Cytokine & Growth Factor Reviews最新文献

Cytokine storm divergence in viral infections of the upper respiratory tract 上呼吸道病毒感染的细胞因子风暴分化。

IF 11.8 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2026-02-04 DOI: 10.1016/j.cytogfr.2026.01.008

Keda Chen , Qiuyi Xu , Jiaxuan Li , Guangshang Wu , Hao Wu , Xiaotian Tie , Jinghan Xu , Jianhua Li , Yanjun Zhang

Cytokine storm (CS) is a pathological state of dysregulated, hyperactive host immunity that arises in the context of infection, malignancy, or immunotherapy. CS is characterized by the sustained, markedly elevated release of multiple pro-inflammatory mediators, ultimately leading to tissue damage and multi-organ dysfunction. Upper respiratory viral infections, including SARS, MERS, SARS-CoV-2, influenza, adenovirus, and respiratory syncytial virus (RSV), are among the most prominent CS triggers. Inflammatory storms triggered by different pathogens exhibit distinct variations in their cytokine profiles and downstream immune signaling pathways. Underlying comorbidities—such as diabetes, obesity, and cardiovascular disease—together with complications such as coagulopathies and secondary infections, can profoundly alter both the threshold and the magnitude of the cytokine storm. This review systematically compares cytokine profiles elicited by distinct upper respiratory pathogens, with population stratification by age and underlying comorbidities, to clarify how these patterns relate to disease severity and complication risk. Collectively, the available evidence supports a shared inflammatory backbone across respiratory virus–induced cytokine storms, overlaid by pathogen-specific cytokine fingerprints and host-dependent plasticity that shapes clinical trajectories and outcomes.

细胞因子风暴（CS）是在感染、恶性肿瘤或免疫治疗的情况下出现的一种失调、过度活跃的宿主免疫的病理状态。CS的特点是多种促炎介质的持续、显著升高的释放，最终导致组织损伤和多器官功能障碍。上呼吸道病毒感染，包括SARS、MERS、SARS- cov -2、流感、腺病毒和呼吸道合胞病毒（RSV），是最主要的CS触发因素。由不同病原体引发的炎症风暴在其细胞因子谱和下游免疫信号通路中表现出明显的变化。潜在的合并症——如糖尿病、肥胖和心血管疾病——以及凝血功能障碍和继发感染等并发症，可以深刻地改变细胞因子风暴的阈值和强度。本综述系统地比较了不同上呼吸道病原体引起的细胞因子谱，以及按年龄和潜在合并症进行的人群分层，以阐明这些模式与疾病严重程度和并发症风险的关系。总的来说，现有证据支持呼吸道病毒诱导的细胞因子风暴具有共同的炎症主干，由病原体特异性细胞因子指纹和宿主依赖的可塑性覆盖，从而形成临床轨迹和结果。

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引用次数: 0

Cytokine circuitry in pancreatic cancer: Targets for overcoming immune checkpoint inhibitor resistance in PDAC 胰腺癌细胞因子通路：PDAC中克服免疫检查点抑制剂耐药性的靶点。

IF 11.8 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2026-02-03 DOI: 10.1016/j.cytogfr.2026.01.009

Dhanisha Sulekha Suresh , Maria Fernanda Salcedo-Noriega , Utpreksha Vaish , Abhiram Beena Kannan , Suryansh Suryansh , Sweta Bhandari , Saikiran Chatre , Tejeshwar Jain , Vivaan Dudeja , Srikanth Iyer

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a poor prognosis due to its complex and highly immunosuppressive tumor microenvironment (TME). The PDAC TME, characterized by dense desmoplasia and enhanced infiltration of immunosuppressive immune cells, acts as a physical and immunological barrier, rendering most patients unresponsive to conventional and immune checkpoint inhibitor (ICI) therapies. This resistance is critically mediated by the cytokine network, where pro-tumorigenic factors such as IL-6 and TGF-β drive T-cell exclusion and myeloid-dependent suppression from PSCs, CAFs, and immune cells. The key to improving the therapeutic approaches lies in effectively reprogramming this hostile milieu. This review focuses on the dual and paradoxical role of cytokines as drivers of immune evasion (IL-6, TGF-β, MIF) and mediators of anti-tumor immunity (IL-12, IL-15). Herein, we outline the strategic shift toward cytokine-based combination immunotherapy designed to remodel the TME through the disruption of cytokine-driven resistance pathways. Key strategies currently under investigation include targeting TGF-β and IL-6 to sensitize tumors to ICIs, while antagonizing chemokines like CXCL12/CXCR4 to enhance T-cell trafficking. Furthermore, we detailed cutting-edge approaches to overcome systemic toxicity and poor drug delivery, specifically through cytokine-based nanotechnology, including nanocarriers and mRNA lipid nanoparticles, for localized expression of immunogenic signals. As well as the cutting-edge field of chimeric cytokine engineering, including VHH-fusions, to selectively activate anti-tumor immunity, highlighting promising candidates in late-stage clinical trials. The successful application of these engineered cytokine strategies is crucial to unlocking effective immunotherapy for PDAC patients.

胰腺导管腺癌（Pancreatic ductal adencarcinoma， PDAC）是一种高致死率、预后差的恶性肿瘤，其肿瘤微环境复杂且具有高度免疫抑制作用。PDAC TME以致密的结缔组织增生和免疫抑制免疫细胞的浸润增强为特征，作为物理和免疫屏障，使大多数患者对常规和免疫检查点抑制剂（ICI）治疗无反应。这种耐药性是由细胞因子网络介导的，其中促肿瘤因子如IL-6和TGF-β驱动t细胞排斥和来自psc、CAFs和免疫细胞的骨髓依赖性抑制。改善治疗方法的关键在于有效地重新编程这种敌对环境。本文综述了细胞因子作为免疫逃避的驱动因子（IL-6, TGF-β， MIF）和抗肿瘤免疫的介质（IL-12, IL-15）的双重和矛盾作用。在此，我们概述了向基于细胞因子的联合免疫疗法的战略转变，旨在通过破坏细胞因子驱动的耐药途径来重塑TME。目前正在研究的关键策略包括靶向TGF-β和IL-6使肿瘤对ICIs敏感，同时拮抗趋化因子如CXCL12/CXCR4以增强t细胞运输。此外，我们详细介绍了克服全身毒性和药物递送不良的尖端方法，特别是通过基于细胞因子的纳米技术，包括纳米载体和mRNA脂质纳米颗粒，用于免疫原性信号的局部表达。以及嵌合细胞因子工程的前沿领域，包括vhh融合，选择性地激活抗肿瘤免疫，在后期临床试验中突出了有希望的候选药物。这些工程化细胞因子策略的成功应用对于开启PDAC患者有效的免疫治疗至关重要。

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引用次数: 0

The role of neurotransmitter signaling in colorectal cancer progression: Opportunities for drug repurposing 神经递质信号在结直肠癌进展中的作用：药物再利用的机会。

IF 11.8 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2026-01-31 DOI: 10.1016/j.cytogfr.2026.01.010

He Jiang , Guangming Zhang , Wanjun Sun , Heng Zhang , Shiwu Zhang , Hui Wang

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with treatment challenges often arising from drug resistance and the complexity of the tumor microenvironment (TME). Emerging evidence has repositioned the nervous system from a passive bystander to an active participant in cancer progression. Neurotransmitters, such as serotonin, glutamate, GABA, dopamine, acetylcholine, and norepinephrine, are now recognized as crucial regulators of CRC. They directly influence tumor cell proliferation, metastasis, stemness, and therapy resistance by activating their cognate receptors on cancer cells. Furthermore, they modulate the TME by affecting immune cells and stromal components. This intricate crosstalk presents a novel therapeutic avenue. Drug repurposing, the strategy of finding new uses for approved non-cancer drugs, offers a time-efficient and cost-effective path to translate these insights into clinical practice. A growing body of preclinical and clinical studies indicates that various psychoactive agents, including antidepressants, such as Selective Serotonin Reuptake Inhibitors, antipsychotics, anesthetics, and beta-blockers, exhibit potent anti-CRC effects. This review systematically summarizes the roles of key neurotransmitter systems in CRC pathogenesis and progression. It further explores the promising potential of repurposing existing neuropharmacological agents as novel therapeutic or adjunctive strategies for CRC, highlighting both the compelling opportunities and the challenges within this burgeoning field.

结直肠癌（CRC）仍然是全球癌症相关死亡的主要原因，其治疗挑战往往来自耐药性和肿瘤微环境（TME）的复杂性。新出现的证据将神经系统从一个被动的旁观者重新定位为癌症进展的积极参与者。神经递质，如血清素、谷氨酸、GABA、多巴胺、乙酰胆碱和去甲肾上腺素，现在被认为是结直肠癌的关键调节因子。它们通过激活肿瘤细胞上的同源受体直接影响肿瘤细胞的增殖、转移、干性和治疗耐药性。此外，它们通过影响免疫细胞和基质成分来调节TME。这种错综复杂的相声呈现出一种新的治疗途径。药物再利用是为已批准的非癌症药物寻找新用途的策略，它为将这些见解转化为临床实践提供了一条既省时又经济的途径。越来越多的临床前和临床研究表明，各种精神活性药物，包括抗抑郁药，如选择性5 -羟色胺再摄取抑制剂，抗精神病药，麻醉剂和β受体阻滞剂，显示出有效的抗crc作用。本文系统综述了关键神经递质系统在结直肠癌发病和进展中的作用。它进一步探讨了将现有的神经药理药物作为结直肠癌的新治疗或辅助策略的潜力，强调了这一新兴领域的引人注目的机遇和挑战。

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引用次数: 0

Cytokine MicroRNA regulatory networks in colorectal cancer: Contemporary research insights and mechanistic analysis 结直肠癌中的细胞因子MicroRNA调控网络：当代研究见解和机制分析。

IF 11.8 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2026-01-23 DOI: 10.1016/j.cytogfr.2026.01.007

Aneth Ochoa Negrete , Vanessa Duran , Natalie Gierat , Adithi Kankanala , Kalyani Narra , Riyaz Basha

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Effective CRC screening in the United States has reduced incidence of CRC in populations over 50 years of age. Early-onset CRC is emerging as a significant issue. There is need for better understanding of CRC biology to develop screening techniques, diagnostic markers and novel therapies to improve outcomes. MicroRNAs (miRNAs) are involved in several cellular processes and function as tumor suppressors and oncogenes. The miRNA/cytokine networks play a critical role in CRC pathogenesis by contributing to an extended period of inflammation which promotes tumorigenesis, tumor progression, and immune evasion. Certain miRNAs such as miR-21 and miR-155 are pro-inflammatory while others like miR-34, miR-143, miR-145 and mi146a are protective against cancer. When using miRNAs as therapeutics in CRC, the therapies rely on miRNA inhibitors to either suppress the miRNAs that have a role in activating oncogenic pathways or replacing miRNAs with mimics that can upregulate tumor suppressors which have been dysregulated due to cancerous mutations. Key immune checkpoint pathways such as PD-1/PD-L1, NF-κB, MAPK, PI3/AKT, and Wnt/β-catenin signaling cascades are regulated by miRNAs. A number of miRNAs are also tested as therapeutic co-targets for boosting immunotherapy effectiveness. Several clinical trials are underway to incorporate miRNAs into CRC screening or detecting early recurrence. Since the administration of targeted treatments can result in an immune-related adverse effect, growing interest has focused on exosomes as alternative carriers for miRNA-based therapeutics. Overall, applications of miRNAs have the potential to improve CRC outcomes.

结直肠癌（CRC）仍然是世界范围内癌症相关死亡的主要原因。在美国，有效的CRC筛查降低了50岁以上人群的CRC发病率。早发性结直肠癌正在成为一个重要的问题。有必要更好地了解结直肠癌生物学，以开发筛查技术、诊断标志物和新疗法来改善预后。MicroRNAs （miRNAs）参与多种细胞过程，并作为肿瘤抑制因子和癌基因发挥作用。miRNA/细胞因子网络在结直肠癌的发病机制中起着关键作用，通过延长炎症期促进肿瘤发生、肿瘤进展和免疫逃逸。某些mirna如miR-21和miR-155具有促炎作用，而其他mirna如miR-34、miR-143、miR-145和mi146a具有抗癌作用。当使用miRNA作为结直肠癌的治疗方法时，治疗依赖于miRNA抑制剂来抑制在激活致癌途径中起作用的miRNA，或者用可以上调因癌性突变而失调的肿瘤抑制因子的模拟物取代miRNA。关键免疫检查点通路如PD-1/PD-L1、NF-κB、MAPK、PI3/AKT和Wnt/β-catenin信号级联受mirna调控。一些mirna也被测试作为提高免疫治疗效果的治疗共同靶点。一些将mirna纳入CRC筛查或早期复发检测的临床试验正在进行中。由于靶向治疗可能导致免疫相关的不良反应，人们越来越关注外泌体作为mirna治疗的替代载体。总的来说，mirna的应用有可能改善结直肠癌的预后。

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引用次数: 0

Spatiotemporal dynamic regulation of the CX3CL1-CX3CR1 axis: A double-edged sword in the tumor immune microenvironment and new strategies for precision therapy CX3CL1-CX3CR1轴的时空动态调控：肿瘤免疫微环境中的双刃剑与精准治疗新策略

IF 11.8 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2026-01-17 DOI: 10.1016/j.cytogfr.2026.01.006

Jingtian Liang , Wenlong Zhu , Ruohan Pan , Shuli Wei, Shuangling Zhang, Zhe Zhang, Hongfei Tian

The CX3CL1-CX3CR1 signaling axis is a key yet functionally contradictory regulatory hub within the tumor immune microenvironment (TME), with its output shaped by spatiotemporal dynamics. This review seeks to address the core scientific question of how this axis mediates both pro-tumor and anti-tumor effects simultaneously by analyzing a multi-layered regulatory framework. The duality of its function is rooted in two main mechanisms: (1) the regulation of CX3CL1 ligand cleavage by ADAM10/17 proteases, which determines the balance between membrane-bound (mCX3CL1, mediating adhesion) and soluble (sCX3CL1, mediating chemotaxis) isoforms; (2) the expression gradient of its sole receptor CX3CR1 on immune cells, which functions as a molecular code that precisely programs cell differentiation trajectories, such as the differentiation of CD8⁺T cells from a stem-like state to a terminally exhausted state. Specific TME signals (such as TGF-β in pancreatic ductal adenocarcinoma (PDAC) and TLR4 signaling in colorectal cancer (CRC)) integrate these mechanisms and ultimately dictate distinct functional outputs. We propose that interventions targeting this axis must move beyond traditional agonist/antagonist approaches toward spatiotemporally specific precision control strategies, including intelligent delivery systems, CRISPR-based cell engineering, and AI-driven personalized treatments. Rationally reprogramming the functional orientation of this axis holds promise in overcoming immune checkpoint inhibitor resistance and provides a theoretical foundation for the development of a new generation of cancer immunotherapies.

CX3CL1-CX3CR1信号轴是肿瘤免疫微环境（TME）中一个关键但功能矛盾的调控枢纽，其输出受时空动态影响。这篇综述试图通过分析一个多层次的调控框架来解决这个轴如何同时介导促肿瘤和抗肿瘤作用的核心科学问题。其功能的二元性主要基于两个机制：(1)ADAM10/17蛋白酶对CX3CL1配体切割的调控，决定了膜结合（mCX3CL1，介导粘附）和可溶性（sCX3CL1，介导趋化）亚型之间的平衡；(2)其唯一受体CX3CR1在免疫细胞上的表达梯度，作为精确编程细胞分化轨迹的分子密码，如CD8+T细胞从干细胞样状态向终衰竭状态的分化。特定的TME信号（如胰腺导管腺癌（PDAC）中的TGF-β和结直肠癌（CRC）中的TLR4信号）整合了这些机制，并最终决定了不同的功能输出。我们建议，针对这一轴的干预措施必须超越传统的激动剂/拮抗剂方法，转向时空特异性精确控制策略，包括智能递送系统、基于crispr的细胞工程和人工智能驱动的个性化治疗。合理地重新编程该轴的功能取向有望克服免疫检查点抑制剂的耐药性，并为开发新一代癌症免疫疗法提供理论基础。

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引用次数: 0

TGF-β–YY1 signaling as a key driver of immune evasion in pancreatic cancer: Therapeutic implications TGF-β-YY1信号作为胰腺癌免疫逃避的关键驱动因素：治疗意义

IF 11.8 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2026-01-16 DOI: 10.1016/j.cytogfr.2026.01.005

Mai P. Ho , Megan Jung , William Ung , Evagelia Skouradaki , Stavroula Baritaki , Benjamin Bonavida

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by a dense desmoplastic stroma, profound immune suppression, and resistance to conventional therapeutics. Poor patient outcomes are driven by resistance to chemotherapy and immunotherapy arising from both tumor-intrinsic and microenvironmental mechanisms. Elucidating the molecular pathways underlying therapeutic failure is therefore critical. Transforming growth factor-β (TGF-β) is a central regulator of PDAC progression, promoting epithelial–mesenchymal-transition (EMT), stromal remodeling, immune exclusion, and checkpoint activation at advanced disease stages. The transcription factor Yin Yang 1 (YY1) is a critical downstream integrator and amplifier of TGF-β–driven signaling programs. YY1 reinforces EMT, metabolic adaptation, and immune evasion through transcriptional, epigenetic, and post-transcriptional regulations. Several key immune modulators of immune evasion include PD-L1, indoleamine 2,3-dioxygenase, FOXP3, and pro-tumoral chemokines. The coordinated TGF-β–YY1 signaling suppresses CD8 cytotoxic T-cell (CTL) and natural killer (NK) cell functions, promotes regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), and establishes an immune-cold, therapy-resistant tumor microenvironment. This review explores the mechanistic basis of the TGF-β-YY1 cross-talk regulation in the immune evasion of PDAC. It also discusses emerging therapeutic opportunities in targeting the TGF-β-YY1 axis to overcome immune escape and improve treatment outcomes in PDAC.

胰腺导管腺癌（PDAC）是一种高度致命的恶性肿瘤，其特征是致密的间质，严重的免疫抑制，以及对传统治疗的耐药性。不良的患者预后是由肿瘤内在机制和微环境机制引起的对化疗和免疫治疗的耐药性所驱动的。因此，阐明治疗失败的分子途径至关重要。转化生长因子-β (TGF-β)是PDAC进展的中心调节因子，在疾病晚期促进上皮-间质转化（EMT）、基质重塑、免疫排斥和检查点激活。转录因子阴阳1 （YY1）是TGF-β驱动信号程序的关键下游积分器和放大器。YY1通过转录、表观遗传和转录后调控加强EMT、代谢适应和免疫逃避。免疫逃避的几个关键免疫调节剂包括PD-L1、吲哚胺2,3-双加氧酶、FOXP3和促肿瘤趋化因子。TGF-β-YY1信号协同抑制CD8细胞毒性T细胞（CTL）和自然杀伤细胞（NK）功能，促进调节性T细胞（Treg）和髓源性抑制细胞（MDSCs），建立免疫冷、治疗耐药的肿瘤微环境。本文就TGF-β-YY1串扰调控PDAC免疫逃避的机制基础进行探讨。它还讨论了靶向TGF-β-YY1轴克服免疫逃逸和改善PDAC治疗结果的新治疗机会。

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引用次数: 0

GDF15 in the tumor microenvironment: A central mediator of cancer immunometabolism and therapeutic resistance 肿瘤微环境中的GDF15：癌症免疫代谢和治疗抵抗的中心介质

IF 11.8 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2026-01-13 DOI: 10.1016/j.cytogfr.2026.01.004

Lingeng Lu , Caroline H. Johnson , Sajid A. Khan , Melinda L. Irwin

Growth differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β (TGFβ) superfamily, has emerged as a pivotal cytokine linking cancer metabolism, immune suppression, and systemic energy balance. Initially characterized as a stress-induced cytokine with roles in appetite regulation and cachexia, GDF15 was first identified in activated macrophages and is also secreted by tumor cells, stromal cells and stressed epithelial cells across multiple tissues. Functionally, GDF15 exerts pleiotropic effects on both immune and nonimmune cell populations, modulating T cells, dendritic cells, and macrophages in the tumor microenvironment (TME), and metabolic tissues such as liver, adipose and muscle, thereby promoting tumor progression, therapeutic resistance, and cancer-associated metabolic dysregulation. In several human cancers of such as colorectal, pancreatic, breast and brain, elevated GDF15 levels correlate with poor prognosis, immune evasion, and chemoresistance. Mechanistically, GDF15 modulates fatty acid metabolism, promotes epithelial-mesenchymal transition, and suppresses anti-tumor immunity by impairing dendritic cell maturation and excluding CD8⁺ T cell infiltration. Targeting GDF15 may reprogram immunometabolic suppression and enhance checkpoint blockade efficacy. This review synthesizes current knowledge on GDF15’s multifaceted roles in tumor biology, emphasizing its function as a central node of cancer immunometabolism. We highlight advances in spatial multi-omics, integrating transcriptomics and immune imaging, that reveal GDF15 spatially restricted immunosuppression in the tumor microenvironment.

生长分化因子15 （GDF15）是转化生长因子-β (TGFβ)超家族的一个不同成员，已成为连接癌症代谢、免疫抑制和全身能量平衡的关键细胞因子。GDF15最初被认为是一种应激诱导的细胞因子，在食欲调节和恶病质中发挥作用，GDF15首先在活化的巨噬细胞中被发现，并在多种组织中由肿瘤细胞、基质细胞和应激上皮细胞分泌。在功能上，GDF15对免疫和非免疫细胞群均有多种作用，调节肿瘤微环境（TME）和代谢组织（如肝脏、脂肪和肌肉）中的T细胞、树突状细胞和巨噬细胞，从而促进肿瘤进展、治疗抵抗和癌症相关的代谢失调。在结直肠癌、胰腺癌、乳腺癌和脑癌等几种人类癌症中，GDF15水平升高与预后不良、免疫逃避和化疗耐药相关。在机制上，GDF15通过抑制树突状细胞成熟和排除CD8+ T细胞浸润，调节脂肪酸代谢，促进上皮-间质转化，抑制抗肿瘤免疫。靶向GDF15可能会重编程免疫代谢抑制并增强检查点阻断效果。本文综合了目前关于GDF15在肿瘤生物学中的多方面作用的知识，强调了其作为癌症免疫代谢中心节点的功能。我们强调了空间多组学，整合转录组学和免疫成像的进展，揭示了GDF15在肿瘤微环境中的空间限制性免疫抑制。

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引用次数: 0

Reprogramming immunity at the metabolic–epidermal interface in obesity-associated psoriasis 肥胖相关性银屑病代谢-表皮界面免疫重编程

IF 11.8 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2026-01-09 DOI: 10.1016/j.cytogfr.2026.01.003

Jinsun Jang , Minji Park , Hee Joo Kim , YunJae Jung

Obesity and psoriasis are chronic inflammatory disorders, now recognized to be interconnected, in which metabolic overload drives immune dysregulation and therapeutic resistance. Excess adiposity converts adipose tissue into an inflammatory organ that releases adipokines and cytokine-like mediators, reprogramming keratinocytes and immune cells to sustain cytokine-driven inflammatory circuits in the skin. Excess nutrients and lipotoxic stress impair mitochondrial function, enhance glycolysis, and induce epigenetic remodeling in myeloid and epithelial lineages, generating metabolic memory that perpetuates inflammation. Increased body mass index and insulin resistance are clinically associated with reduced responses to biologics targeting tumor necrosis factor, interleukin (IL)-17, and IL-23, whereas metabolic interventions including caloric restriction and glucagon-like peptide-1 receptor agonists improve responsiveness. Recent multi-omics, single-cell, and spatial studies demonstrate that obesity reshapes dermal and adipose immune niches and rewires epidermal innate immunity, attenuating cytokine blockade. Obesity-associated psoriasis thus represents a metabolically imprinted inflammatory state driven by chronic metabolic stress. This review integrates mechanistic and clinical insights and discusses strategies to restore metabolic–immune plasticity to sustain disease remission.

肥胖和牛皮癣是慢性炎症性疾病，现在被认为是相互关联的，其中代谢过载导致免疫失调和治疗抵抗。过多的脂肪将脂肪组织转化为炎症器官，释放脂肪因子和细胞因子样介质，重新编程角质形成细胞和免疫细胞，以维持皮肤中细胞因子驱动的炎症回路。过量的营养和脂毒性应激损害线粒体功能，增强糖酵解，诱导髓系和上皮谱系的表观遗传重塑，产生代谢记忆，使炎症持续存在。体重指数增加和胰岛素抵抗在临床上与针对肿瘤坏死因子、白细胞介素(IL)-17和IL-23的生物制剂的反应降低有关，而代谢干预包括热量限制和胰高血糖素样肽-1受体激动剂可改善反应性。最近的多组学、单细胞和空间研究表明，肥胖重塑了皮肤和脂肪免疫生态位，重塑了表皮先天免疫，减弱了细胞因子的阻断。因此，肥胖相关的牛皮癣代表了一种由慢性代谢应激驱动的代谢印迹炎症状态。这篇综述整合了机制和临床见解，并讨论了恢复代谢免疫可塑性以维持疾病缓解的策略。

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引用次数: 0

cPLA2 in musculoskeletal and autoimmune diseases: Molecular mechanisms and therapeutic insights cPLA2在肌肉骨骼和自身免疫性疾病中的作用：分子机制和治疗见解

IF 11.8 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2026-01-06 DOI: 10.1016/j.cytogfr.2026.01.002

Chaopeng He , Guiwu Huang , Jingwei Bi, Wenyu Fu, Chuan-ju Liu

Cytosolic phospholipase A2 (cPLA2) is a central regulator of lipid signaling that links cytokine and growth factor signaling to arachidonic acid metabolism and downstream eicosanoid production. Dysregulated cPLA2 activity is increasingly recognized as a shared pathogenic mechanism across musculoskeletal and autoimmune diseases, including osteoarthritis, rheumatoid arthritis, intervertebral disc degeneration, osteoporosis, inflammatory myopathies, sarcopenia and Duchenne muscular dystrophy, as well as inflammatory bowel disease and multiple sclerosis. This review provides a focused and mechanistic overview of cPLA2 biology, emphasizing its regulation by Ca²⁺-dependent membrane translocation and MAPK-mediated phosphorylation, and its cell type specific actions in chondrocytes, osteoblasts, osteoclasts, myocytes, and immune cells. We discuss how cPLA2-driven lipid mediators coordinate inflammation, extracellular-matrix turnover, mitochondrial dysfunction, cellular senescence, and immune cell activation to drive chronic tissue degeneration. Importantly, we summarize emerging therapeutic strategies targeting cPLA2, spanning selective small-molecule inhibitors, gene-editing approaches, and drug repurposing (e.g., pyruvate and fexofenadine), and discuss their translational promise. Collectively, these insights position cPLA2 as a master regulator linking lipid metabolism with inflammation and tissue remodeling and may provide a unifying framework for developing disease-modifying therapies across diverse inflammatory and degenerative conditions, particularly musculoskeletal and autoimmune disorders.

胞质磷脂酶A2 （cPLA2）是脂质信号的中枢调节因子，将细胞因子和生长因子信号与花生四烯酸代谢和下游类二十烷酸生产联系起来。cPLA2活性失调越来越被认为是肌肉骨骼和自身免疫性疾病的共同致病机制，包括骨关节炎、类风湿性关节炎、椎间盘退变、骨质疏松症、炎症性肌病、肌肉减少症和杜氏肌营养不良症，以及炎症性肠病和多发性硬化症。这篇综述提供了cPLA2生物学的重点和机制概述，强调了ca2 +依赖的膜易位和mapk介导的磷酸化对其的调节，以及它在软骨细胞、成骨细胞、破骨细胞、肌细胞和免疫细胞中的细胞类型特异性作用。我们讨论了cpla2驱动的脂质介质如何协调炎症、细胞外基质转换、线粒体功能障碍、细胞衰老和免疫细胞激活来驱动慢性组织变性。重要的是，我们总结了针对cPLA2的新兴治疗策略，包括选择性小分子抑制剂、基因编辑方法和药物再利用（例如丙酮酸盐和非索非那定），并讨论了它们的转化前景。总的来说，这些见解将cPLA2定位为连接脂质代谢与炎症和组织重塑的主要调节因子，并可能为开发针对各种炎症和退行性疾病（特别是肌肉骨骼和自身免疫性疾病）的疾病修饰疗法提供统一框架。

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引用次数: 0

Cytokine associated neuroinflammation in Parkinson’s disease: Molecular pathways, therapeutic targets, and translational insights 细胞因子相关神经炎症在帕金森病：分子途径，治疗靶点，和翻译的见解

IF 11.8 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cytokine & Growth Factor Reviews

Pub Date : 2026-01-05 DOI: 10.1016/j.cytogfr.2026.01.001

Rishika Dhapola , Sneha Kumari , Prajjwal Sharma , Mohit Paidlewar , Balachandar Vellingiri , Bikash Medhi , Dibbanti HariKrishnaReddy

Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which neuroinflammation plays a key role. An imbalance between pro- and anti-inflammatory cytokines has been observed in both experimental models and PD patients. The inflammatory mediators activate signaling pathways that lead to oxidative stress, excitotoxicity, blood-brain barrier (BBB) disruption, gut dysbiosis, and hypothalamic–pituitary–adrenal axis (HPA-axis) dysregulation. Increased levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and others, following PD, stimulate both glial and peripheral immune cells to migrate to injury sites, further promoting neuroinflammation. Cytokines can directly cause neuronal damage and death through various mechanisms. These pathological changes eventually contribute to α-synuclein aggregation and the loss of dopaminergic neurons. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which promotes IL-1β maturation and caspase-1-driven neurotoxicity, has become a critical molecular hub linking innate immune activation to disease progression. Preclinical and clinical studies support that drugs targeting cytokine signaling can reduce neurotoxicity and neurodegeneration. Therapeutic agents that modulate pathways such as ephrin, cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING), Hippo, Receptor-Interacting Protein Kinase 1 (RIPK1), Leucine-rich repeat kinase 2 (LRRK2), and sirtuin pathways have shown anti-inflammatory effects in PD models. Combining approaches targeting immune and cytokine pathways offers a promising strategy for neuroprotection and disease modification in PD.

帕金森病（PD）是一种进行性神经退行性疾病，其中神经炎症起关键作用。在实验模型和PD患者中均观察到促炎性和抗炎性细胞因子之间的不平衡。炎症介质激活导致氧化应激、兴奋性毒性、血脑屏障（BBB）破坏、肠道生态失调和下丘脑-垂体-肾上腺轴（hpa -轴）失调的信号通路。PD后，促炎细胞因子如肿瘤坏死因子-α (TNF-α)、白细胞介素-1β (IL-1β)、白细胞介素-6 （IL-6）等水平升高，刺激神经胶质细胞和外周免疫细胞向损伤部位迁移，进一步促进神经炎症。细胞因子可通过多种机制直接导致神经元损伤和死亡。这些病理改变最终导致α-突触核蛋白聚集和多巴胺能神经元的丧失。含有3 （NLRP3）炎性体的nod样受体家族pyrin结构域促进IL-1β成熟和caspase-1驱动的神经毒性，已成为连接先天免疫激活与疾病进展的关键分子枢纽。临床前和临床研究支持靶向细胞因子信号传导的药物可以减少神经毒性和神经变性。在PD模型中，调节ephrin、环GMP-AMP合成酶刺激干扰素基因（cGAS-STING）、Hippo、受体相互作用蛋白激酶1 （RIPK1）、富亮氨酸重复激酶2 （LRRK2）和sirtuin通路等通路的治疗药物显示出抗炎作用。结合针对免疫和细胞因子途径的方法为PD的神经保护和疾病改变提供了有前途的策略。

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引用次数: 0