International immunopharmacology最新文献_第5页

Corrigendum to "Unravelling the role of Interleukin-12 in Neuroinflammatory mechanisms: Pathogenic pathways linking Neuroinflammation to neuropsychiatric disorders" [Int. Immunopharmacol. 156 (2025) 114654]. “揭示白细胞介素-12在神经炎症机制中的作用：将神经炎症与神经精神疾病联系起来的致病途径”的勘误表[j]。免疫药理，156 (2025)114654 [j]。

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2026-01-29 DOI: 10.1016/j.intimp.2026.116239

Rupali Chauhan, Maneesh Mohan, Ashi Mannan, Sushma Devi, Thakur Gurjeet Singh

引用次数: 0

Umbilical cord mesenchymal stem cell-derived exosomes delivered via a thermosensitive hydrogel ameliorate atopic dermatitis by mitigating keratinocyte mitochondrial damage through activating the Wnt/β-catenin pathway 通过热敏水凝胶递送的脐带间充质干细胞来源的外泌体通过激活Wnt/β-catenin通路减轻角质细胞线粒体损伤，改善特应性皮炎

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2026-01-29 DOI: 10.1016/j.intimp.2026.116297

Xueping Zhao , Yue Zhang , Yue Dong , Chunrui Shi , Yi Wu

Atopic dermatitis (AD) is a chronic inflammatory skin condition with a high global prevalence and a multifactorial etiology. Its development is primarily attributed to defective skin barrier function, immune dysregulation, and oxidative stress-induced impairments in mitochondrial activity within keratinocytes. While mesenchymal stem cell-derived exosomes show promise as a cell-free therapy, their limited efficacy via traditional systemic administration is a major challenge. To address this, we developed a thermosensitive poloxamer hydrogel-based system for the local delivery of human umbilical cord mesenchymal stem cell-derived exosomes(hUCMSC-exo).

Our in vitro studies demonstrated that hUCMSC-exo were effectively internalized by HaCaT keratinocytes, significantly mitigating inflammatory responses, abnormal differentiation, and mitochondrial damage caused by IL-4/TNF-α. Through RNA-seq and mechanistic validation, we found that hUCMSC-exo exert their protective effects by activating the Wnt/β-catenin signaling pathway, which repairs the skin barrier and reduces oxidative stress. We successfully prepared and characterized the hydrogel, confirming its excellent biocompatibility and sustained-release properties. In a MC903-induced AD mouse model, local administration of the hUCMSC-exo hydrogel significantly improved AD-like symptoms and lowered serum IgE and Th2 cytokine levels. Compared to the topical steroid mometasone furoate, our formulation demonstrated comparable efficacy with a superior safety profile. Our study is the first to combine a thermosensitive hydrogel with hUCMSC-exo for local delivery, providing a safe and effective new therapeutic strategy for AD.

特应性皮炎（AD）是一种慢性炎症性皮肤病，具有高全球患病率和多因素病因。其发展主要归因于皮肤屏障功能缺陷、免疫失调和氧化应激诱导的角化细胞线粒体活性损伤。虽然间充质干细胞衍生的外泌体作为一种无细胞治疗有希望，但其通过传统系统给药的有限疗效是主要挑战。为了解决这个问题，我们开发了一种基于热敏波洛沙姆水凝胶的系统，用于人脐带间充质干细胞衍生的外泌体（hUCMSC-exo）的局部递送。我们的体外研究表明，hUCMSC-exo被HaCaT角质形成细胞有效内化，显著减轻炎症反应、异常分化和IL-4/TNF-α引起的线粒体损伤。通过RNA-seq和机制验证，我们发现hUCMSC-exo通过激活Wnt/β-catenin信号通路发挥保护作用，修复皮肤屏障，减少氧化应激。我们成功制备并表征了该水凝胶，证实了其良好的生物相容性和缓释性能。在mc903诱导的AD小鼠模型中，局部给药hUCMSC-exo水凝胶可显著改善AD样症状，降低血清IgE和Th2细胞因子水平。与外用类固醇糠酸莫米松相比，我们的配方显示出相当的疗效和优越的安全性。我们的研究首次将热敏水凝胶与hUCMSC-exo结合局部给药，为阿尔茨海默病提供了一种安全有效的新治疗策略。

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引用次数: 0

The circRNA0001707/miR-203a-3p/TLR4 regulatory axis drives macrophage polarization in enthesitis of newly diagnosed ankylosing spondylitis circRNA0001707/miR-203a-3p/TLR4调控轴在新诊断的强直性脊柱炎中驱动巨噬细胞极化

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2026-01-29 DOI: 10.1016/j.intimp.2026.116262

Biqi Fu , Yao Zhou , Wei Long , Xinhua Yu , Qianbin Dai , Qing Luo , Rui Wu

Objectives

This study aimed to identify circular RNAs (circRNAs) associated enthesitis in patient with ankylosing spondylitis (AS) and to elucidate the underlying mechanism.

Methods

A multi-phase study was conducted. In the discovery phase, circRNA microarray analysis was performed on peripheral blood mononuclear cells (PBMCs) isolated from 3 AS patients and 3 healthy controls. Differentially expressed circRNAs were subsequently validated in two stages: an initial pilot verification followed by replication in an expanded cohort. The functional role of hsa_circ_0001707 in macrophage polarization was investigated in vitro using THP-1 cells.

Results

Microarray analysis and subsequent validation showed that AS patients exhibited significantly increased levels of hsa_circ_0001707 and reduced levels of hsa_circ_0075522 in PBMC compared to healthy controls. Stratified analysis revealed that hsa_circ_0001707 expression was significantly upregulated in AS patients with enthesitis compared to those without. Multivariate logistic regression analyses demonstrated that hsa_circ_0001707 was independently associated with enthesitis. In vitro, hsa_circ_0001707 overexpression promoted M1 polarization, increasing the secretion of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-23. Conversely, knockdown of hsa_circ_0001707 showed an opposite effect. Mechanistically, hsa_circ_0001707 acted as a molecular sponge for miR-203a-3p, thereby relieving repression of TLR4. Dual-luciferase assays confirmed direct interactions between miR-203a-3p and both hsa_circ_0001707 and TLR4.

Conclusion

This study identifies hsa_circ_0001707 as a novel biomarker for AS-associated enthesitis and suggests its role in promoting macrophage M1 polarization through the miR-203a-3p/TLR4 axis. These findings provide new insights into the pathogenesis of enthesitis and suggest potential therapeutic targets for AS.

目的：本研究旨在鉴定强直性脊柱炎（AS）患者中与疼痛相关的环状rna (circRNAs)，并阐明其潜在机制。方法采用多期研究方法。在发现阶段，对3名AS患者和3名健康对照者的外周血单个核细胞（PBMCs）进行了circRNA微阵列分析。差异表达的circrna随后分两个阶段进行验证：最初的试点验证，然后在扩大的队列中进行复制。利用THP-1细胞体外研究hsa_circ_0001707在巨噬细胞极化中的功能作用。结果微阵列分析和随后的验证表明，与健康对照相比，AS患者PBMC中hsa_circ_0075522水平显著升高，hsa_circ_0001707水平显著降低。分层分析显示，hsa_circ_0001707在AS患者中表达明显上调。多因素logistic回归分析显示hsa_circ_0001707与炎症独立相关。在体外，hsa_circ_0001707过表达促进M1极化，增加促炎细胞因子如TNF-α、IL-6、IL-23的分泌。相反，敲低hsa_circ_0001707则表现出相反的效果。机制上，hsa_circ_0001707作为miR-203a-3p的分子海绵，从而缓解TLR4的抑制。双荧光素酶测定证实了miR-203a-3p与hsa_circ_0001707和TLR4之间的直接相互作用。本研究发现hsa_circ_0001707是as相关炎症的一种新的生物标志物，并提示其通过miR-203a-3p/TLR4轴促进巨噬细胞M1极化的作用。这些发现为阑尾炎的发病机制提供了新的见解，并提出了AS的潜在治疗靶点。

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引用次数: 0

Unrevealing role of TLRs/NLRP receptors in halting Alzheimer's neuroinflammation: Current progress and existing therapies TLRs/NLRP受体在阻止阿尔茨海默病神经炎症中的作用尚不明确：目前的进展和现有的治疗方法

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2026-01-29 DOI: 10.1016/j.intimp.2026.116285

Shubham Upadhayay

Alzheimer's disease (AD) is a multifactorial condition caused by genetic, environmental, metabolic, and immunological factors. These pathological alterations trigger oxidative stress, excitotoxicity, and neuroinflammation, leading to the degeneration of cholinergic neurons in the brain. Several studies have found that persistent neuroinflammation plays a key role in AD progression; still, no curative medicine is available to halt the disease progression. For this reason, exploring new target-based therapy is necessary for AD treatment. The current review aims to understand the inflammatory processes associated with the activation of toll-like receptors (TLRs) and Inflammasomes (NLRPs) in AD progression. Additionally, the impact of TLR and NLRP inhibitors on improving the condition of AD patients. As multiple studies have confirmed, TLR/NLRP activation stimulates the infiltration of inflammatory cytokines, which enhances AD severity. Similarly, various studies have shown that inhibition of the TLR/NLRP signaling axis reduces oxidative stress, inflammatory cytokines, and apoptosis, thereby demonstrating a neuroprotective effect. This review examines the roles of TLR and NLRP pathways in AD progression, focusing on preclinical and clinical evidence supporting the neuroprotective benefits of targeting these pathways in AD. This review extensively examined the molecular mechanisms of TLR/NLRP inhibitors, highlighting recent discoveries that could be used to initiate clinical trials in patients with Alzheimer's.

阿尔茨海默病（AD）是一种由遗传、环境、代谢和免疫因素引起的多因素疾病。这些病理改变引发氧化应激、兴奋性毒性和神经炎症，导致大脑胆碱能神经元的退化。一些研究发现，持续的神经炎症在阿尔茨海默病的进展中起着关键作用；然而，目前还没有有效的药物来阻止这种疾病的发展。因此，探索新的靶向治疗方法对阿尔茨海默病的治疗是必要的。本综述旨在了解AD进展中与toll样受体（TLRs）和炎性小体（nlrp）激活相关的炎症过程。此外，TLR和NLRP抑制剂对改善AD患者病情的影响。多项研究证实，TLR/NLRP激活刺激炎症细胞因子的浸润，从而加重AD的严重程度。同样，各种研究表明，抑制TLR/NLRP信号轴可减少氧化应激、炎症细胞因子和细胞凋亡，从而显示出神经保护作用。本综述探讨了TLR和NLRP通路在AD进展中的作用，重点关注支持靶向这些通路治疗AD的神经保护作用的临床前和临床证据。本综述广泛研究了TLR/NLRP抑制剂的分子机制，重点介绍了可用于阿尔茨海默病患者临床试验的最新发现。

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引用次数: 0

Corrigendum to "Sodium nitroprusside induces apoptosis of H9C2 cardiac muscle cells in a c-Jun N-terminal kinase-dependent manner" [Int. Immunopharmacol. 1 (2001) 967-978]. “硝普钠以c-Jun n末端激酶依赖的方式诱导H9C2心肌细胞凋亡”的更正[j]。免疫药理，1(2001)967-978。

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2026-01-29 DOI: 10.1016/j.intimp.2026.116236

Han-Jung Chae, Hong-Seob So, Soo-Wan Chae, Ji-Sun Park, Myung-Sun Kim, Jay-Min Oh, Yeun-Tai Chung, Sei-Hoon Yang, Eun-Taik Jeong, Hyung-Min Kim, Rae-Kil Park, Hyung-Ryong Kim

引用次数: 0

Molecular and functional characterization of a novel Toll-like receptor 9-specific DNA aptamer with therapeutic potential 具有治疗潜力的新型toll样受体9特异性DNA适体的分子和功能表征

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2026-01-28 DOI: 10.1016/j.intimp.2025.116134

Mariya Farooq , Bilal Ahmad , Abdul Waheed Khan , Hongjoon Choi , Moon Suk Kim , Sangdun Choi

Toll-like receptor 9 (TLR9) plays a pivotal role in immune activation through recognition of DNA motifs, making it a compelling target for immunomodulatory therapies. We employed an integrative approach combining computational docking, biophysical characterization, and functional assays to identify and characterize DNA aptamers targeting TLR9. From an initial pool of candidates, ATA2 (agonistic TLR9 aptamer) emerged as a potent TLR9 agonist, demonstrating dose-dependent induction of TNF-α production in macrophages with specificity confirmed by TLR9 antagonist inhibition. ATA2 also enhanced macrophage migration and activated dendritic cells but showed limited effects on B cells. Surface plasmon resonance revealed a moderate affinity interaction between ATA2 and TLR9 (KD = 2.94 μM). Structural analyses via HPLC indicated the presence of discrete conformational states and high thermal and chemical stability of ATA2. Molecular dynamics simulations further highlighted ATA2’s superior conformational stability and flexibility in binding TLR9 compared to another aptamer, ATA1, suggesting a versatile mode of interaction. Collectively, these findings elucidate the molecular basis of ATA2’s TLR9 agonistic activity and underscore its therapeutic potential as a stable and specific immunomodulatory agent.

toll样受体9 （TLR9）通过识别DNA基序在免疫激活中起着关键作用，使其成为免疫调节治疗的一个引人注目的靶点。我们采用了结合计算对接、生物物理表征和功能分析的综合方法来鉴定和表征靶向TLR9的DNA适体。从最初的候选药物中，ATA2（激动型TLR9适配体）作为一种有效的TLR9激动剂出现，显示出剂量依赖性诱导巨噬细胞中TNF-α的产生，其特异性被TLR9拮抗剂抑制证实。ATA2还能增强巨噬细胞迁移和激活树突状细胞，但对B细胞的作用有限。表面等离子体共振显示ATA2与TLR9之间存在中等亲和作用（KD = 2.94 μM）。高效液相色谱分析表明，ATA2具有离散构象，具有较高的热稳定性和化学稳定性。分子动力学模拟进一步表明，与另一种适体ATA1相比，ATA2在结合TLR9方面具有优越的构象稳定性和灵活性，这表明ATA2具有多种相互作用模式。总的来说，这些发现阐明了ATA2的TLR9激动活性的分子基础，并强调了其作为稳定和特异性免疫调节剂的治疗潜力。

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引用次数: 0

Periplogenin alleviates osteoarthritis by suppressing NF-κB-mediated inflammation and apoptosis in chondrocytes 周plogenin通过抑制NF-κ b介导的炎症和软骨细胞凋亡来缓解骨关节炎

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2026-01-28 DOI: 10.1016/j.intimp.2026.116296

Zhonghua Zhou , Jinxu Li , Qiong Wang , Shengling Zhang , Yang Li , Shaobin Jin , Zhe Wang , Junfei Chen , Weiwei Yang , Tianyi Liu , Xinyu Wang , Cheng Qiu , Fan Zhang , Yawen Wang

Osteoarthritis (OA), a prevalent chronic degenerative disorder among middle-aged and elderly populations, is closely linked to inflammatory responses and subsequent extracellular matrix degradation. This condition causes significant patient suffering and imposes substantial socioeconomic burdens. Current therapies primarily focus on symptomatic relief (pain reduction and functional improvement), lacking targeted approaches addressing OA's underlying pathophysiological processes, while drug-related adverse effects remain problematic. Periplogenin, a natural compound with documented anti-inflammatory and anti-tumor properties, has garnered increasing attention; however, its potential role in OA pathogenesis is unexplored. This study first investigated periplogenin's effects on primary murine chondrocytes. Utilizing multiple experimental approaches, we demonstrated that periplogenin effectively attenuates TNF-α-induced inflammation, apoptosis, and consequent metabolic imbalance in chondrocytes. Furthermore, in a murine OA model, periplogenin administration conferred protective effects in vivo, mitigating OA progression. RNA sequencing analysis suggested suppression of the NF-κB signaling pathway as the potential mechanism, which was subsequently validated through both cellular and animal-level experiments. Collectively, our findings establish that periplogenin alleviates OA by inhibiting the NF-κB pathway, thereby reducing inflammation and chondrocyte apoptosis. This study identifies periplogenin as a promising candidate and provides a novel therapeutic strategy for targeted OA intervention.

骨关节炎（OA）是一种在中老年人群中普遍存在的慢性退行性疾病，与炎症反应和随后的细胞外基质降解密切相关。这种情况造成严重的患者痛苦，并造成巨大的社会经济负担。目前的治疗主要集中在症状缓解（疼痛减轻和功能改善），缺乏针对OA潜在病理生理过程的针对性方法，而药物相关的不良反应仍然存在问题。环草原素是一种具有抗炎和抗肿瘤特性的天然化合物，已引起越来越多的关注；然而，其在OA发病机制中的潜在作用尚不清楚。本研究首次探讨了周plogenin对小鼠原代软骨细胞的影响。利用多种实验方法，我们证明了周plogenin有效地减弱TNF-α-诱导的炎症、细胞凋亡和随之而来的软骨细胞代谢失衡。此外，在小鼠OA模型中，给药周plogenin在体内具有保护作用，减缓OA进展。RNA测序分析提示NF-κB信号通路的抑制是潜在的机制，随后通过细胞和动物水平的实验验证了这一点。综上所述，我们的研究结果表明，periplogenin通过抑制NF-κB途径减轻OA，从而减少炎症和软骨细胞凋亡。本研究确定了periplogenin作为一种有希望的候选药物，并为针对性OA干预提供了新的治疗策略。

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引用次数: 0

A novel mouse model of arthritis with enthesitis and heterotopic ossification 一种新型的关节炎小鼠模型，伴膝炎和异位骨化

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2026-01-28 DOI: 10.1016/j.intimp.2026.116273

Shanshan Kang , Shuqiong Zhang , Xingyi Wang , Jianyong Chen , Qinyi Cai , Lvlv Ye , Huilin Hu , Ling Lin , Peng Cao , Yang Sun , Fenli Shao

Ankylosing spondylitis (AS), enthesitis-related arthritis, and psoriatic arthritis are autoimmune bone diseases that share the characteristic pathological features of enthesitis and heterotopic ossification. This sets them apart from bone-eroding inflammatory joint diseases such as rheumatoid arthritis. The lack of effective animal models severely hampers the research on their pathogenesis and treatment. Here, we report that a peptide derived from amino acids 91–115 in the G1 domain of the chondroitin sulfate proteoglycan versican potently increases the incidence of type II collagen-induced arthritis in BALB/c mice from less than 20% to over 95%. This novel model, designated the C2V7 model, exhibited key features of these types of arthritis, including enthesitis, arthritis, and extensive ectopic ossification. The joint inflammation level in the C2V7 model was comparable to that in the curdlan-induced SKG model established in BALB/c-ZAP70^W163C mice. Moreover, co-administration of the versican peptide with type II collagen exacerbated arthritis in this SKG strain. Notably, the C2V7 model showed a significantly higher proportion of IL-17 A⁺CD3⁺ T cells than the SKG model. Therapeutic blockade of IL-17 A in the C2V7 model markedly reduced both inflammatory infiltration and ectopic bone formation. Owing to its rapid onset, robustness, cost-effectiveness, and defined antigenic trigger, the C2V7 model is well-suited for probing the pathogenesis of these types of arthritis. The pronounced IL-17 A response further establishes it as a rigorous platform for evaluating related therapeutics.

强直性脊柱炎（AS）、骨髓炎相关性关节炎和银屑病关节炎是具有骨髓炎和异位骨化特征的自身免疫性骨病。这将它们与侵蚀骨骼的炎症性关节疾病（如风湿性关节炎）区分开来。缺乏有效的动物模型严重阻碍了其发病机制和治疗的研究。在这里，我们报道了硫酸软骨素蛋白多糖的G1结构域的氨基酸91-115衍生的肽强有力地增加了BALB/c小鼠II型胶原诱导的关节炎的发病率，从不到20%增加到95%以上。这个新的模型，被命名为C2V7模型，显示了这些类型关节炎的主要特征，包括炎、关节炎和广泛的异位骨化。C2V7模型的关节炎症水平与BALB/c-ZAP70W163C小鼠curdlan诱导的SKG模型相当。此外，与II型胶原蛋白共同给药会加重这种SKG菌株的关节炎。值得注意的是，C2V7模型IL-17 a +CD3+ T细胞比例明显高于SKG模型。在C2V7模型中，治疗性阻断il - 17a可显著减少炎症浸润和异位骨形成。C2V7模型由于其快速起效、稳健性、成本效益和明确的抗原触发，非常适合用于探索这些类型关节炎的发病机制。明显的IL-17 A应答进一步确立了其作为评估相关治疗方法的严格平台。

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引用次数: 0

Treponema pallidum lipoprotein Tp0768 promotes H3K18 Lactylation modification to target PTK2 and enhance endothelial permeability 梅毒螺旋体脂蛋白Tp0768促进H3K18乳酸化修饰靶向PTK2，增强内皮通透性

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2026-01-28 DOI: 10.1016/j.intimp.2026.116248

Yue Li , Liena He , Ting Cao , Jiajun Chen , Rong He , Fei Zou , Yibao Hu , Jiayin Shi , Jirong Luo , Xiangping Zhou , Qian Cao , Feijun Zhao , Xiaopeng Lan , Shuangquan Liu

Syphilis is a systemic sexually transmitted disease, yet the mechanisms underlying the dissemination of its causative pathogen, Treponema pallidum (T.pallidum), within the host remain incompletely understood. Previous studies have shown that T.pallidum can damage vascular endothelial cells, thereby breaching the endothelial barrier to invade lymph nodes at the infection site. This facilitates its systemic dissemination via the bloodstream, leading to persistent infection across multiple vascular and tissue compartments. However, the precise molecular mechanisms governing this process remain elusive. In this study, we identified that the key pathogenic antigen Tp0768 of T.pallidum significantly enhances lactate secretion and global histone lactylation upon interaction with endothelial cells. Further investigations revealed a marked increase in histone H3 lysine 18 lactylation (H3K18la) in response to Tp0768 exposure. We demonstrated that elevated H3K18la enhances the accessibility of the PTK2 promoter, thereby directly upregulating PTK2 expression. This, in turn, leads to the downregulation of the tight junction proteins ZO-1 and occluding, ultimately increasing endothelial permeability. Collectively, our in vitro findings identify the H3K18la-PTK2 axis as a novel epigenetic-metabolic pathway through which Tp0768 may compromise endothelial barrier integrity. These results provide a potential molecular framework for understanding T.pallidum dissemination, highlighting a target for future investigation into therapeutic strategies against syphilitic vascular injury.

梅毒是一种全身性传播疾病，但其致病病原体梅毒螺旋体（T.pallidum）在宿主体内传播的机制尚不完全清楚。既往研究表明，苍白球绦虫可损伤血管内皮细胞，从而突破内皮屏障侵入感染部位的淋巴结。这有利于其通过血液系统传播，导致多个血管和组织室的持续感染。然而，控制这一过程的精确分子机制仍然难以捉摸。在这项研究中，我们发现T.pallidum的关键致病抗原Tp0768在与内皮细胞相互作用后显著增强乳酸分泌和全局组蛋白乳酸化。进一步的研究显示，暴露于Tp0768后，组蛋白H3赖氨酸18乳酸化（H3K18la）显著增加。我们证明了H3K18la的升高增强了PTK2启动子的可及性，从而直接上调了PTK2的表达。这反过来导致紧密连接蛋白ZO-1的下调和闭塞，最终增加内皮细胞的通透性。总之，我们的体外研究结果确定H3K18la-PTK2轴是一种新的表观遗传代谢途径，Tp0768可能通过该途径损害内皮屏障的完整性。这些结果为理解梅毒螺旋体传播提供了一个潜在的分子框架，为未来研究针对梅毒血管损伤的治疗策略提供了一个目标。

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引用次数: 0

RICTOR-mediated GPX4 downregulation regulates chondrocyte ferroptosis in osteoarthritis progression rictor介导的GPX4下调调控骨关节炎进展中的软骨细胞下垂

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology

Pub Date : 2026-01-27 DOI: 10.1016/j.intimp.2026.116274

Jingting Xu , Zehang Zheng , Fei Xin , Xiong Zhang , Liangcai Hou , Wenxin Zhong , Eryou Feng , Genchun Wang , Fengjing Guo

Osteoarthritis (OA) is the most common degenerative joint disease worldwide and the leading cause of chronic pain and mobility limitation in the elderly. Numerous studies have demonstrated that ferroptosis plays a crucial role in the development and progression of OA; however, the precise mechanisms remain to be elucidated. RICTOR (Rapamycin-Insensitive Companion of mTOR) is a key protein in cellular signal transduction and an essential component of mTORC2 (mammalian target of rapamycin complex 2), vital for the stability and activity of the complex. Our previous work established that RICTOR regulates autophagy to influence OA, yet whether RICTOR affects ferroptosis is unclear. This study aims to investigate the role of RICTOR in chondrocyte ferroptosis and to explore the RICTOR–ferroptosis axis as a potential therapeutic target.First, we observed elevated RICTOR expression in cartilage from OA patients and destabilization of the medial meniscus (DMM) mice, as well as in erastin-treated OA chondrocytes. RICTOR knockdown attenuated erastin-induced reduction of Col2a1 and promoted down-regulation of MMP13. Moreover, the RICTOR inhibitor JR-AB2 ameliorated cartilage degradation in the DMM-induced OA mouse model and mitigated the decline of GPX4 in vivo. Overall, our results indicate that RICTOR induces ferroptosis in OA by regulating GPX4 expression.

骨关节炎（OA）是世界范围内最常见的退行性关节疾病，也是老年人慢性疼痛和活动受限的主要原因。大量研究表明，铁下垂在OA的发生和发展中起着至关重要的作用；然而，确切的机制仍有待阐明。RICTOR （rapamycin - insensitive Companion of mTOR）是细胞信号转导的关键蛋白，也是mTORC2（哺乳动物雷帕霉素复合物2靶点）的重要组成部分，对该复合物的稳定性和活性至关重要。我们之前的研究证实，RICTOR通过调节自噬影响OA，但目前尚不清楚RICTOR是否影响铁下垂。本研究旨在探讨RICTOR在软骨细胞铁下垂中的作用，并探索RICTOR -铁下垂轴作为潜在的治疗靶点。首先，我们在OA患者的软骨和内侧半月板（DMM）小鼠的不稳定中观察到RICTOR的表达升高，以及在石膏蛋白处理的OA软骨细胞中。RICTOR的敲除减弱了erastin诱导的Col2a1的减少，并促进了MMP13的下调。此外，RICTOR抑制剂JR-AB2改善了dmm诱导的OA小鼠模型中的软骨降解，并减轻了GPX4在体内的下降。总之，我们的研究结果表明RICTOR通过调节GPX4的表达诱导OA中的铁下垂。

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引用次数: 0