Cellular signalling最新文献_第7页

CREG1 promotes bone formation via targeting RAB7 to activate autophagy in osteoporosis CREG1通过靶向RAB7激活骨质疏松症的自噬来促进骨形成。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-05-01 Epub Date: 2026-01-21 DOI: 10.1016/j.cellsig.2026.112386

Xiaofeng Li , Yi Liu , Shiyu Sha , Haoling Li , Yingqiang Fu , Shenghou Liu , Qingfeng Yin , Xin Pan , Wenguang Liu

Osteoporosis is characterized by reduced bone mass and impaired skeletal microarchitecture, with impaired osteogenic differentiation capacity of bone marrow mesenchymal stem cells (BMSCs) serving as a key contributing factor in its development. Cellular repressor of E1A-stimulated genes 1 (CREG1), a lysosomal glycoprotein, has been implicated in the regulation of autophagy and osteogenic differentiation. However, the molecular mechanisms underlying CREG1-mediated bone homeostasis remain unclear. In this study, we identified RAB7, a small GTPase involved in endosomal trafficking and autophagy, as a downstream effector of CREG1. We found that RAB7 expression progressively increased during osteogenic differentiation of BMSCs. RAB7 knockdown impaired osteogenesis, whereas its overexpression enhanced the process. Functional assays demonstrated that modulation of RAB7 expression significantly influenced the effects of CREG1 on BMSCs. RAB7 knockdown inhibited CREG1-induced osteogenic differentiation and autophagy activation, whereas RAB7 overexpression restored the osteogenic potential suppressed by CREG1 knockdown. Our findings suggest that CREG1 facilitates osteogenic differentiation and bone homeostasis via RAB7-mediated regulation of autophagy.

骨质疏松症以骨量减少和骨骼微结构受损为特征，骨髓间充质干细胞（BMSCs）成骨分化能力受损是其发展的关键因素。e1a刺激基因1的细胞抑制因子（CREG1）是一种溶酶体糖蛋白，与自噬和成骨分化的调节有关。然而，creg1介导的骨稳态的分子机制尚不清楚。在这项研究中，我们发现RAB7是一个参与内体运输和自噬的小GTPase，是CREG1的下游效应物。我们发现RAB7的表达在骨髓间充质干细胞成骨分化过程中逐渐增加。RAB7敲除会破坏成骨，而其过表达则会增强成骨过程。功能分析表明，RAB7表达的调节显著影响了CREG1对骨髓间充质干细胞的作用。RAB7敲低可抑制CREG1诱导的成骨分化和自噬激活，而RAB7过表达可恢复被CREG1敲低抑制的成骨潜能。我们的研究结果表明，CREG1通过rab7介导的自噬调节促进成骨分化和骨稳态。

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引用次数: 0

The Limb-bud and Heart (LBH) promotes renal fibrosis through endoplasmic reticulum stress-induced pyroptosis and partial epithelial-mesenchymal transition in renal tubular epithelial cells 肢体芽和心脏（LBH）通过内质网应激诱导的焦亡和肾小管上皮细胞部分上皮-间质转化促进肾纤维化。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-05-01 Epub Date: 2026-01-09 DOI: 10.1016/j.cellsig.2026.112359

Tao Shu , Ning Luo , Yuqi Shu , Jingyan Wei , Hongxin Niu , Qicai Liu

Renal fibrosis is a primary pathological feature of chronic kidney disease, with a current lack of effective treatments. In this study, we observed that Limb-bud and Heart (LBH) expression was upregulated in kidney specimens obtained from patients with chronic kidney disease. During UUO-induced renal fibrosis, both the protein level and mRNA level of LBH were significantly elevated. Furthermore, knockout of the mouse LBH gene significantly ameliorated renal fibrosis. The application of inhibitors, agonists, and knockout mouse models uniformly verified the role of LBH deficiency in alleviating both endoplasmic reticulum stress (ERS) and pyroptosis. Although renal tubular epithelial cells (RTECs) are conventionally considered the initial responders to renal fibrosis, the role and mechanism of LBH in these cells during disease progression remain unclear. Therefore, this study focused on investigating LBH's effects in damaged RTECs. Mechanistic studies demonstrated that within renal tubular epithelial cells, LBH significantly promotes renal fibrosis by forming a positive feedback loop with TGFβ1 and ERS. This activated ERS subsequently further induces pyroptosis and partial epithelial-mesenchymal transition (pEMT), thereby promoting renal fibrosis. Importantly, LBH deficiency was shown to significantly attenuate renal fibrosis. These collective findings strongly suggest that LBH may constitute a promising therapeutic target for the treatment of renal fibrosis.

肾纤维化是慢性肾脏疾病的主要病理特征，目前缺乏有效的治疗方法。在这项研究中，我们观察到从慢性肾病患者的肾脏标本中获得的肢体芽和心脏（LBH）表达上调。在uuo诱导的肾纤维化过程中，LBH蛋白水平和mRNA水平均显著升高。此外，敲低小鼠LBH基因可显著改善肾纤维化。抑制剂、激动剂和敲除小鼠模型的应用一致证实了LBH在缓解内质网应激（ERS）和焦死方面的作用。尽管肾小管上皮细胞（RTECs）通常被认为是肾纤维化的初始应答者，但LBH在疾病进展过程中在这些细胞中的作用和机制尚不清楚。因此，本研究的重点是研究LBH对受损rtec的影响。机制研究表明，在肾小管上皮细胞内，LBH通过与tgf - β1和ERS形成正反馈回路，显著减轻肾纤维化。这种激活的ERS随后进一步诱导焦亡和部分上皮-间质转化（ppt），从而促进肾纤维化。重要的是，LBH缺乏被证明可以显著减轻肾纤维化。这些共同的发现强烈表明，LBH可能是治疗肾纤维化的一个有希望的治疗靶点。

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引用次数: 0

Multi-omics identifies an epithelial–B cell cross-talk that drives functional B cell diversion in breast cancer lymph node metastasis 多组学鉴定了乳腺癌淋巴结转移中上皮- B细胞串扰驱动功能性B细胞转移

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-05-01 Epub Date: 2026-01-27 DOI: 10.1016/j.cellsig.2026.112394

Xin Li , Yu Zhang , Dongchen Ji , Lin Li , Yu Deng , Hongbin Wang , Jinsong Wang

Lymph node metastasis is a critical determinant of poor prognosis in breast cancer, yet the functional heterogeneity of B cells and their roles during metastasis remain poorly understood. Through integrated single-cell RNA sequencing of paired primary tumors and metastatic lymph nodes in HR⁺/HER2⁻ breast cancer, spatial transcriptomics, and in vivo functional models, we systematically mapped B cell states and interactions during metastatic progression. We found that IgA⁺ plasma cells, which promote tumor progression, were significantly expanded in metastatic lymph nodes, whereas immunostimulatory IgG⁺ plasma cells predominated in primary tumors. The distinct functional phenotypes of these subsets were validated by in vivo antibody supplementation. Additionally, KLF2⁺ B cells exhibited divergent functional differentiation between carcinoma and lymph node sites. Functional in vivo assays confirmed that epithelial-derived LPAR2 signaling modulates B cell activation and cytotoxic function, thereby facilitating metastatic progression. We developed a ligand-receptor interaction score that robustly predicted prognosis across independent cohorts. Together, our findings elucidate the spatial and functional reprogramming of B cells in breast cancer metastasis and highlight their potential as therapeutic targets.

淋巴结转移是乳腺癌预后不良的关键决定因素，但B细胞的功能异质性及其在转移过程中的作用仍然知之甚少。通过整合HR+/HER2−乳腺癌配对原发肿瘤和转移淋巴结的单细胞RNA测序、空间转录组学和体内功能模型，我们系统地绘制了B细胞状态和转移进展过程中的相互作用。我们发现促进肿瘤进展的IgA+浆细胞在转移性淋巴结中显著扩增，而免疫刺激的IgG+浆细胞在原发肿瘤中占主导地位。这些亚群的不同功能表型通过体内抗体补充得到验证。此外，KLF2+ B细胞在癌和淋巴结部位表现出不同的功能分化。体内功能实验证实，上皮来源的LPAR2信号传导调节B细胞活化和细胞毒性功能，从而促进转移进展。我们开发了一个配体-受体相互作用评分，在独立队列中可靠地预测预后。总之，我们的研究结果阐明了B细胞在乳腺癌转移中的空间和功能重编程，并强调了它们作为治疗靶点的潜力。

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引用次数: 0

Circ_Mkrn2 facilitates the progression of atrial fibrillation via sponging miR-10b-5p Circ_Mkrn2通过海绵miR-10b-5p促进房颤的进展。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-05-01 Epub Date: 2026-01-29 DOI: 10.1016/j.cellsig.2026.112400

Yanshu Zhao , Pengyu Sun , Tianshu Gu , Zhipeng Lai , Qiankun Bao , Yue Zhang , Xue Liang , Guangping Li , Tong Liu , Enzhao Liu , Hui Wang

Chronic intermittent hypoxia (CIH) is the predominant pathophysiological disorder of obstructive sleep apnea (OSA), known to be an important risk factor for atrial fibrillation (AF). MicroRNA-10b-5p levels are significantly reduced under hypoxic conditions. Nevertheless, the role and underlying mechanism of miR-10b-5p in CIH-induced AF remain elusive. In this study, we found that miR-10b-5p expression was downregulated in the atrial tissues of patients and rats with AF. Functionally, miR-10b-5p exerts protective roles in CIH induced atrial fibroblasts activation and AF development by inhibiting the expression of Smad ubiquitin regulatory factor 1 (SMURF1) and TGFβ/Smads signaling activation. RNA sequencing and bioinformatics identified that circ_Mkrn2, as possessing multiple putative binding sites for miR-10b-5p, was increased in patients and rats with AF. Circ_Mkrn2 overexpression promoted SMURF1 expression and atrial fibroblast activation, which were effectively reversed by miR-10b-5p overexpression. Circ_Mkrn2 silencing alleviated the expression of SMURF1 and TGFβ/Smads signaling activation, atrial fibroblasts activation and AF induced by CIH. Our findings showed that circ_Mkrn2 serves as an miR-10b-5p sponge，promotes Smurf1 expression, regulates atrial fibroblast activation, cardiac fibrosis and the development of AF, revealing a potential new target for the prevention of CIH-induced AF.

慢性间歇性缺氧（CIH）是阻塞性睡眠呼吸暂停（OSA）的主要病理生理障碍，是心房颤动（AF）的重要危险因素。在缺氧条件下，MicroRNA-10b-5p水平显著降低。然而，miR-10b-5p在cih诱导AF中的作用和潜在机制尚不清楚。在这项研究中，我们发现miR-10b-5p在房颤患者和大鼠的心房组织中表达下调。功能上，miR-10b-5p通过抑制Smad泛素调节因子1 （SMURF1）的表达和TGFβ/Smads信号激活，在CIH诱导的心房成纤维细胞活化和房颤发展中发挥保护作用。RNA测序和生物信息学发现，circ_Mkrn2具有miR-10b-5p的多个推测结合位点，在AF患者和大鼠中增加。circ_Mkrn2过表达促进SMURF1表达和心房成纤维细胞活化，而miR-10b-5p过表达可有效逆转这一过程。Circ_Mkrn2沉默可减轻SMURF1和TGFβ/Smads信号的表达、心房成纤维细胞的激活和CIH诱导的AF。我们的研究结果表明circ_Mkrn2作为miR-10b-5p海绵，促进Smurf1表达，调节心房成纤维细胞活化，心脏纤维化和房颤的发展，揭示了预防cih诱导的房颤的潜在新靶点。

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引用次数: 0

The YAP1 and EPHA3 receptor tyrosine kinase axis regulates cellular plasticity and treatment response YAP1与EphA3受体酪氨酸激酶协同作用调控前列腺癌细胞可塑性和治疗反应。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-05-01 Epub Date: 2026-01-12 DOI: 10.1016/j.cellsig.2026.112368

Marwah M. Al-Mathkour , Abdulrahman M. Dwead , Kezhan Khazaw , Bekir Cinar

The transcriptional coregulator YAP1 and the receptor tyrosine kinase EPHA3 regulate key cellular processes, including cell interactions, motility, survival, tissue development, carcinogenesis, and metastasis. Although their individual roles have been extensively studied, their cooperative functions remain poorly understood. Here, we investigated the relationship between EPHA3 and YAP1 in human prostate tumor tissues and cell models. Integrated transcriptomic and immunological analyses reveal a strong positive correlation between YAP1 and EPHA3 expression, which is significantly associated with tumor progression. EPHA3 knockout reduces cell proliferation and increases sensitivity to the androgen receptor inhibitor enzalutamide and the YAP1-TEAD inhibitor CA3 in vitro. EPHA3 depletion also reduces GTP-bound active RHOA and phosphorylated ERK levels and differentially affects epithelial-mesenchymal transition and cancer stem cell programs. In addition, EPHA3 silencing attenuates cell migration and invasion, an effect dependent on YAP1 activation. Bioinformatics analysis further indicates that high YAP1 and EPHA3 correlate with developmental and EMT-related gene signatures. These results demonstrate that the YAP1-EPHA3 axis is a key mediator of cell survival, plasticity, and tumor progression, and may serve as a promising cancer drug target.

转录共调节剂YAP1和受体酪氨酸激酶EPHA3调节关键的细胞过程，包括细胞相互作用、运动、存活、组织发育、致癌和转移。虽然它们的个体作用已被广泛研究，但它们的合作功能仍然知之甚少。在此，我们研究了EPHA3和YAP1在人前列腺肿瘤组织和细胞模型中的关系。综合转录组学和免疫学分析显示，YAP1和EPHA3的表达呈正相关，与肿瘤进展显著相关。在体外实验中，敲除EPHA3可降低细胞增殖，增加对雄激素受体抑制剂enzalutamide和YAP1-TEAD抑制剂CA3的敏感性。EPHA3缺失也会降低gtp结合的活性RHOA和磷酸化的ERK水平，并对上皮-间质转化和癌症干细胞程序产生不同的影响。此外，EPHA3沉默会减弱细胞迁移和侵袭，这是一种依赖于YAP1激活的效应。生物信息学分析进一步表明，高水平的YAP1和EPHA3与发育和emt相关的基因特征相关。这些结果表明，YAP1-EPHA3轴是细胞存活、可塑性和肿瘤进展的关键介质，可能是一个有希望的癌症药物靶点。

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引用次数: 0

Anti-fibrotic activity of nobiletin and nintedanib: In vitro and in vivo evidence in pulmonary fibrosis models 诺匹莱素和尼达尼布的抗纤维化活性：肺纤维化模型的体外和体内证据。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-05-01 Epub Date: 2026-01-12 DOI: 10.1016/j.cellsig.2026.112364

Xue Yang , Yuanru Wang , Luyao Li , Qiqi Lei , Liuyan Xiang , Xiaoqian Zhang , Jie Liu , Yajun Cao , Huifang Li , Xuejun Li

Background

Pulmonary fibrosis, a well-known chronic and progressive lung disease, primarily impacts the interstitial tissues of the lungs, with a lack of effective therapies. Nobiletin is a polymethoxyflavonoid that exhibits characteristics of BH3 mimetics. It is mainly extracted from citrus peels and is known for its diverse pharmacological activities. Given the unsatisfactory clinical trial results of nintedanib, a combined treatment approach may represent a viable strategy for combating pulmonary fibrosis.

Methods

An in vitro pulmonary fibrosis model was established by inducing MRC-5 cells with transforming growth factor-β1 (TGF-β1). The impact of nobiletin combined with nintedanib on the migration of MRC-5 cells was assessed by wound healing and Transwell assays. Immunofluorescence and Western blot analyses were employed to assess the effect of drug combination on fibrosis-related markers, while Co-Immunoprecipitation (Co-IP) experiments were performed to assess the effects on autophagy. The anti-fibrotic effects and potential mechanisms of the combination of nobiletin and nintedanib were further explored using a bleomycin-induced pulmonary fibrosis model in C57BL/6 J mice.

Results

In vitro, the combination of nobiletin and nintedanib significantly inhibited MRC-5 cells' migration and extracellular matrix deposition, while simultaneously promoting apoptosis and autophagy. In addition, this combination exerted an anti-pulmonary fibrosis effect by regulating epigenetic mechanisms and the PI3K-AKT-mTOR signaling pathway. In vivo studies further revealed that the combination of nobiletin and nintedanib significantly reduced hydroxyproline levels in mice, attenuated lung inflammation, and helped to limit or prevent collagen accumulation.

Conclusions

Our study demonstrates that the combination of nobiletin and nintedanib exhibits promising anti-fibrotic effects both in vitro and in vivo.

背景：肺纤维化是一种众所周知的慢性进行性肺病，主要影响肺间质组织，缺乏有效的治疗方法。苦楝素是一种多甲氧基类黄酮，具有BH3模拟物的特性。它主要是从柑橘皮中提取的，以其多种药理活性而闻名。鉴于尼达尼布的临床试验结果不令人满意，联合治疗方法可能是对抗肺纤维化的可行策略。方法：采用转化生长因子-β1 （TGF-β1）诱导MRC-5细胞建立体外肺纤维化模型。nobiletin联合尼达尼布对MRC-5细胞迁移的影响通过伤口愈合和Transwell试验进行评估。采用免疫荧光和Western blot分析评估联合用药对纤维化相关标志物的影响，采用共免疫沉淀（Co-Immunoprecipitation, Co-IP）实验评估对自噬的影响。采用博莱霉素诱导C57BL/6 J小鼠肺纤维化模型，进一步探讨诺比莱素与尼达尼布联合抗纤维化作用及可能机制。结果：诺比莱素与尼达尼布联合在体外显著抑制MRC-5细胞的迁移和细胞外基质沉积，同时促进细胞凋亡和自噬。此外，该组合通过调节表观遗传机制和PI3K-AKT-mTOR信号通路发挥抗肺纤维化作用。体内研究进一步表明，诺biletin和尼达尼布联合使用可显著降低小鼠体内羟脯氨酸水平，减轻肺部炎症，并有助于限制或阻止胶原蛋白的积累。结论：我们的研究表明，诺匹莱素和尼达尼布联合使用在体内和体外都有很好的抗纤维化作用。

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引用次数: 0

LINC00942 accelerates esophageal cancer progression via NAT10/HSPD1 LINC00942通过NAT10/HSPD1加速食管癌进展

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-05-01 Epub Date: 2026-01-27 DOI: 10.1016/j.cellsig.2026.112393

Luoshai Wang , Rongrong Ge , Hang Li , Jiazhi Yang , Juan Yao , Zhongqiu Wang

Long non-coding RNAs (lncRNAs) have been implicated in the progression of esophageal cancer (ESCA). This study investigates the oncogenic role of LINC00942 in ESCA, revealing its upregulation in tumor tissues and cell lines. Functional assays demonstrated that suppression of LINC00942 significantly reduced cell viability and tumor growth while promoting apoptosis both in vitro and in vivo using a xenograft tumor model. Mechanistically, LINC00942 silencing decreased NAT10 expression in ESCA cells and tumors, with NAT10 overexpression rescuing the inhibition of ESCA cell proliferation, migration, and invasion induced by LINC00942 knockdown, alongside a reduction in apoptosis and tumor growth inhibition. Notably, LINC00942 directly interacted with NAT10, which were co-localized in the nucleus. Further analysis indicated that NAT10 overexpression enhanced the stability and expression of HSPD1 through increased N4-acetylcytidine (ac4C) modification, thereby exerting its effects by interacting with HSPD1. These findings highlight the pivotal role of the LINC00942/NAT10/HSPD1 axis in ESCA development, suggesting it as a potential biomarker and therapeutic target for the disease.

长链非编码rna （lncRNAs）与食管癌（ESCA）的进展有关。本研究探讨了LINC00942在ESCA中的致癌作用，揭示了其在肿瘤组织和细胞系中的上调。功能分析表明，在异种移植肿瘤模型中，抑制LINC00942可显著降低细胞活力和肿瘤生长，同时促进细胞凋亡。在机制上，LINC00942沉默降低了ESCA细胞和肿瘤中NAT10的表达，NAT10过表达恢复了LINC00942敲低诱导的ESCA细胞增殖、迁移和侵袭的抑制，同时减少了细胞凋亡和肿瘤生长抑制。值得注意的是，LINC00942直接与NAT10相互作用，它们在细胞核中共定位。进一步分析表明，NAT10过表达通过增加n4 -乙酰胞苷（ac4C）修饰增强HSPD1的稳定性和表达，从而通过与HSPD1相互作用发挥作用。这些发现强调了LINC00942/NAT10/HSPD1轴在ESCA发展中的关键作用，表明它是该疾病的潜在生物标志物和治疗靶点。

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引用次数: 0

Role of disulfidptosis in cancer: Molecular mechanisms and therapeutic opportunities 双曲下垂在癌症中的作用：分子机制和治疗机会。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-05-01 Epub Date: 2025-11-27 DOI: 10.1016/j.cellsig.2025.112277

Hang-Shen Han , Meng-Yuan Hao , Hong-Jie Li , Yan-Ge Li , Ti Chu , Yan-Wen Wang , Wei-Rong Si , Qi-Ying Jiang , Dong-Dong Wu

Disulfidptosis, as a novel form of programmed cell death, is different from ferroptosis and cuproptosis. Numerous studies have shown that glucose starvation is a key characteristic of disulfidptosis. Under the condition of high expression of solute carrier family 7 member 11, the content of nicotinamide adenine dinucleotide phosphate hydrogen changes, and cystine and other disulfides in cells accumulate, which leads to actin cytoskeleton collapse and subsequent cell death. This review summarizes recent discoveries of disulfidptosis, a novel form of cell death, from the scientific community in the context of cancer; it elaborates on its discovery background, molecular mechanisms, and regulatory networks, and explores the regulatory roles of its key genes and regulatory proteins. Additionally, this review discusses the prognostic value and application potential of disulfidptosis in the treatment of lung cancer, pancreatic cancer, gastric cancer, colorectal cancer, and other cancers, providing references for clinical cancer therapy.

二硫细胞下垂是一种不同于铁下垂和铜下垂的新型程序性细胞死亡形式。大量研究表明，葡萄糖饥饿是二翘症的一个关键特征。在溶质载体家族7成员11 （SLC7A11）高表达的情况下，细胞内烟酰胺腺嘌呤二核苷酸磷酸（NADPH）含量发生变化，胱氨酸等二硫化物积聚，导致肌动蛋白细胞骨架崩溃，进而导致细胞死亡。这篇综述总结了最近发现的二硫体下垂，一种新的细胞死亡形式，从科学界在癌症的背景下；阐述其发现背景、分子机制和调控网络，探讨其关键基因和调控蛋白的调控作用。此外，本文还讨论了二硫垂下术在肺癌（LC）、胰腺癌（PC）、胃癌（GC）、结直肠癌（CRC）等癌症治疗中的预后价值和应用潜力，为临床癌症治疗提供参考。

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引用次数: 0

Tumour endothelial cells in cancer: Chemo-physical crosstalk and angiogenic signalling in the tumour microenvironment 肿瘤内皮细胞：肿瘤微环境中的化学物理串扰和血管生成信号。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-05-01 Epub Date: 2026-01-23 DOI: 10.1016/j.cellsig.2026.112391

Arian Ansardamavandi , Mohammad Tafazzoli-Shadpour

The tumour microenvironment (TME) represents a complex, dynamic ecosystem comprising cellular and acellular elements that collectively facilitate tumour progression, invasion, and metastasis through intricate chemo-mechanical interactions. Cancer cells drive TME remodelling by recruiting and reprogramming stromal components, including cancer-associated fibroblasts (CAFs) that alter extracellular matrix (ECM) composition and stiffness, tumour-associated macrophages (TAMs) that promote immunosuppressive conditions, and tumour endothelial cells (TECs) that establish aberrant vascular networks. This review synthesises current literature on the pivotal role of TECs in tumour angiogenesis, emphasising their bidirectional crosstalk with cancer and stromal cells via chemical signals (e.g., growth factors under hypoxia) and mechanical cues (e.g., ECM stiffness and topography) that modulate cellular contractility, adhesion, and biochemical release. Key findings reveal how TECs integrate these multifaceted stimuli to orchestrate vascular remodelling, enhance permeability, and foster metastatic dissemination, often through dysregulated pathways distinct from normal endothelium. Ultimately, elucidating these mechanisms offers promising avenues for developing targeted therapies that selectively inhibit TEC-mediated angiogenesis while preserving physiological vascular function.

肿瘤微环境（TME）是一个复杂的、动态的生态系统，由细胞和非细胞元素组成，通过复杂的化学-机械相互作用共同促进肿瘤的进展、侵袭和转移。癌细胞通过招募和重编程基质成分来驱动TME重塑，包括改变细胞外基质（ECM）组成和硬度的癌症相关成纤维细胞（CAFs），促进免疫抑制条件的肿瘤相关巨噬细胞（tam），以及建立异常血管网络的肿瘤内皮细胞（tec）。这篇综述综合了目前关于tec在肿瘤血管生成中的关键作用的文献，强调了它们通过化学信号（如缺氧下的生长因子）和机械信号（如ECM刚度和地形）与癌症和基质细胞的双向交互，从而调节细胞收缩性、粘附性和生化释放。主要研究结果揭示了tec如何整合这些多方面的刺激来协调血管重塑，增强通透性，并促进转移性传播，通常通过不同于正常内皮的失调途径。最终，阐明这些机制为开发靶向治疗提供了有希望的途径，可以选择性地抑制tec介导的血管生成，同时保持生理血管功能。

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引用次数: 0

AKR1C3 promotes aerobic glycolysis in hepatic stellate cells via the AKT/mTOR pathway to induce liver fibrosis AKR1C3通过AKT/mTOR通路促进肝星状细胞有氧糖酵解，诱导肝纤维化。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-05-01 Epub Date: 2026-01-17 DOI: 10.1016/j.cellsig.2026.112369

Tao Ran , Qing-xiu Zhang , Hua-yue Wu , Shu Feng , Lu Han , Yuan Qin , Guo-yuan Lin , Ya Zhang , Shi-liang Li , Ji-yu Chen , Yu-mei Zhou , Shi-qian Cai , Xue-ke Zhao

Liver fibrosis (LF) represents a common wound-healing response to various forms of liver injury. Activation of hepatic stellate cells (HSCs) is a central event in this process. Aerobic glycolysis plays a critical role in the sustained activation of HSCs. Human aldo-keto reductase family 1 member C3 (AKR1C3), a multifunctional enzyme, is upregulated in many diseases and has been identified as a drug target in cancer treatment. However, the underlying mechanism through which AKR1C3 is involved in LF remains unclear. This study indicated the elevated expression of AKR1C3 in the fibrotic tissues of both humans and rats. AKR1C3 overexpression stimulated the proliferation, migration, and activation of HSCs in vitro. These effects were reversed by inhibiting AKR1C3. Based on RNA-seq analysis, we investigated the underlying mechanism of AKR1C3 and found that glycolysis and the AKT/mTOR pathway may contribute to the effect of AKR1C3 on LF. Mechanistically, AKR1C3 may act as a molecular scaffold to mediate the binding of mTORC2 to AKT, thereby promoting the phosphorylation of AKT at Ser473 and activating the signaling pathway. In addition, AKR1C3 overexpression promoted aerobic glycolysis in HSCs by activating the AKT/mTOR pathway, but these effects were partly reversed by glycolysis inhibitors (2-DG) and AKT inhibitors (MK-2206). Our findings revealed the mechanism by which AKR1C3 promotes LF, suggesting that AKR1C3 may serve as a potential therapeutic target for LF, warranting further studies.

肝纤维化（LF）代表了对各种形式肝损伤的一种常见的伤口愈合反应。肝星状细胞（hsc）的激活是这一过程的中心事件。有氧糖酵解在造血干细胞的持续激活中起着关键作用。人类醛酮还原酶家族1成员C3 （AKR1C3）是一种多功能酶，在许多疾病中上调，已被确定为癌症治疗的药物靶点。然而，AKR1C3参与LF的潜在机制尚不清楚。本研究表明，AKR1C3在人和大鼠的纤维化组织中表达升高。AKR1C3过表达可刺激体外造血干细胞的增殖、迁移和活化。这些作用通过抑制AKR1C3而被逆转。基于RNA-seq分析，我们研究了AKR1C3的潜在机制，发现糖酵解和AKT/mTOR通路可能参与了AKR1C3对LF的作用。在机制上，AKR1C3可能作为分子支架介导mTORC2与AKT的结合，从而促进AKT Ser473位点的磷酸化，激活信号通路。此外，AKR1C3过表达通过激活AKT/mTOR通路促进造血干细胞的有氧糖酵解，但这些作用被糖酵解抑制剂（2-DG）和AKT抑制剂（MK-2206）部分逆转。我们的研究结果揭示了AKR1C3促进LF的机制，提示AKR1C3可能作为LF的潜在治疗靶点，值得进一步研究。

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引用次数: 0