_1A-AR) upon agonist stimulation and put forward a unique strategy for designing chemical degraders of GPCRs utilizing α_1A-AR as an exemplary target.

Methods

The protein–protein interaction (PPI) of GASP1, Beclin 2, and α_1A-AR was investigated by co-immunoprecipitation and GST pull-down, and the regulatory mechanism was explored using immunofluorescence imaging and biotin protection degradation assay. By conjugating the agonistic phenylephrine moiety and a Beclin 2-recruiting moiety, ML246 with linkers, the Endolysosomal Trafficking TArgeting Chimera (ETTAC) molecules were constructed as GPCR degraders for proof-of-concept studies.

Results

Mechanistically, the binding of Beclin 2 to GASP1 is crucial to the endolysosomal sorting and degradation of α_1A-ARs. Recruiting Beclin 2 to enhance the Beclin 2-GASP1 binding, the ETTAC molecular proved to be highly efficient in reducing recycling and facilitating the degradation of α_1A-AR. Furthermore, the representative ETTAC, PMA-37, effectively induces the α_1A-ARs degradation in transfected and cancerous cells at the nanomole range in a GASP1 and Beclin 2-dependant manner and thus exhibits significant therapeutic effects against prostate tumor and benign prostatic hyperplasia.

Conclusions

Proof-of-concept studies of the ETTAC degraders for GPCR successfully elucidate the roles of post-endocytic sorting proteins and applied to directing the lysosomal degradation of α_1A-ARs. Consequently, the ETTAC strategy represents a promising approach for the selective degradation of GPCRs and paves the way for future drug development.

尽管靶向蛋白降解技术蓬勃发展，但降解细胞膜蛋白仍然是一个巨大的挑战。特别是，只有一种有限的方法适合于G蛋白偶联受体（GPCR）超家族的降解。令人鼓舞的是，加速gpcr的内吞作用，将其内吞后命运从循环利用转变为溶酶体降解，将是开发gpcr化学降解物的一个有希望的策略。目的本研究旨在阐明内化α 1a -肾上腺素能受体（α1A-AR）在激动剂刺激下的内吞后分选机制，并提出以α1A-AR为典型靶点设计gpcr化学降解物的独特策略。方法采用共免疫沉淀法和GST下拉法研究GASP1、Beclin 2和α1A-AR蛋白-蛋白相互作用（PPI），并采用免疫荧光成像法和生物素保护降解法探讨其调控机制。通过将拮抗剂苯肾上腺素片段和Beclin 2-募集片段ML246与连接物偶联，构建了靶向嵌合体内溶酶体运输（Endolysosomal Trafficking TArgeting Chimera, etac）分子作为GPCR降解物，用于概念验证研究。结果从机制上看，Beclin 2与GASP1的结合对α1A-ARs的内溶酶体分选和降解至关重要。通过招募Beclin 2增强Beclin 2- gasp1的结合，ETTAC分子被证明具有高效的减少循环和促进α1A-AR降解的作用。此外，具有代表性的etac PMA-37在纳米级范围内以GASP1和Beclin 2依赖的方式有效诱导转染细胞和癌细胞中α1A-ARs的降解，从而对前列腺肿瘤和良性前列腺增生具有显著的治疗作用。结论ETTAC降解物对GPCR的概念验证研究成功阐明了内吞后分选蛋白的作用，并应用于指导溶酶体对α1A-ARs的降解。因此，ETTAC策略代表了gpcr选择性降解的一种有希望的方法，并为未来的药物开发铺平了道路。

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引用次数: 0

Construction of mitochondrial-targeted ferritin carrier: subunit-terminal fused mitochondrial presequences facilitate efficient delivery 线粒体靶向铁蛋白载体的构建：亚基末端融合线粒体前序促进高效递送

IF 13 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2026-03-01 Epub Date: 2025-06-09 DOI: 10.1016/j.jare.2025.06.015

Jia Zeng , Yitong Li , Xinning Fang , Han Yu , Mengyuan Xu , Xiangyu Zhao , Zhenghong Wu , Xiaole Qi

Introduction

Protein sorting within mitochondria is intricately linked to the amino acid sequence facilitating the transmembrane transport of proteins into this organelle. Leveraging the Mitochondrial Targeting Signal (MTS)-mediated protein sorting mechanism presents a promising strategy for directing therapeutic agents into the mitochondria.

Objectives

By fusing MTS to the subunit terminus of recombinant heavy chain ferritin (HFn), we aim to establish a highly effective mitochondrial targeting vector. This fusion is designed to enhance the ability to specifically direct and accumulate within mitochondria, and to precisely deliver Lonidamine (LND), a selective metabolic inhibitor, into these organelles, ultimately realizing potent anti-tumor activity.

Methods

Utilizing gene engineering strategies, a plasmid encoding MTS-modified HFn (MTS-HFn) was transferred into E.coli to induce protein expression. At the cellular level, the mitochondrial targeting capacity of MTS-HFn was investigated. Subsequently, LND was encapsulated within MTS-HFn, and its tumoral accumulation and anti-tumor efficacy were studied in tumor-bearing models.

Results

MTS-HFn demonstrated exceptional mitochondrial targeting, achieving a 2.7-fold higher accumulation in mitochondria compared to wild-type HFn. The targeting mechanism exploration unveiled that the positive charge of MTS drives aggregation of HFn around mitochondria, and mediates its entry into the mitochondrial matrix via the TOM/TIM complex. In vivo antitumor activity studies revealed that MTS-HFn preserved its inherent tumor targeting ability and significantly enhanced the tumor suppressive effect of LND, yielding an inhibition rate of 51.06%.

Conclusion

This vector inspired by natural mitochondrial protein sorting represents an optimal hierarchical delivery system for targeting both tumor and mitochondrial, offering a dependable alternative for precise treatment strategies in mitochondrial diseases.

线粒体内的蛋白质分选与促进蛋白质跨膜转运到该细胞器的氨基酸序列有着复杂的联系。利用线粒体靶向信号（MTS）介导的蛋白质分选机制为指导治疗剂进入线粒体提供了一种有前途的策略。目的将MTS与重组重链铁蛋白（HFn）亚基末端融合，建立高效的线粒体靶向载体。这种融合旨在增强线粒体内特异性指导和积累的能力，并精确地将Lonidamine (LND)，一种选择性代谢抑制剂，传递到这些细胞器中，最终实现有效的抗肿瘤活性。方法利用基因工程技术，将mts修饰的HFn质粒（MTS-HFn）转染大肠杆菌，诱导蛋白表达。在细胞水平上，研究MTS-HFn的线粒体靶向能力。随后，将LND包埋在MTS-HFn中，在荷瘤模型中研究其肿瘤蓄积和抗肿瘤功效。结果smts -HFn表现出特殊的线粒体靶向性，与野生型HFn相比，其在线粒体中的积累量高出2.7倍。靶向机制探索揭示了MTS的正电荷驱动HFn在线粒体周围聚集，并通过TOM/TIM复合物介导其进入线粒体基质。体内抗肿瘤活性研究表明，MTS-HFn保留了其固有的肿瘤靶向能力，并显著增强了LND的肿瘤抑制作用，抑制率为51.06%。结论该载体受天然线粒体蛋白分选的启发，代表了一种针对肿瘤和线粒体的最佳分层递送系统，为线粒体疾病的精确治疗策略提供了可靠的替代方案。

{"title":"Construction of mitochondrial-targeted ferritin carrier: subunit-terminal fused mitochondrial presequences facilitate efficient delivery","authors":"Jia Zeng , Yitong Li , Xinning Fang , Han Yu , Mengyuan Xu , Xiangyu Zhao , Zhenghong Wu , Xiaole Qi","doi":"10.1016/j.jare.2025.06.015","DOIUrl":"10.1016/j.jare.2025.06.015","url":null,"abstract":"<div><h3>Introduction</h3><div>Protein sorting within mitochondria is intricately linked to the amino acid sequence facilitating the transmembrane transport of proteins into this organelle. Leveraging the Mitochondrial Targeting Signal (MTS)-mediated protein sorting mechanism presents a promising strategy for directing therapeutic agents into the mitochondria.</div></div><div><h3>Objectives</h3><div>By fusing MTS to the subunit terminus of recombinant heavy chain ferritin (HFn), we aim to establish a highly effective mitochondrial targeting vector. This fusion is designed to enhance the ability to specifically direct and accumulate within mitochondria, and to precisely deliver Lonidamine (LND), a selective metabolic inhibitor, into these organelles, ultimately realizing potent anti-tumor activity.</div></div><div><h3>Methods</h3><div>Utilizing gene engineering strategies, a plasmid encoding MTS-modified HFn (MTS-HFn) was transferred into <em>E.coli</em> to induce protein expression. At the cellular level, the mitochondrial targeting capacity of MTS-HFn was investigated. Subsequently, LND was encapsulated within MTS-HFn, and its tumoral accumulation and anti-tumor efficacy were studied in tumor-bearing models.</div></div><div><h3>Results</h3><div>MTS-HFn demonstrated exceptional mitochondrial targeting, achieving a 2.7-fold higher accumulation in mitochondria compared to wild-type HFn. The targeting mechanism exploration unveiled that the positive charge of MTS drives aggregation of HFn around mitochondria, and mediates its entry into the mitochondrial matrix via the TOM/TIM complex. <em>In vivo</em> antitumor activity studies revealed that MTS-HFn preserved its inherent tumor targeting ability and significantly enhanced the tumor suppressive effect of LND, yielding an inhibition rate of 51.06%.</div></div><div><h3>Conclusion</h3><div>This vector inspired by natural mitochondrial protein sorting represents an optimal hierarchical delivery system for targeting both tumor and mitochondrial, offering a dependable alternative for precise treatment strategies in mitochondrial diseases.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 1023-1036"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144237837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integrative multi-omics profiling deciphers tumor microenvironment heterogeneity and immunotherapy vulnerabilities in lung neuroendocrine carcinomas 综合多组学分析揭示了肺神经内分泌癌的肿瘤微环境异质性和免疫治疗脆弱性

IF 13 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2026-03-01 Epub Date: 2025-06-11 DOI: 10.1016/j.jare.2025.06.017

Zicheng Zhang , Modi Zhai , Siqi Bao , Xujie Sun , Ruanqi Chen , Bingning Wang , Fan Yang , Lin Yang , Meng Zhou

Introduction

Lung neuroendocrine carcinomas (Lu-NECs) are rare, highly aggressive lung tumors with poor prognosis and limited therapeutic options. Understanding the tumor immune microenvironment (TIME) is crucial towards personalized therapeutic strategies.

Objectives

This study aims to systematically characterize the heterogeneity and complexity of the TIME in Lu-NECs by integrating proteomic, transcriptomic, and genomic data.

Methods

We performed comprehensive immune-proteomic profiling of 76 Lu-NECs across diverse histopathological subtypes to elucidate intra-tumoral TIME heterogeneity at the proteomic level. Validation was conducted in multiple independent cohorts, including 112 Lu-NECs using immunohistochemistry, 147 Lu-NECs, and 17 small cell lung carcinoma samples using transcriptomics. We integrated proteomic, transcriptomic, genomic, and clinical data to assess molecular, immunological, and clinical features, as well as therapeutic vulnerabilities across different immune subtypes.

Results

We delineated the immuno-proteomic landscape of Lu-NECs and identified two major immuno-proteomic clusters with distinct immunological, molecular, and clinical characteristics. IPC1 was characterized by high immune cell infiltration, while IPC2 exhibited sparse immune cell presence. Genomic analysis revealed distinct mutational patterns, with IPC1 showing a higher incidence of APOBEC-associated mutation signatures and IPC2 being enriched for mutations associated with defective DNA mismatch repair and tobacco-related mutagens. Functional analyses indicated that IPC1 was related to immune and oncogenic signaling activity, whereas IPC2 was associated with cancer stemness and proliferation-related features. Furthermore, IPC1 and IPC2 demonstrated histological subtype-specific clinical benefits from postoperative chemotherapy. Finally, we developed a machine learning model (iPROM) to predict Lu-NECs immune classification and improve risk stratification, which was validated across multiple independent cohorts.

Conclusions

This study advances the understanding of the tumor immune microenvironment in Lu-NECs through multi-omics characterization and highlights potential personalized therapeutic vulnerabilities tailored to the specific immune landscapes of Lu-NECs.

肺神经内分泌癌（luc - nec）是一种罕见的高侵袭性肺肿瘤，预后差，治疗选择有限。了解肿瘤免疫微环境（TIME）对个性化治疗策略至关重要。本研究旨在通过整合蛋白质组学、转录组学和基因组数据，系统地表征Lu-NECs中TIME的异质性和复杂性。方法对76个不同组织病理学亚型的lu - nec进行了全面的免疫蛋白质组学分析，以阐明蛋白质组学水平上肿瘤内TIME的异质性。在多个独立队列中进行了验证，包括免疫组织化学方法的112个lu - nec样本，转录组学方法的147个lu - nec样本和17个小细胞肺癌样本。我们整合了蛋白质组学、转录组学、基因组学和临床数据，以评估不同免疫亚型的分子、免疫学和临床特征，以及治疗脆弱性。结果我们描绘了luc - necs的免疫蛋白质组学景观，并确定了两个主要的免疫蛋白质组学簇，它们具有不同的免疫学、分子和临床特征。IPC1表现为免疫细胞高度浸润，而IPC2表现为免疫细胞稀疏。基因组分析揭示了不同的突变模式，IPC1显示apobecc相关突变特征的发生率较高，IPC2富集与DNA错配修复缺陷和烟草相关突变相关的突变。功能分析表明，IPC1与免疫和致癌信号活性相关，而IPC2与癌症干性和增殖相关特征相关。此外，IPC1和IPC2显示了术后化疗对组织学亚型特异性的临床益处。最后，我们开发了一个机器学习模型（iPROM）来预测lu - nec的免疫分类并改善风险分层，并在多个独立队列中进行了验证。结论本研究通过多组学表征提高了对Lu-NECs肿瘤免疫微环境的认识，并突出了针对Lu-NECs特异性免疫景观的潜在个性化治疗脆弱性。

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引用次数: 0

A novel peptide MIB1-223aa encoded by exosomal circMIB1 from cancer-associated fibroblasts drives triple-negative breast cancer metastasis and stemness via stabilizing MIB1 to activate Notch signaling 来自癌症相关成纤维细胞的外泌体circMIB1编码的一种新型肽MIB1-223aa通过稳定MIB1激活Notch信号来驱动三阴性乳腺癌的转移和干细胞

IF 13 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2026-03-01 Epub Date: 2025-06-11 DOI: 10.1016/j.jare.2025.06.023

Fangzhou Ye , Yiran Liang , Jianing Wang , Jiayin Song , Yuhan Jin , Lei Wang , Dan Luo , Xiaoyan Li , Yaming Li , Dianwen Han , Tong Chen , Bing Chen , Wenjing Zhao , Lijuan Wang , Qifeng Yang

Introduction

Emerging evidence has indicated that the complex interactions between tumor microenvironment (TME) and cancer cells play a pivotal role in driving tumor initiation and metastasis. Cancer associated fibroblasts (CAFs), major cell components in the TME, exert significant effects on malignant behaviors of various cancers. Triple negative breast cancer (TNBC) is the most malignant subtype of breast cancer with a high metastatic potential and poorer prognosis. However, the underlying mechanism by which CAFs promote TNBC development has not been sufficiently studied.

Objectives

The study aims to elucidate how CAFs promote TNBC aggressiveness by delivering protein-coding circMIB1 to activate MIB1/DLL4/Notch pathway, and provide a potential clinical biomarker for TNBC management.

Methods

The oncogenic exosomal circMIB1 with protein-coding potential was identified through high-throughput RNA sequencing and ribosome nascent-chain complex sequencing (RNC-seq). The enrichment of circMIB1 in CAFs was confirmed using in situ hybridization (ISH) and qRT-PCR. The protein-coding capacity of circMIB1 was validated based on the polysome profiling, and luciferase assays. Functional roles of circMIB1 were explored using in vitro and in vivo models, while the underlying mechanism was dissected via co-immunoprecipitation (Co-IP) and western blotting.

Results

CAF-secreted exosomal circMIB1 promoted TNBC metastasis and stemness by translating a functional peptide, MIB1-223aa. Mechanistically, MIB1-223aa competitively bound to the E3 ubiquitin ligase RNF213, which blocked the RNF213-mediated K48-linked ubiquitination and degradation of MIB1. Moreover, the stabilized MIB1 enhanced the Notch signaling via a ubiquitination-dependent activation of the ligand DLL4, thereby driving TNBC malignancy. Clinically, high expression of circMIB1 or MIB1-223aa in TNBC tissues was correlated with poor clinical prognosis, as evidenced by reduced overall survival, shortened disease-free survival, and elevated lymphatic metastasis rates.

Conclusion

This study provides the first evidence of exosome-transmitted protein-coding circRNAs in CAF-TNBC crosstalk, offering novel insights into the TME-driven metastasis and providing promising biomarker for TNBC management.

越来越多的证据表明，肿瘤微环境（tumor microenvironment， TME）与癌细胞之间复杂的相互作用在肿瘤的发生和转移中起着关键作用。癌相关成纤维细胞（Cancer associated fibroblasts, CAFs）是TME中的主要细胞成分，在多种癌症的恶性行为中发挥着重要作用。三阴性乳腺癌（TNBC）是乳腺癌中最恶性的亚型，具有高转移潜力和较差的预后。然而，CAFs促进TNBC发展的潜在机制尚未得到充分研究。本研究旨在阐明CAFs如何通过传递编码蛋白circMIB1激活MIB1/DLL4/Notch通路来促进TNBC侵袭性，并为TNBC治疗提供潜在的临床生物标志物。方法采用高通量RNA测序和核糖体新生链复合体测序（RNA -seq）技术，鉴定具有蛋白编码潜力的致癌外泌体circMIB1。利用原位杂交（ISH）和qRT-PCR证实了CAFs中circMIB1的富集。circMIB1的蛋白质编码能力是基于多体分析和荧光素酶测定来验证的。通过体外和体内模型探索circMIB1的功能作用，并通过免疫共沉淀（Co-IP）和western blotting分析其潜在机制。结果scaf分泌的外泌体circMIB1通过翻译功能肽MIB1-223aa促进TNBC的转移和干细胞性。在机制上，MIB1-223aa竞争性地与E3泛素连接酶RNF213结合，从而阻断RNF213介导的k48相关的MIB1泛素化和降解。此外，稳定的MIB1通过泛素化激活配体DLL4来增强Notch信号，从而驱动TNBC恶性肿瘤。在临床上，circMIB1或MIB1-223aa在TNBC组织中的高表达与临床预后不良相关，表现为总生存期降低、无病生存期缩短、淋巴转移率升高。本研究首次提供了外泌体传递蛋白编码环状rna在cafc -TNBC串扰中的证据，为tme驱动的转移提供了新的见解，并为TNBC的治疗提供了有希望的生物标志物。

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引用次数: 0

Three-dimensional multimodal imaging for predicting early recurrence of hepatocellular carcinoma after surgical resection 三维多模态成像预测肝细胞癌术后早期复发

IF 13 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Journal of Advanced Research

Pub Date : 2026-03-01 Epub Date: 2025-06-16 DOI: 10.1016/j.jare.2025.06.031

Jie Peng , Jiaren Wang , Hongbo Zhu , Pu Jiang , Ji Xia , Hao Cui , Chang Hong , Lin Zeng , Ruining Li , Yan Li , Shengxing Liang , Qijie Deng , Huangying Deng , Hengtian Xu , Hanzhi Dong , Lushan Xiao , Li Liu

Background

High tumor recurrence after surgery remains a significant challenge in managing hepatocellular carcinoma (HCC). We aimed to construct a multimodal model to forecast the early recurrence of HCC after surgical resection and explore the associated biological mechanisms.

Materials and methods

Overall, 519 patients with HCC were included from three medical centers. 433 patients from Nanfang Hospital were used as the training cohort, and 86 patients from the other two hospitals comprised validation cohort. Radiomics and deep learning (DL) models were developed using contrast-enhanced computed tomography images. Radiomics feature visualization and gradient-weighted class activation mapping were applied to improve interpretability. A multimodal model (MM-RDLM) was constructed by integrating radiomics and DL models. Associations between MM-RDLM and recurrence-free survival (RFS) and overall survival were analyzed. Gene set enrichment analysis (GSEA) and multiplex immunohistochemistry (mIHC) were used to investigate the biological mechanisms.

Results

Models based on hepatic arterial phase images exhibited the best predictive performance, with radiomics and DL models achieving areas under the curve (AUCs) of 0.770 (95 % confidence interval [CI]: 0.725–0.815) and 0.846 (95 % CI: 0.807–0.886), respectively, in the training cohort. MM-RDLM achieved an AUC of 0.955 (95 % CI: 0.937–0.972) in the training cohort and 0.930 (95 % CI: 0.876–0.984) in the validation cohort. MM-RDLM (high vs. low) was notably linked to RFS in the training (hazard ratio [HR] = 7.80 [5.74 − 10.61], P < 0.001) and validation (HR = 10.46 [4.96 − 22.68], P < 0.001) cohorts. GSEA revealed enrichment of the natural killer cell-mediated cytotoxicity pathway in the MM-RDLM low cohort. mIHC showed significantly higher percentages of CD3-, CD56-, and CD8-positive cells in the MM-RDLM low group.

Conclusion

The MM-RDLM model demonstrated strong predictive performance for early postoperative recurrence of HCC. These findings contribute to identifying patients at high risk for early recurrence and provide insights into the potential underlying biological mechanisms.

背景：肝细胞癌术后高肿瘤复发仍然是治疗肝细胞癌（HCC）的一个重大挑战。我们的目的是建立一个多模式模型来预测肝癌手术切除后的早期复发，并探讨相关的生物学机制。材料和方法共纳入来自三个医疗中心的519例HCC患者。以南方医院的433例患者为训练队列，另外两家医院的86例患者为验证队列。放射组学和深度学习（DL）模型是使用对比度增强的计算机断层扫描图像开发的。采用放射组学特征可视化和梯度加权类激活映射来提高可解释性。将放射组学模型与DL模型相结合，构建了多模态模型（MM-RDLM）。分析MM-RDLM与无复发生存期（RFS）和总生存期之间的关系。采用基因集富集分析（GSEA）和多重免疫组化（mIHC）研究其生物学机制。结果基于肝动脉期图像的模型表现出最好的预测效果，在训练队列中，放射组学和DL模型的曲线下面积（auc）分别为0.770（95 %置信区间[CI]: 0.725-0.815）和0.846（95 % CI: 0.807-0.886）。MM-RDLM在训练组的AUC为0.955(95 % CI: 0.937 ~ 0.972)，在验证组的AUC为0.930（95 % CI: 0.876 ~ 0.984）。MM-RDLM(高与低)特别是培训与RFS(危险比[HR] = 7.80[5.74 − 10.61],P & lt; 0.001)和验证(HR = 10.46[4.96 − 22.68],P & lt; 0.001)军团。GSEA显示自然杀伤细胞介导的细胞毒性途径在MM-RDLM低队列中富集。在MM-RDLM低浓度组，mIHC显示CD3-、CD56-和cd8阳性细胞的百分比显著增加。结论MM-RDLM模型对肝癌术后早期复发具有较强的预测能力。这些发现有助于识别早期复发高风险患者，并为潜在的潜在生物学机制提供见解。

{"title":"Three-dimensional multimodal imaging for predicting early recurrence of hepatocellular carcinoma after surgical resection","authors":"Jie Peng , Jiaren Wang , Hongbo Zhu , Pu Jiang , Ji Xia , Hao Cui , Chang Hong , Lin Zeng , Ruining Li , Yan Li , Shengxing Liang , Qijie Deng , Huangying Deng , Hengtian Xu , Hanzhi Dong , Lushan Xiao , Li Liu","doi":"10.1016/j.jare.2025.06.031","DOIUrl":"10.1016/j.jare.2025.06.031","url":null,"abstract":"<div><h3>Background</h3><div>High tumor recurrence after surgery remains a significant challenge in managing hepatocellular carcinoma (HCC). We aimed to construct a multimodal model to forecast the early recurrence of HCC after surgical resection and explore the associated biological mechanisms.</div></div><div><h3>Materials and methods</h3><div>Overall, 519 patients with HCC were included from three medical centers. 433 patients from Nanfang Hospital were used as the training cohort, and 86 patients from the other two hospitals comprised validation cohort. Radiomics and deep learning (DL) models were developed using contrast-enhanced computed tomography images. Radiomics feature visualization and gradient-weighted class activation mapping were applied to improve interpretability. A multimodal model (MM-RDLM) was constructed by integrating radiomics and DL models. Associations between MM-RDLM and recurrence-free survival (RFS) and overall survival were analyzed. Gene set enrichment analysis (GSEA) and multiplex immunohistochemistry (mIHC) were used to investigate the biological mechanisms.</div></div><div><h3>Results</h3><div>Models based on hepatic arterial phase images exhibited the best predictive performance, with radiomics and DL models achieving areas under the curve (AUCs) of 0.770 (95 % confidence interval [CI]: 0.725–0.815) and 0.846 (95 % CI: 0.807–0.886), respectively, in the training cohort. MM-RDLM achieved an AUC of 0.955 (95 % CI: 0.937–0.972) in the training cohort and 0.930 (95 % CI: 0.876–0.984) in the validation cohort. MM-RDLM (high vs. low) was notably linked to RFS in the training (hazard ratio [HR] = 7.80 [5.74 − 10.61], <em>P</em> < 0.001) and validation (HR = 10.46 [4.96 − 22.68], <em>P</em> < 0.001) cohorts. GSEA revealed enrichment of the natural killer cell-mediated cytotoxicity pathway in the MM-RDLM low cohort. mIHC showed significantly higher percentages of CD3-, CD56-, and CD8-positive cells in the MM-RDLM low group.</div></div><div><h3>Conclusion</h3><div>The MM-RDLM model demonstrated strong predictive performance for early postoperative recurrence of HCC. These findings contribute to identifying patients at high risk for early recurrence and provide insights into the potential underlying biological mechanisms.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"81 ","pages":"Pages 865-875"},"PeriodicalIF":13.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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