Cellular signalling最新文献_第8页

Localization, trafficking, and signaling of trace amine-associated receptor 2 in mouse neuroblastoma cells 小鼠神经母细胞瘤细胞中微量胺相关受体2的定位、运输和信号传导。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-11-30 DOI: 10.1016/j.cellsig.2025.112289

Jonathan C. Mayer , Wanxin Li , Anna I. Neel , Phillip J. McPherson , Saanvi Deb , Haiguo Sun , Glen S. Marrs , Rong Chen

Trace amine-associated receptors (TAARs) are a family of G protein-coupled receptors increasingly recognized for their role in modulating neurotransmission. Among the TAAR isoforms, TAAR2 remains poorly understood despite growing appreciation of its involvement in neurological disorders. In this study, we characterized the subcellular localization and agonist-induced trafficking dynamics of TAAR2 in mouse Neuro-2a cells stably expressing N-terminal His-tagged TAAR2. Under basal conditions, immunocytochemical analysis revealed that TAAR2 was predominantly localized intracellularly. Upon stimulation with β-phenethylamine (β-PEA), a pan-TAAR agonist, TAAR2 underwent rapid and dynamic redistribution across subcellular compartments. Specifically, within 5 min, TAAR2 exited the endoplasmic reticulum (ER) and accumulated in the Golgi. By 10–20 min, its localization in the ER and Golgi returned to baseline, while TAAR2 slowly translocated to the plasma membrane, reaching peak surface expression at 20 min. Functional assays demonstrated that TAAR2 coupled to Gαi/o proteins, but not Gαs proteins, as evidenced by β-PEA-induced inhibition of forskolin-stimulated cAMP production. Notably, this inhibition became significant at 20 min of agonist treatment, coinciding with peak plasma membrane localization of TAAR2 following agonist treatment. Together, these findings establish a clear temporal link between TAAR2 trafficking and signaling, suggesting that subcellular localization is tightly coupled to receptor function. This study provides the first characterization of TAAR2's trafficking and signaling in a neuronal-like context, laying the groundwork for future investigations into its role in neurological disorders.

微量胺相关受体（TAARs）是G蛋白偶联受体的一个家族，因其在调节神经传递中的作用而日益得到认可。在TAAR亚型中，尽管越来越多的人认识到TAAR2与神经系统疾病的关系，但对TAAR2的了解仍然很少。在本研究中，我们在稳定表达n端his标记的TAAR2的小鼠神经-2a细胞中表征了TAAR2的亚细胞定位和激动剂诱导的转运动力学。在基础条件下，免疫细胞化学分析显示TAAR2主要定位于细胞内。在泛taar激动剂β-苯乙胺（β-PEA）的刺激下，TAAR2在亚细胞间进行了快速和动态的重新分配。具体来说，在5 min内，TAAR2退出内质网（ER）并在高尔基体中积累。在10-20 min时，其在内质网和高尔基体中的定位恢复到基线水平，而TAAR2缓慢转移到质膜，在20 min时达到表面表达峰值。功能分析表明，TAAR2与Gαi/o蛋白偶联，而与Gαs蛋白偶联，β- pea诱导的forskolin刺激的cAMP产生抑制证明了这一点。值得注意的是，这种抑制作用在激动剂治疗20 min时变得显著，与激动剂治疗后TAAR2质膜定位的峰值一致。总之，这些发现在TAAR2运输和信号传导之间建立了明确的时间联系，表明亚细胞定位与受体功能紧密耦合。这项研究首次描述了TAAR2在神经元样环境中的运输和信号传导，为未来研究其在神经系统疾病中的作用奠定了基础。

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引用次数: 0

TET1 regulates self-renewal of porcine skin-derived stem cells through TGF-β signaling pathway TET1通过TGF-β信号通路调控猪皮肤源性干细胞自我更新。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-11-30 DOI: 10.1016/j.cellsig.2025.112292

Chun-Xiao Li , Ping Wang , Ying Zhang , Gui-Li Ruan , Zhan-Zhong Qiao , Tian Qiao , Qian-Ru Han , Chang Xu , Yong-Chao Liu , Wei Ge , Wei Shen , Shun-Feng Cheng

Skin-derived stem cells (SDSCs) are a subtype of adult stem cells (ASCs). How to improve the self-renewal ability of stem cells has been a focus of recent research. However, the underlying self-renewal mechanism of SDSCs remains to be fully understood. Here, this study investigates the mechanism by which TET1 functions in the self-renewal of porcine SDSCs (pSDSCs). The results showed that the self-renewal capacity of pSDSCs gradually enhanced and the expression level of TET1 significantly increased during in vitro culture. Additionally, the self-renewal capacity of pSDSCs was inhibited after silencing TET1 by small interfering RNA (siRNA). RNA-seq analysis revealed that TET1 knockdown significantly inhibited the transforming growth factor-β (TGF-β) signaling pathway. Detailed analysis of key molecules in the TGF-β signaling pathway indicated that TET1 knockdown reduced the protein levels of TGF-β1, phosphorylated SMAD2 (p-SMAD2), and phosphorylated SMAD3 (p-SMAD3). SRI-011381, activated the TGF-β/SMAD pathway, saving the self-renewal defect caused by TET1 knockdown. Treating pSDSCs with LY2109761, a TGF-β signaling inhibitor, produced a phenotype similar to TET1 knockdown. This work identified that TET1 was a critical regulatory factor that plays a key role in maintaining pSDSCs self-renewal through the TGF-β signaling pathway. Unlike previous studies that primarily emphasized the epigenetic role of TET1, this study reveals its functional link to a signaling pathway. These findings provide a deeper understanding of SDSCs and suggest that targeting the TET1–TGF-β axis may represent a promising approach to enhance the self-renewal capacity of SDSCs.

皮肤源性干细胞（SDSCs）是成体干细胞（ASCs）的一个亚型。如何提高干细胞的自我更新能力一直是近年来研究的热点。然而，SDSCs潜在的自我更新机制尚不完全清楚。本研究探讨了TET1在猪SDSCs （pSDSCs）自我更新中的作用机制。结果表明，在体外培养过程中，pSDSCs的自我更新能力逐渐增强，TET1的表达水平显著升高。此外，通过小干扰RNA （sirna）沉默TET1后，pSDSCs的自我更新能力受到抑制。RNA-seq分析显示，TET1敲低可显著抑制转化生长因子-β (TGF-β)信号通路。对TGF-β信号通路关键分子的详细分析表明，TET1敲低可降低TGF-β1蛋白水平，磷酸化SMAD2 (p-SMAD2)，磷酸化SMAD3 （p-SMAD3）。SRI-011381激活了TGF-β/SMAD通路，挽救了TET1敲低导致的自我更新缺陷。用TGF-β信号抑制剂LY2109761处理pSDSCs，产生类似TET1敲低的表型。本研究发现TET1是一个关键的调节因子，通过TGF-β信号通路在维持pSDSCs自我更新中起关键作用。与以往的研究主要强调TET1的表观遗传作用不同，本研究揭示了其与信号通路的功能联系。这些发现提供了对SDSCs更深入的了解，并表明靶向TET1-TGF-β轴可能是增强SDSCs自我更新能力的一种有希望的方法。

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引用次数: 0

Chromatin remodeling factor CHRAC1 regulates doxorubicin-induced cardiotoxicity via IRF9/GSDMD/CASP-1 染色质重塑因子CHRAC1通过IRF9/GSDMD/CASP-1调控阿霉素诱导的心脏毒性。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-11-29 DOI: 10.1016/j.cellsig.2025.112290

Tongtong Zang , Changyi Zhou , Yue Yu , Wenhui Lin , Qiang Xu , Li Shen

Doxorubicin-induced cardiotoxicity (DIC) is a severe complication of cancer therapy, yet the contribution of epigenetic regulators remains largely unknown. In this study, we identify the chromatin remodeler CHRAC1 as a novel determinant of DIC. Using murine and cellular models, we observed that CHRAC1 knockdown significantly preserved cardiac function, improved cell viability, and reduced reactive oxygen species accumulation and cardiomyocyte death. In contrast, CHRAC1 overexpression aggravated cardiac injury and enhanced cell death. Integrated RNA-seq and ATAC-seq analyses revealed that CHRAC1 transcriptionally activates the NOD-like receptor signaling pathway, with IRF9 identified as a critical downstream mediator. Silencing IRF9 reversed CHRAC1-driven pathological phenotypes, thereby establishing a functional connection between CHRAC1 and the IRF9/GSDMD/CASP-1 axis. These findings demonstrate that CHRAC1 promotes caspase-1–dependent pyroptosis through transcriptional regulation of IRF9, highlighting a previously unrecognized epigenetic–immune signaling network. Collectively, our work uncovers the CHRAC1–IRF9–pyroptosis axis as a promising therapeutic target for preventing and treating anthracycline cardiotoxicity.

阿霉素诱导的心脏毒性（DIC）是癌症治疗的严重并发症，但表观遗传调节因子的作用在很大程度上仍然未知。在这项研究中，我们发现染色质重塑因子CHRAC1是DIC的一个新的决定因素。通过小鼠和细胞模型，我们观察到CHRAC1敲低可显著保护心功能，提高细胞活力，减少活性氧积累和心肌细胞死亡。相反，CHRAC1过表达加重心脏损伤，增强细胞死亡。综合RNA-seq和ATAC-seq分析显示，CHRAC1转录激活nod样受体信号通路，IRF9被鉴定为一个关键的下游介质。沉默IRF9逆转了CHRAC1驱动的病理表型，从而建立了CHRAC1与IRF9/GSDMD/CASP-1轴之间的功能联系。这些发现表明CHRAC1通过IRF9的转录调控促进caspase-1依赖性焦亡，突出了一个以前未被认识的表观遗传免疫信号网络。总之，我们的工作揭示了chrac1 - irf9焦亡轴作为预防和治疗蒽环类药物心脏毒性的有希望的治疗靶点。

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引用次数: 0

MarvelD3 regulates the radiosensitivity of Esophageal squamous cell carcinoma via the MYB/IFI6 axis MarvelD3通过MYB/IFI6轴调节食管鳞状细胞癌的放射敏感性。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-11-28 DOI: 10.1016/j.cellsig.2025.112282

Xi Wang , Jinming Cao , Kaixiao Zhou , Yangyang Ge , Wei Zhu , Qi Zhang , Yang Jiao , Jianping Cao

Tight junction proteins have been implicated in the progression of various diseases. MarvelD3, a member of the MARVEL domain protein family involved in tight junction formation, exhibits diverse expression patterns and functions across different tissues. However, its specific role in esophageal squamous cell carcinoma (ESCC) remains to be elucidated. This study demonstrated that MarvelD3 is significantly overexpressed in ESCC tissues. Furthermore, the knockdown of MarvelD3 enhances the radiosensitivity of ESCC in both in vitro and in vivo models. RNA-sequencing analysis identified Interferon alpha inducible protein 6 (IFI6) as a target of MarvelD3. Co-immunoprecipitation assays revealed an interactive regulatory relationship between MarvelD3 and MYB. Additionally, dual-luciferase reporter gene assays and chromatin immunoprecipitation assays confirmed that MYB directly binds to the promoter of the IFI6 gene, thereby regulating IFI6 transcription. Collectively, these findings suggest that MarvelD3 plays a critical role in modulating the radiosensitivity of ESCC via the MYB/IFI6 axis, uncovering a promising mechanism underlying the pathogenesis and progression of ESCC.

紧密连接蛋白与各种疾病的进展有关。MarvelD3是MARVEL结构域蛋白家族的一员，参与紧密连接的形成，在不同组织中表现出不同的表达模式和功能。然而，其在食管鳞状细胞癌（ESCC）中的具体作用仍有待阐明。本研究表明，MarvelD3在ESCC组织中显著过表达。此外，在体外和体内模型中，敲低MarvelD3可增强ESCC的放射敏感性。rna测序分析发现干扰素α诱导蛋白6 （IFI6）是MarvelD3的靶点。共免疫沉淀试验显示了MarvelD3和MYB之间的相互调节关系。此外，双荧光素酶报告基因试验和染色质免疫沉淀试验证实MYB直接结合IFI6基因的启动子，从而调节IFI6的转录。总之，这些发现表明，MarvelD3在通过MYB/IFI6轴调节ESCC的放射敏感性中起关键作用，揭示了ESCC发病和进展的潜在机制。

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引用次数: 0

Deficiency of NR2C2 accelerates senescence of testicular Leydig cells and infertility in male mice NR2C2缺乏加速雄性小鼠睾丸间质细胞衰老和不育。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-11-28 DOI: 10.1016/j.cellsig.2025.112284

Dalian Gong , Zhihui Liu , Rongda Kang , Xiaowen Liu , Ziqian Min , Huan Xin , Yanan Liu , Yuanyuan Chen , Min Liu , Ying Liang , Anji Chen , Lifang Yang , Zenghui Mao , Dan Li

The Leydig cell is one of the components that make up the testicular microenvironment, playing a crucial role in male reproductive function by secreting androgens and cytokines. The present study found that knocking down NR2C2, a member of the 2C group of the nuclear receptor family, can lead to senescent phenotype in mouse primary Leydig cells, with increased cell apoptosis and DNA damage, enhanced SA-β-Gal activity, and decreased glutathione levels. The fertility of Nr2c2 heterozygous knockout mice (Nr2c2^+/−) is impaired. The testosterone levels of Nr2c2^+/− mice at 12 months of age were lower than those of wild-type littermates of the same age, accompanied by increased expression of P21 protein in testicular tissue. Mechanistically, NR2C2 promotes transcription of target genes such as Akt2 and Qsox2 by binding to DR elements on their promoters. In addition, NR2C2 participates in regulating alternative splicing of target mRNAs (Rnf111, Cdkn2c, Igf1r and Fnip2) at the post transcriptional level by interacting with hnRNPH1 or other splicing factors. Our study for the first time reveals that NR2C2 is a core regulatory factor in resisting aging in testicular Leydig cells. It provides a novel potential target for male infertility and reproductive aging-related disorders.

间质细胞是睾丸微环境的组成部分之一，通过分泌雄激素和细胞因子在男性生殖功能中起着至关重要的作用。本研究发现，敲低核受体家族2C组成员NR2C2可导致小鼠原代间质细胞出现衰老表型，细胞凋亡和DNA损伤增加，SA-β-Gal活性增强，谷胱甘肽水平降低。Nr2c2杂合敲除小鼠（Nr2c2+/-）的生育能力受损。12 月龄时Nr2c2+/-小鼠睾丸激素水平低于同龄野生型鼠，睾丸组织中P21蛋白表达增加。从机制上讲，NR2C2通过结合靶基因（如Akt2和Qsox2）启动子上的DR元件来促进靶基因的转录。此外，NR2C2通过与hnRNPH1或其他剪接因子相互作用，在转录后水平参与调控靶mrna （Rnf111、Cdkn2c、Igf1r和Fnip2）的选择性剪接。我们的研究首次揭示了NR2C2是睾丸间质细胞抗衰老的核心调控因子。它为男性不育和生殖衰老相关疾病提供了新的潜在靶点。

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引用次数: 0

Progress in targeted ferroptosis regulation and mechanism of action in hepatocellular carcinoma 肝细胞癌铁下垂靶向调控及作用机制研究进展

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-11-27 DOI: 10.1016/j.cellsig.2025.112283

Ying Liu , Jing Fu , Lei Shi , Chong Chen , Tianhao Bao

Iron dependent programmed cell death is a newly discovered form of cell death that relies on iron ions and is accompanied by excessive accumulation of reactive oxygen species (ROS), which in turn mediates lipid peroxidation reactions, ultimately leading to loss of cell membrane integrity and cell death. This process is tightly regulated by various classical signaling pathways and biological processes. Ferroptosis, plays a crucial role in the occurrence and development of HCC, especially Hepatocellular carcinoma (HCC). Due to their high ROS basal levels, unique metabolic reprogramming, and special demand for iron, HCC cells are more sensitive to ferroptosis. Recent studies have shown that inducing ferroptosis not only inhibits the proliferation of HCC cells and hinders tumor progression, but also reshapes the tumor immune microenvironment, enhances anti-tumor immune response, and synergistically improves the efficacy of immunotherapy. Therefore, targeting ferroptosis has become an emerging and important strategy in the field of HCC treatment. This article systematically reviews the molecular mechanisms, regulatory networks, and functional characteristics of ferroptosis in HCC, and looks forward to its future therapeutic application prospects, in order to provide theoretical basis for the development of new HCC treatment methods.

铁依赖性程序性细胞死亡是一种新发现的细胞死亡形式，它依赖于铁离子，伴随着活性氧（ROS）的过度积累，进而介导脂质过氧化反应，最终导致细胞膜完整性丧失和细胞死亡。这一过程受到多种经典信号通路和生物过程的严格调控。铁下垂在HCC，尤其是肝细胞癌（HCC）的发生发展中起着至关重要的作用。由于其较高的ROS基础水平、独特的代谢重编程和对铁的特殊需求，HCC细胞对铁凋亡更敏感。近期研究表明，诱导铁下垂不仅可以抑制HCC细胞的增殖，阻碍肿瘤进展，还可以重塑肿瘤免疫微环境，增强抗肿瘤免疫反应，协同提高免疫治疗的疗效。因此，靶向铁下垂已成为HCC治疗领域新兴的重要策略。本文系统综述了铁下垂在HCC中的分子机制、调控网络及功能特点，并展望了其未来的治疗应用前景，以期为肝癌治疗新方法的开发提供理论依据。

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引用次数: 0

Mechanism of LncRNA ST7-AS2/RBM22/SOX2 axis regulating vasculogenic mimicry of glioma LncRNA ST7-AS2/RBM22/SOX2轴调控胶质瘤血管生成模拟的机制

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-11-27 DOI: 10.1016/j.cellsig.2025.112285

Lu Liu , Di Wang , Ping Wang , Xuelei Ruan , Libo Liu , Yang Lin , Hongda Lin , Xiaobai Liu

Glioma is the most common type of primary intracranial malignancy. The average survival time of patients with malignant glioma is less than 15 months. Vasculogenic mimicry (VM) is a tubular structure independent of vascular endothelial cells formed by malignant tumor cell. VM is closely related to the pathological grade and cell malignant biological behavior of glioma. Inhibition of vasculogenic mimicry in glioma cells can be used as one of the main steps of anti-angiogenesis therapy. The study revealed that long non-coding RNA ST7 antisense RNA 2 (lncRNA ST7-AS2) changes RNA binding motif protein 22 (RBM22) nucleoplasmic distribution by promoting small ubiquitin like modifier (SUMO) modification of RBM22. RBM22 upregulates the transcription activity of vascular endothelial growth factor recptor 2 (VEGFR2) promotor by binding SRY-box transcription factor 2 (SOX2). The results of xenograft tumor model in nude mice showed that combined knockdown of RBM22 and lncRNA ST7-AS2 was the most effective in inhibiting tumor formation in vivo, with the least formation of vasculogenic mimicry and the longest survival time in nude mice. The lncRNA ST7-AS2/RBM22/SOX2 axis play a crucial part in the process of VM formation in gliomas and could provide potential alternative strategies for the combined anti-tumor therapy.

胶质瘤是最常见的原发性颅内恶性肿瘤。恶性胶质瘤患者的平均生存时间小于15个月。血管源性拟态（vascular genic mimicry， VM）是恶性肿瘤细胞形成的独立于血管内皮细胞的管状结构。VM与胶质瘤的病理分级及细胞恶性生物学行为密切相关。抑制胶质瘤细胞的血管生成模拟可以作为抗血管生成治疗的主要步骤之一。研究发现，长链非编码RNA ST7反义RNA 2 （lncRNA ST7- as2）通过促进RBM22的小泛素样修饰物（SUMO）修饰而改变RNA结合基序蛋白22 （RBM22）核质分布。RBM22通过结合SRY-box转录因子2 （SOX2）上调血管内皮生长因子受体2 （VEGFR2）启动子的转录活性。裸鼠异种移植肿瘤模型实验结果显示，RBM22与lncRNA ST7-AS2联合敲低在体内抑制肿瘤形成最有效，裸鼠血管源性模拟形成最少，存活时间最长。lncRNA ST7-AS2/RBM22/SOX2轴在胶质瘤VM形成过程中起着至关重要的作用，可能为联合抗肿瘤治疗提供潜在的替代策略。

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引用次数: 0

RhoA/ROCK1 aggravates transverse aortic constriction-induced atrial fibrillation by enhancing NF-κBp65/CCL2 signaling pathway RhoA/ROCK1通过增强NF-κBp65/CCL2信号通路加重横主动脉缩窄所致心房颤动

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-11-27 DOI: 10.1016/j.cellsig.2025.112275

Mingzhi Wan , Yao Li , Nana Qin , Zijun Zhou , Boxuan Sun , Bo Xing , Yiwen Wang , Jinfeng Duan , Yuting Huang , Liming Yu , Huishan Wang

Atrial fibrillation (AF) is closely associated with atrial electrical and structural remodeling, yet effective pharmacological treatment strategies remain limited. The Ras homolog gene family member A (RhoA) and its downstream effector rho-kinase 1 (ROCK1) act as central regulators of cytoskeletal dynamics and inflammatory signaling. However, the mechanism of the RhoA/ROCK1 signaling pathway in atrial inflammation and AF pathogenesis is poorly understood. In this study, we demonstrate that activation of RhoA/ROCK1 signaling exacerbates atrial inflammation and remodeling, consequently increasing susceptibility to AF. Fasudil-mediated inhibition of RhoA/ROCK1 significantly attenuated atrial fibrosis, inflammation, and AF inducibility by suppressing the nuclear factor kappa-B p65 (NF-κBp65)/chemokine C-C-Motif ligand 2 (CCL2) signaling pathway. Restoring NF-κBp65 expression abolished these protective effects, establishing a causal relationship between RhoA/ROCK1 activation and NF-κB-mediated inflammation. Our results thus identify RhoA/ROCK1 as a critical mediator of pressure overload-induced AF and point to the RhoA/ROCK1-NF-κB/CCL2 axis as a promising therapeutic target for AF.

心房颤动（AF）与心房电和结构重构密切相关，但有效的药物治疗策略仍然有限。Ras同源基因家族成员A （RhoA）及其下游效应物rho1激酶1 （ROCK1）作为细胞骨架动力学和炎症信号传导的中枢调节因子。然而，RhoA/ROCK1信号通路在心房炎症和房颤发病中的作用机制尚不清楚。在这项研究中，我们证明RhoA/ROCK1信号的激活会加剧心房炎症和重构，从而增加对房颤的易感性。法索地尔介导的RhoA/ROCK1抑制通过抑制核因子κ b p65 (NF-κBp65)/趋化因子C-C-Motif配体2 （CCL2）信号通路显著减轻心房纤维化、炎症和房颤诱导。恢复NF-κBp65的表达消除了这些保护作用，建立了RhoA/ROCK1激活与NF-κ b介导的炎症之间的因果关系。因此，我们的研究结果确定RhoA/ROCK1是压力过载诱导AF的关键介质，并指出RhoA/ROCK1- nf -κB/CCL2轴是AF的一个有希望的治疗靶点。

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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 : 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 Solute Carrier Family 7 Member 11 (SLC7A11) expression, the content of nicotinamide adenine dinucleotide phosphate (NADPH) 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 (LC), pancreatic cancer (PC), gastric cancer (GC), colorectal cancer (CRC), 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

PPARG-FABP4 regulates PI3K/Akt pathway to promote lung cancer-associated macrophage endoplasmic reticulum stress-mediated CD36 expression and affects lung squamous cell carcinoma metastasis ppar - fabp4调控PI3K/Akt通路，促进肺癌相关巨噬细胞内质网应激介导的CD36表达，影响肺鳞癌转移。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-11-27 DOI: 10.1016/j.cellsig.2025.112281

Zhen Li , Dongping Yu , Ning Wang , Hui Chen , Zhi Duan , Qiang Wu

Background

Lung squamous cell carcinoma (LUSC) is a common subtype of primary lung cancer. Macrophage endoplasmic reticulum stress (ERS) is crucial in regulating lung cancer metastasis. Here, effects of Fatty acid binding protein 4 (FABP4) on macrophage ERS and lung cancer metastasis were evaluated.

Methods

First, we used CancerSCEM single cell database to analyze interaction between tumor cells in LUSC and various immune cells in surrounding microenvironment. Database of The Cancer GenomeAtlas (TCGA) was utilized to analyze variations in mRNA expression and conduct survival analysis within lung cancer tissues. Then, 42 samples of LUSC tissue and corresponding adjacent normal tissues were obtained from patients. IHC staining evaluated FABP4 expression and co-localization with CD163. Lipid metabolic changes in macrophages were evaluated utilizing immunofluorescence and oil red O staining. Lung cancer cells (H520) were co-cultured with primary macrophages from lung cancer patients, and H520 cell proliferation, migration and invasion were detected. ChIP and dual luciferase reporter assays validated direct binding between peroxisome proliferator-activated receptor gamma (PPARG) and FABP4. Subcutaneous and metastatic tumor models were set up to confirm FABP4's impact on lung cancer progression in vivo.

Results

FABP4 expression was upregulated in macrophages near cancer sites but declined in LUSC cancer epithelial cells. Silencing FABP4 in primary macrophages from lung cancer patients suppressed lipid metabolism in macrophages, reducing macrophage ERS and hindering lung cancer cell metastasis. PPARG enhanced FABP4 expression at the transcriptional level. PPARG-FABP4 controlled PI3K/Akt pathway, promoting ERS-induced CD36 expression in lung cancer-related macrophages, impacting lung cancer metastasis. Deleting macrophage FABP4 impaired both proliferation and metastasis of lung cancer in mice.

Conclusion

PPARG regulates FABP4 mRNA transcription, initiating macrophage ERS through PI3K/Akt-mediated lipid metabolism, thus modulating macrophage CD36 levels and influencing lung cancer metastasis.

背景：肺鳞状细胞癌（LUSC）是原发性肺癌的常见亚型。巨噬细胞内质网应激（ERS）在调控肺癌转移中起着至关重要的作用。本研究探讨了脂肪酸结合蛋白4 （FABP4）对巨噬细胞ERS和肺癌转移的影响。方法：首先，利用CancerSCEM单细胞数据库分析LUSC中肿瘤细胞与周围微环境中多种免疫细胞的相互作用。利用The Cancer GenomeAtlas （TCGA）数据库分析肺癌组织中mRNA的表达变化并进行生存分析。然后，从患者身上获得42个LUSC组织和相应的邻近正常组织。免疫组化染色评价FABP4的表达及与CD163的共定位。利用免疫荧光和油红O染色评价巨噬细胞脂质代谢的变化。将肺癌细胞（H520）与肺癌患者原代巨噬细胞共培养，检测H520细胞的增殖、迁移和侵袭情况。ChIP和双荧光素酶报告基因检测证实了过氧化物酶体增殖物激活受体γ (PPARG)与FABP4之间的直接结合。建立皮下和转移性肿瘤模型来证实FABP4在体内对肺癌进展的影响。结果：FABP4在癌旁巨噬细胞中表达上调，而在LUSC癌上皮细胞中表达下调。沉默肺癌原代巨噬细胞FABP4抑制巨噬细胞脂质代谢，降低巨噬细胞ERS，阻碍肺癌细胞转移。PPARG在转录水平上增强FABP4的表达。PPARG-FABP4控制PI3K/Akt通路，促进ers诱导的肺癌相关巨噬细胞CD36表达，影响肺癌转移。删除巨噬细胞FABP4可抑制小鼠肺癌的增殖和转移。结论：PPARG调节FABP4 mRNA转录，通过PI3K/ akt介导的脂质代谢启动巨噬细胞ERS，从而调节巨噬细胞CD36水平，影响肺癌转移。

{"title":"PPARG-FABP4 regulates PI3K/Akt pathway to promote lung cancer-associated macrophage endoplasmic reticulum stress-mediated CD36 expression and affects lung squamous cell carcinoma metastasis","authors":"Zhen Li , Dongping Yu , Ning Wang , Hui Chen , Zhi Duan , Qiang Wu","doi":"10.1016/j.cellsig.2025.112281","DOIUrl":"10.1016/j.cellsig.2025.112281","url":null,"abstract":"<div><h3>Background</h3><div>Lung squamous cell carcinoma (LUSC) is a common subtype of primary lung cancer. Macrophage endoplasmic reticulum stress (ERS) is crucial in regulating lung cancer metastasis. Here, effects of Fatty acid binding protein 4 (FABP4) on macrophage ERS and lung cancer metastasis were evaluated.</div></div><div><h3>Methods</h3><div>First, we used CancerSCEM single cell database to analyze interaction between tumor cells in LUSC and various immune cells in surrounding microenvironment. Database of The Cancer GenomeAtlas (TCGA) was utilized to analyze variations in mRNA expression and conduct survival analysis within lung cancer tissues. Then, 42 samples of LUSC tissue and corresponding adjacent normal tissues were obtained from patients. IHC staining evaluated FABP4 expression and co-localization with CD163. Lipid metabolic changes in macrophages were evaluated utilizing immunofluorescence and oil red O staining. Lung cancer cells (H520) were co-cultured with primary macrophages from lung cancer patients, and H520 cell proliferation, migration and invasion were detected. ChIP and dual luciferase reporter assays validated direct binding between peroxisome proliferator-activated receptor gamma (PPARG) and FABP4. Subcutaneous and metastatic tumor models were set up to confirm FABP4's impact on lung cancer progression in vivo.</div></div><div><h3>Results</h3><div>FABP4 expression was upregulated in macrophages near cancer sites but declined in LUSC cancer epithelial cells. Silencing FABP4 in primary macrophages from lung cancer patients suppressed lipid metabolism in macrophages, reducing macrophage ERS and hindering lung cancer cell metastasis. PPARG enhanced FABP4 expression at the transcriptional level. PPARG-FABP4 controlled PI3K/Akt pathway, promoting ERS-induced CD36 expression in lung cancer-related macrophages, impacting lung cancer metastasis. Deleting macrophage FABP4 impaired both proliferation and metastasis of lung cancer in mice.</div></div><div><h3>Conclusion</h3><div>PPARG regulates FABP4 mRNA transcription, initiating macrophage ERS through PI3K/Akt-mediated lipid metabolism, thus modulating macrophage CD36 levels and influencing lung cancer metastasis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112281"},"PeriodicalIF":3.7,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630549","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}

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