Cellular signalling最新文献

英文中文

Cross-talk between neuroinflammation and α-synuclein aggregation: The central role of the cGAS-STING pathway in Parkinson's disease 神经炎症与α-突触核蛋白聚集之间的相互作用：cGAS-STING通路在帕金森病中的核心作用

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-23 DOI: 10.1016/j.cellsig.2026.112390

Rong Fu , Lei Shi

Parkinson's Disease (PD) is a common neurodegenerative disorder with a complex and incompletely elucidated pathogenesis. Dysregulated immunity plays a pivotal role in the initiation and progression of the disease. The cyclic guanosine monophosphate (GMP)- adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway, an intracellular innate immune signaling cascade that has attracted considerable attention in recent years, exerts crucial functions in sensing pathogen invasion and endogenous damage-associated molecular patterns (DAMPs), as well as regulating immune responses. This review thoroughly explores the role of the cGAS-STING pathway in PD immune regulation. It first details the pathway's structural components and activation mechanism, then analyzes its aberrant activation under PD pathological conditions. Furthermore, it discusses in detail the specific mechanisms underlying its role in PD immune regulation, including its impacts on microglial activation, inflammatory cytokine release, α-synuclein (α-syn) aggregation and clearance, as well as neuronal survival. Meanwhile, it summarizes the current research progress in targeting the cGAS-STING pathway for PD treatment. Finally, it points out the existing challenges and future research directions in this field, aiming to provide novel insights and theoretical foundations for investigating PD pathogenesis and developing clinical therapeutic strategies.

帕金森病（PD）是一种常见的神经退行性疾病，其发病机制复杂且尚未完全阐明。失调的免疫在疾病的发生和发展中起着关键作用。环鸟苷单磷酸(GMP)-腺苷单磷酸（AMP）合成酶(cGAS)-干扰素基因刺激因子（STING）通路是近年来备受关注的细胞内先天免疫信号级联，在感知病原体入侵和内源性损伤相关分子模式（DAMPs）以及调节免疫应答中发挥重要作用。本文综述了cGAS-STING通路在PD免疫调节中的作用。首先详细介绍了该通路的结构组成和激活机制，然后分析了其在PD病理条件下的异常激活。此外，详细讨论了其在PD免疫调节中的具体机制，包括其对小胶质细胞激活、炎症细胞因子释放、α-突触核蛋白（α-syn）聚集和清除以及神经元存活的影响。同时总结了目前针对cGAS-STING通路治疗PD的研究进展。最后指出了该领域存在的挑战和未来的研究方向，旨在为研究PD的发病机制和制定临床治疗策略提供新的见解和理论基础。

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引用次数: 0

Mechanisms and therapeutic potential of migrasomes in neurological disorders 偏头痛在神经系统疾病中的作用机制和治疗潜力。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-23 DOI: 10.1016/j.cellsig.2026.112389

Simeng Zhang, Yanhua Yang, Tiancheng Zhang, Ye Pan, Qinggang Xu, Peng Lü

Migrasomes, a recently identified class of organelles, form at the tips or intersections of retraction fibers during cell migration. These structures carry various bioactive cargoes, including proteins, mRNAs, and cytokines, and play significant roles in intercellular communication, immune regulation, and tissue homeostasis. As specialized membrane structures generated during cell migration, migrasomes are not only involved in physiological processes such as embryonic development and vascular homeostasis but are also critically implicated in the pathogenesis of neurological disorders. In this review, we outline the fundamental biological characteristics and functions of migrasomes, provide an in-depth analysis of their pathological mechanisms in neurological diseases, and evaluate their clinical potential as novel diagnostic biomarkers, drug delivery vehicles, and therapeutic targets. Overall, this review offers new perspectives for precision diagnostics and therapeutics of neurological diseases and lays a foundation for diagnosing and treating migrasome-related pathologies.

迁移体是最近发现的一类细胞器，在细胞迁移过程中在收缩纤维的尖端或交叉处形成。这些结构携带多种生物活性物质，包括蛋白质、mrna和细胞因子，在细胞间通讯、免疫调节和组织稳态中发挥重要作用。作为细胞迁移过程中产生的特殊膜结构，迁移体不仅参与胚胎发育和血管稳态等生理过程，而且还与神经系统疾病的发病机制有重要关系。在这篇综述中，我们概述了偏头痛的基本生物学特性和功能，深入分析了它们在神经系统疾病中的病理机制，并评估了它们作为新的诊断生物标志物、药物传递载体和治疗靶点的临床潜力。本文综述为神经系统疾病的精确诊断和治疗提供了新的视角，为偏头痛相关病理的诊断和治疗奠定了基础。

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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 : 2026-01-23 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

Corrigendum to "Puerarin protects against renal ischemia-reperfusion injury by restoring mitochondrial function and modulating the PI3K/AKT/NF-κB pathway and suppressing inflammatory responses" [Cellular Signalling 139 (2026) 112350]. “葛根素通过恢复线粒体功能、调节PI3K/AKT/NF-κB通路和抑制炎症反应来保护肾缺血再灌注损伤”的更正[Cellular signaling] 139(2026) 112350。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-21 DOI: 10.1016/j.cellsig.2026.112383

Kangyu Wang, Changhong Xu, Hao Wang, Yalong Zhang, Zijian Zhang, Rui Yan, Li Wang, Jianwei Yang, Jiangwei Man, Li Yang

引用次数: 0

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 : 2026-01-21 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

Corrigendum to "Hsp70/CHIP E3 ligase complex triggers K149-linked ubiquitination and degradation of BEST1 mutants p.P233L and p.P346H, impairing chloride channel function and retinal integrity" [Cellular Signalling 139 (2026) 112343]. “Hsp70/CHIP E3连接酶复合物触发k149连接的泛素化和降解BEST1突变体p.P233L和p.P346H，损害氯通道功能和视网膜完整性”[Cellular signaling 139(2026) 112343]。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-21 DOI: 10.1016/j.cellsig.2026.112370

Zhongxue Zhou, Hongxia Tian, Ning Ma, Wen Fang, Qingxia Lu, Huiyang, HaiyingTian, Yu Tang, Ling Tian, Xu Jia, Yuanju Zhang, Yuqian Li, Xiaoyan Zhu, Qiao Yu, Ding'an Zhou

引用次数: 0

NR4A1 attenuates neuroinflammation after spinal cord injury by modulating microglial polarization via negatively regulating the VAV1 pathway NR4A1通过负调控VAV1通路，调节小胶质细胞极化，减轻脊髓损伤后的神经炎症。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-20 DOI: 10.1016/j.cellsig.2026.112385

Ning Qu , WenJie You , LingLi Gong , KaiYun Wang , Qi Shu , LuoLong Tao , YanLong Zhong , QiHua Qi , Wei Zuo

Spinal cord injury (SCI) is a global health issue which can lead to severe neurological impairment. NR4A1 is rapidly induced in response to diverse stimuli and shows multiple important functions in the central nervous system (CNS). However, its functional contribution to spinal cord injury remains undefined.

In this study, NR4A1 expression was significantly down-regulated in microglia of a mouse contusion SCI model, accompanied by increased expression of VAV1 and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Treating with cytosporone B (CsnB) can decrease VAV1 expression, reduced inflammatory response, reduced injury area, and improved locomotor function of SCI mice. Further analysis indicated that Csn-B promoted microglial polarization from M1 to M2 phenotype, with decrease of TNF-α, IL-1β and IL-6expression. Conversely, administration of DIM-C-pPhOH (C-DIM8) produced completely opposite results. In vitro, an inflammatory model that mimics SCI in vivo was established by stimulating BV2 microglial cells with LPS (200 ng/ml, 24 h). Further mechanistic investigation revealed that NR4A1 over-expression active BV2 cells from M1 to M2 phenotype and suppressed TNF-α, IL-1β and IL-6 release. NR4A1 knockdown, in contrast, promoted BV2 from M2 to M1 phenotype and enhanced TNF-α, IL-1β and IL-6 release. Further studies identified that NR4A1 functions as a direct transcriptional repressor of VAV1. Knockdown/over-express VAV1 could reverse the effects of NR4A1 knockdown/over-express on LPS-stimulated BV2 cells, respectively.

Collectively, this study demonstrates that NR4A1 alleviates SCI-induced neuroinflammation by modulating microglial polarization via negatively regulating the VAV1 signaling pathway. Targeting the NR4A1-VAV1 axis may be a promising therapeutic target for mitigating SCI progression.

脊髓损伤（SCI）是一个全球性的健康问题，可导致严重的神经损伤。NR4A1在中枢神经系统（CNS）中受到多种刺激的快速诱导，并显示出多种重要功能。然而，其对脊髓损伤的功能贡献仍不明确。在本研究中，NR4A1在小鼠挫伤脊髓损伤模型的小胶质细胞中表达显著下调，并伴有VAV1和促炎细胞因子（TNF-α、IL-1β、IL-6）表达升高。细胞孢素B （CsnB）可降低脊髓损伤小鼠VAV1表达，减轻炎症反应，缩小损伤面积，改善运动功能。进一步分析表明，Csn-B促进小胶质细胞从M1表型向M2表型极化，降低TNF-α、IL-1β和il -6的表达。相反，给药DIM-C-pPhOH （C-DIM8）产生完全相反的结果。体外，通过LPS（200 ng/ml, 24 h）刺激BV2小胶质细胞，建立体内模拟SCI的炎症模型。进一步的机制研究发现NR4A1过表达激活了M1到M2表型的BV2细胞，抑制了TNF-α、IL-1β和IL-6的释放。相反，NR4A1敲低可促进BV2从M2表型向M1表型转变，并增强TNF-α、IL-1β和IL-6的释放。进一步的研究发现NR4A1是VAV1的直接转录抑制因子。敲低/过表达VAV1分别可以逆转NR4A1敲低/过表达对lps刺激的BV2细胞的影响。综上所述，本研究表明NR4A1通过负向调节VAV1信号通路，调节小胶质细胞极化，从而减轻sci诱导的神经炎症。靶向NR4A1-VAV1轴可能是缓解脊髓损伤进展的一个有希望的治疗靶点。

{"title":"NR4A1 attenuates neuroinflammation after spinal cord injury by modulating microglial polarization via negatively regulating the VAV1 pathway","authors":"Ning Qu , WenJie You , LingLi Gong , KaiYun Wang , Qi Shu , LuoLong Tao , YanLong Zhong , QiHua Qi , Wei Zuo","doi":"10.1016/j.cellsig.2026.112385","DOIUrl":"10.1016/j.cellsig.2026.112385","url":null,"abstract":"<div><div>Spinal cord injury (SCI) is a global health issue which can lead to severe neurological impairment. NR4A1 is rapidly induced in response to diverse stimuli and shows multiple important functions in the central nervous system (CNS). However, its functional contribution to spinal cord injury remains undefined.</div><div>In this study, NR4A1 expression was significantly down-regulated in microglia of a mouse contusion SCI model, accompanied by increased expression of VAV1 and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6). Treating with cytosporone B (Csn<img>B) can decrease VAV1 expression, reduced inflammatory response, reduced injury area, and improved locomotor function of SCI mice. Further analysis indicated that Csn-B promoted microglial polarization from M1 to M2 phenotype, with decrease of TNF-α, IL-1β and IL-6expression. Conversely, administration of DIM-C-pPhOH (C-DIM8) produced completely opposite results. In vitro, an inflammatory model that mimics SCI in vivo was established by stimulating BV2 microglial cells with LPS (200 ng/ml, 24 h). Further mechanistic investigation revealed that NR4A1 over-expression active BV2 cells from M1 to M2 phenotype and suppressed TNF-α, IL-1β and IL-6 release. NR4A1 knockdown, in contrast, promoted BV2 from M2 to M1 phenotype and enhanced TNF-α, IL-1β and IL-6 release. Further studies identified that NR4A1 functions as a direct transcriptional repressor of VAV1. Knockdown/over-express VAV1 could reverse the effects of NR4A1 knockdown/over-express on LPS-stimulated BV2 cells, respectively.</div><div>Collectively, this study demonstrates that NR4A1 alleviates SCI-induced neuroinflammation by modulating microglial polarization via negatively regulating the VAV1 signaling pathway. Targeting the NR4A1-VAV1 axis may be a promising therapeutic target for mitigating SCI progression.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"141 ","pages":"Article 112385"},"PeriodicalIF":3.7,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","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 the hedgehog signaling pathway in the regulation of gastrointestinal cancer cell death hedgehog信号通路在胃肠道癌细胞死亡调控中的作用。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-19 DOI: 10.1016/j.cellsig.2026.112384

Wenyu Zang , Wenshuai Zhu , Fubo Jing , He Qi , Xiaoli Ma , Yunshan Wang , Yanfei Jia

The Hh signaling pathway critically drives tumorigenesis and progression in multiple cancers, including gastrointestinal cancers such as gastric, hepatic, pancreatic, esophageal, and colorectal cancer. Aberrant Hh signaling pathway activation, often driven by ligands such as Sonic Hedgehog (Shh) and transcription factors such as Gli1/2, promotes tumor cell proliferation, survival, metastasis, cancer stem cells, and chemoresistance while inhibiting programmed cell death pathways. High levels of Hh signaling pathway activity are a characteristic feature of gastrointestinal cancers. Therapeutic targeting of the Hh signaling pathway has shown promise, with Smoothened (Smo) inhibitors approved for basal cell carcinoma but yielding mixed results in gastrointestinal cancer trials. Emerging strategies, including Hh inhibitors; natural compounds from traditional Chinese medicine; and combinations of chemotherapy, immunotherapy or radiation to induce cell death and remodel the tumor microenvironment, could lead to a new therapeutic avenue for gastrointestinal cancers. In this review, we summarize advances in our understanding of Hh-mediated cell death in gastrointestinal cancers and the role and mechanisms, and highlight the underlying therapeutic opportunities. These new findings advance the rapidly expanding field of translational cancer research focused on the Hh signaling pathway.

Hh信号通路在多种癌症（包括胃肠道癌症，如胃癌、肝癌、胰腺癌、食管癌和结直肠癌）的肿瘤发生和进展中起关键作用。异常的Hh信号通路激活，通常由配体如Sonic Hedgehog （Shh）和转录因子如Gli1/2驱动，促进肿瘤细胞增殖、存活、转移、癌症干细胞和化疗耐药，同时抑制程序性细胞死亡途径。高水平的Hh信号通路活性是胃肠道癌症的一个特征。Hh信号通路的靶向治疗已显示出希望，Smoothened （Smo）抑制剂已被批准用于基底细胞癌，但在胃肠道癌症试验中的结果好坏参半。新兴策略，包括Hh抑制剂；来自中药的天然化合物；结合化疗、免疫治疗或放疗来诱导细胞死亡和重塑肿瘤微环境，可能会为胃肠道癌症带来新的治疗途径。在这篇综述中，我们总结了我们对hh介导的细胞死亡在胃肠道癌症中的作用和机制的理解的进展，并强调了潜在的治疗机会。这些新发现推动了以Hh信号通路为重点的快速扩展的转译性癌症研究领域。

{"title":"The role of the hedgehog signaling pathway in the regulation of gastrointestinal cancer cell death","authors":"Wenyu Zang , Wenshuai Zhu , Fubo Jing , He Qi , Xiaoli Ma , Yunshan Wang , Yanfei Jia","doi":"10.1016/j.cellsig.2026.112384","DOIUrl":"10.1016/j.cellsig.2026.112384","url":null,"abstract":"<div><div>The Hh signaling pathway critically drives tumorigenesis and progression in multiple cancers, including gastrointestinal cancers such as gastric, hepatic, pancreatic, esophageal, and colorectal cancer. Aberrant Hh signaling pathway activation, often driven by ligands such as Sonic Hedgehog (Shh) and transcription factors such as Gli1/2, promotes tumor cell proliferation, survival, metastasis, cancer stem cells, and chemoresistance while inhibiting programmed cell death pathways. High levels of Hh signaling pathway activity are a characteristic feature of gastrointestinal cancers. Therapeutic targeting of the Hh signaling pathway has shown promise, with Smoothened (Smo) inhibitors approved for basal cell carcinoma but yielding mixed results in gastrointestinal cancer trials. Emerging strategies, including Hh inhibitors; natural compounds from traditional Chinese medicine; and combinations of chemotherapy, immunotherapy or radiation to induce cell death and remodel the tumor microenvironment, could lead to a new therapeutic avenue for gastrointestinal cancers. In this review, we summarize advances in our understanding of Hh-mediated cell death in gastrointestinal cancers and the role and mechanisms, and highlight the underlying therapeutic opportunities. These new findings advance the rapidly expanding field of translational cancer research focused on the Hh signaling pathway.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"141 ","pages":"Article 112384"},"PeriodicalIF":3.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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 : 2026-01-17 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。

{"title":"AKR1C3 promotes aerobic glycolysis in hepatic stellate cells via the AKT/mTOR pathway to induce liver fibrosis","authors":"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","doi":"10.1016/j.cellsig.2026.112369","DOIUrl":"10.1016/j.cellsig.2026.112369","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"141 ","pages":"Article 112369"},"PeriodicalIF":3.7,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cellular signaling and radioresistance in prostate cancer 前列腺癌的细胞信号传导和放射耐药。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-16 DOI: 10.1016/j.cellsig.2026.112367

Gustavo A. Sosa, Betsy Crosswhite, Austin N. Kirschner

引用次数: 0

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