International immunopharmacology最新文献

{"title":"IL-6 blockade at the fracture site accelerates bone healing via inflammatory modulation of sensory nerve CGRP signaling","authors":"Lipeng Sun , Shouxiang Kuang , Chang Wang , Yang Li , Guodong Wang , Jianmin Sun , Fengge Zhou , Chenggui Zhang","doi":"10.1016/j.intimp.2026.116258","DOIUrl":"10.1016/j.intimp.2026.116258","url":null,"abstract":"<div><h3>Background</h3><div>Delayed fracture healing and nonunion are commonly associated with impaired callus remodeling and dysregulated interleukin-6 (IL-6) signaling; however, the precise role of IL-6 in fracture repair remains controversial. Calcitonin gene-related peptide (CGRP), a sensory neuropeptide expressed at fracture sites, has been shown to suppress IL-6 expression and promote bone regeneration. Nevertheless, whether IL-6 reciprocally regulates CGRP expression or function, thereby influencing fracture healing, remains unclear. This study aimed to determine whether local inhibition of IL-6 enhances CGRP expression and subsequently promotes femoral fracture healing.</div></div><div><h3>Methods</h3><div>Adult male C57BL/6 J mice were randomly assigned to four groups to receive different post-fracture treatments. On day 7 after femoral fracture, MR16–1 (a monoclonal anti–mouse IL-6 receptor antibody) was locally administered using a poloxamer 407 hydrogel delivery system, with or without the CGRP receptor antagonist BIBN4096. The poloxamer 407 hydrogel was characterized <em>In vitro</em> for encapsulation efficiency, drug-loading capacity, gelation time, swelling behavior, degradation at 37 °C, and drug-release profile.</div><div>Fracture healing was assessed at 4 weeks post-fracture by X-ray imaging, micro-computed tomography, and histological analysis. Immunofluorescence staining was performed to examine the expression of bone-related proteins, CGRP, and IL-6. Protein expression levels of IL-6, CGRP, Alkaline Phosphatase (ALP), Runt-related transcription factor 2 (Runx2), Osteocalcin (OCN), Nuclear Factor of Activated T cells Cytoplasmic 1 (NFATC1), Cathepsin K (CTSK), Sclerostin, Cluster of Differentiation 68 (CD68), Cluster of Differentiation 86 (CD86), Cluster of Differentiation 206 (CD206), Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1 beta (IL-1β), Inducible Nitric Oxide Synthase (iNOS), Interleukin-10 (IL-10), Transforming Growth Factor-beta (TGF-β), and Arginase-1 (Arg1) were analyzed by Western blotting.</div><div>Quantitative real-time PCR (qRT-PCR) was used to quantify mRNA expression of inflammatory cytokines, including the pro-inflammatory markers TNF-α, IL-1β, and iNOS, as well as the anti-inflammatory markers IL-10, TGF-β, and Arg1.</div></div><div><h3>Results</h3><div>X-ray assessment and healing scores showed that MR16–1 markedly accelerated fracture repair and the effects were largely reversed when combined with BIBN4096. μCT analysis further revealed that MR16–1 significantly increased callus volume and mineralization, while bone mass at distant sites, including the L5 vertebra and contralateral femur, remained unchanged. In contrast, its combination with BIBN4096 resulted in a reduction of callus volume and mineralization. Histological analysis showed that MR16–1 promoted collagen deposition, reduced cartilage content, and enhanced new bone formation, whereas combined treatment delayed bone maturation. At the ","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116258"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid metabolism: a molecular switch to control inflammation","authors":"Shilei Cheng ,&nbsp;Lanyun Xie ,&nbsp;Jianbo Wu ,&nbsp;Fan Yang","doi":"10.1016/j.intimp.2026.116294","DOIUrl":"10.1016/j.intimp.2026.116294","url":null,"abstract":"<div><div>Lipid metabolism is essential for cellular energy homeostasis, structural integrity, and signal transduction, and exerts a dual role in inflammation by acting as both an initiator and a regulator. This review comprehensively explores the molecular basis underlying the interactions among lipid metabolic pathways, lipid-derived mediators, and immune-inflammatory processes, while highlighting their profound significance in metabolic and chronic diseases. The core processes of lipid metabolism profoundly influence the initiation and resolution of inflammation through the regulation of oxidative stress, lipid mediators, and key signaling pathways. Furthermore, dysregulated lipid metabolism drives the formation of a chronic inflammatory microenvironment via inducing macrophage polarization, altering lipid droplet dynamics in immune cells, and disrupting adipokine secretion, thereby promoting the progression of metabolic diseases. In addition, this review summarizes intervention strategies targeting key lipid metabolic enzymes, signaling pathways, and epigenetic modifications, demonstrating their remarkable potential in anti-inflammatory and metabolic regulatory applications. As a molecular switch governing inflammation, lipid metabolism establishes a bidirectional regulatory network with inflammation through five core processes, namely lipid uptake and transport, lipogenesis, cholesterol metabolism, fatty acid β-oxidation, and lipolysis. Finally, this review emphasizes the pivotal role of technologies such as lipidomics and systems biology in deciphering the lipid-inflammation interplay, providing detailed insights for targeted anti-inflammatory interventions. Future research should prioritize multidisciplinary collaborations, focus on organ-specific regulatory targets, develop precision therapies, and advance dual-target combination therapies for metabolism and immunity. Moreover, multi-omics technologies should be leveraged to construct disease prediction models for individualized interventions, ultimately driving innovations in therapeutic strategies for chronic inflammation-driven diseases (see <span><span>Fig. 1</span></span>).</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116294"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The circRNA0001707/miR-203a-3p/TLR4 regulatory axis drives macrophage polarization in enthesitis of newly diagnosed ankylosing spondylitis","authors":"Biqi Fu ,&nbsp;Yao Zhou ,&nbsp;Wei Long ,&nbsp;Xinhua Yu ,&nbsp;Qianbin Dai ,&nbsp;Qing Luo ,&nbsp;Rui Wu","doi":"10.1016/j.intimp.2026.116262","DOIUrl":"10.1016/j.intimp.2026.116262","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aimed to identify circular RNAs (circRNAs) associated enthesitis in patient with ankylosing spondylitis (AS) and to elucidate the underlying mechanism.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116262"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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","authors":"Xueping Zhao ,&nbsp;Yue Zhang ,&nbsp;Yue Dong ,&nbsp;Chunrui Shi ,&nbsp;Yi Wu","doi":"10.1016/j.intimp.2026.116297","DOIUrl":"10.1016/j.intimp.2026.116297","url":null,"abstract":"<div><div>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).</div><div>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.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116297"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CircUBXN7 as a prognostic risk biomarker for ARDS modulates LPS-stimulated lung epithelial cell injury and the inflammatory response by competitively binding miR-622","authors":"Fan Xu ,&nbsp;Yifan Chen ,&nbsp;Yao Sun ,&nbsp;Huiying Zhao ,&nbsp;Lei Zhu","doi":"10.1016/j.intimp.2026.116292","DOIUrl":"10.1016/j.intimp.2026.116292","url":null,"abstract":"<div><div>Acute Respiratory Distress Syndrome (ARDS) is a condition involving severe lung injury and respiratory failure that results in high rates of mortality. Although uncontrolled inflammation and alveolar barrier disruption have been reported, the core molecular mechanisms involved in ARDS pathogenesis require clarification. Here, we recruited 35 ARDS patients and investigated the clinical significance of circUBXN7 in ARDS and its molecular mechanism in lipopolysaccharide (LPS)-stimulated acute lung injury. The results revealed that circUBXN7 and IL6ST expression levels were significantly elevated in the plasma of ARDS patients, while miR-622 was downregulated. Plasma circUBXN7 levels were higher and plasma miR-622 levels were lower in patients with severe ARDS, when compared with those with mild and moderate ARDS, whereas IL6ST levels did not significantly differ with disease severity. Furthermore, the non-survivor group exhibited significantly elevated levels of circUBXN7 and IL-1β, when compared with the survivor group. Receiver operating characteristic curve analysis indicated that circUBXN7 and IL-1β may serve as biomarkers for ARDS prognosis. Cellular experiments indicated a significant increase in circUBXN7 levels after LPS treatment. Inhibition of circUBXN7 mitigated the inflammation and cellular barrier damage induced by LPS, whereas its overexpression exacerbated these effects. Additionally, an miR-622 inhibitor or miR-622 mimics significantly reversed the effects of circUBXN7 siRNA or overexpression on cells. These findings demonstrated that circUBXN7 induced an inflammatory response and disrupted barrier integrity by competitively binding to miR-622, thereby impairing its regulatory function on target genes, which provided a novel approach for molecular typing and targeted therapy of ARDS.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116292"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myd88 and Sqstm1 as novel biomarkers for pyroptosis-driven immune checkpoint inhibitors-related myocarditis","authors":"Jian Yu ,&nbsp;Jiangtao Wang ,&nbsp;Ning Feng ,&nbsp;Cancan Wang ,&nbsp;Bohua Ma ,&nbsp;Yuanming Zhang","doi":"10.1016/j.intimp.2026.116336","DOIUrl":"10.1016/j.intimp.2026.116336","url":null,"abstract":"<div><h3>Background</h3><div>Among the adverse effects of immunotherapy in cancer patients, immune checkpoint inhibitors (ICIs)-induced myocarditis is the most severe. Pyroptosis is involved in the pathogenesis of various cardiovascular diseases; however, its relationship with ICIs-related myocarditis remains unclear.</div></div><div><h3>Objective</h3><div>The purpose of this research is to characterize the critical genes mediating pyroptosis in myocarditis related to ICIs, with the goal of informing clinical practice.</div></div><div><h3>Materials and methods</h3><div>Based on single-cell RNA sequencing and bulk RNA sequencing, this study identified pyroptosis key genes in ICIs-related myocarditis and validated their expression levels and diagnostic value. Single-cell level validation of key genes, trajectory analysis and cellular interactions were also performed. Finally, ICIs-related myocarditis mouse model was established to verify the expression levels of key genes and pyroptosis-related markers.</div></div><div><h3>Results</h3><div>Integration of multiple bioinformatic analyses identified two pyroptosis key genes in ICIs-related myocarditis: Myd88 and Sqstm1. The expression levels of pyroptosis key genes were significantly higher in the ICIs-related myocarditis group compared to the normal group (<em>P</em> &lt; 0.05 or <em>P</em> &lt; 0.01), and both demonstrated high diagnostic value. Trajectory analysis and cell interaction analysis revealed the interaction strength and relative expression patterns between these two pyroptosis key genes. In the ICIs-related myocarditis mouse model, cardiac injury markers were significantly elevated (<em>P</em> &lt; 0.001 or <em>P</em> &lt; 0.0001), while cardiac function indices were significantly decreased (<em>P</em> &lt; 0.01) compared to the normal group. Quantitative real time polymerase chain reaction and western blot analyses revealed that the expression levels of Myd88 and Sqstm1 were significantly upregulated in the myocarditis group compared to the normal group, at both the mRNA and protein expression levels (<em>P</em> &lt; 0.05 or <em>P</em> &lt; 0.01 or <em>P</em> &lt; 0.0001). Compared with the normal group, the expression levels of pyroptosis-related markers Caspase-1, IL-1β, and GSDMD-N were significantly elevated in the myocarditis group (<em>P</em> &lt; 0.05 or <em>P</em> &lt; 0.01).</div></div><div><h3>Conclusion</h3><div>Pyroptosis is involved in the pathogenesis of ICIs-related myocarditis, and Myd88 and Sqstm1 may serve as potential biomarkers for future clinical application.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116336"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosome-mediated radioprotection: multimodal mechanisms and therapeutic innovations","authors":"Rongfan Xu ,&nbsp;Yi Qiu ,&nbsp;Teng Xu ,&nbsp;Chenfei Wang ,&nbsp;Guijuan Feng","doi":"10.1016/j.intimp.2026.116263","DOIUrl":"10.1016/j.intimp.2026.116263","url":null,"abstract":"<div><div>Although there are already treatments for radiation damage, including stem cell transplantation, standard cancer treatments that may impair the growth and development of healthy cells have a number of disadvantages, such as severe immunological rejection and numerous side effects. With their cell-free properties, exosomes have demonstrated significant therapeutic potential as a novel treatment approach for radiation-induced tissue damage. Because of their effective tissue penetration, targeting specificity, and the protective nature of their natural phospholipid bilayer structure, exosomes have the potential to become a drug-targeted delivery system for radiation therapy and a biomarker for radiation damage in addition to influencing the damaged tissues by controlling DNA damage, oxidative stress, immune response, and inflammatory response to lessen the negative effects of radiation damage on patients. Exosomes are anticipated to play a major role in the prevention and treatment of radiation damage, leading to new advancements in cancer treatment and nuclear disaster response, provided that technological advancements and related challenges, such as the diversity of contents, the lack of quality control, and safety issues, are resolved.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116263"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146051373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated bioinformatics and machine learning deciphering IL12RB2 and FYN as key immune biomarkers in brucellosis","authors":"Jinhua Yuan ,&nbsp;Yuxia Ding ,&nbsp;Jiaqing Zhao ,&nbsp;Lina Ma ,&nbsp;Xiangchun Ding","doi":"10.1016/j.intimp.2026.116268","DOIUrl":"10.1016/j.intimp.2026.116268","url":null,"abstract":"<div><h3>Background</h3><div>Brucellosis remains a major zoonotic threat worldwide, and early diagnosis is challenging due to nonspecific symptoms and complex immune evasion strategies. Immune-related biomarkers may provide novel diagnostic and therapeutic clues, yet they remain poorly characterized in brucellosis.</div></div><div><h3>Objective</h3><div>This study aimed to identify and validate immune-related biomarkers linked to brucellosis, determine their diagnostic utility, and examine their potential as candidates for further therapeutic investigation, alongside analyses of immune pathways and immune-cell infiltration patterns.</div></div><div><h3>Methods</h3><div>Transcriptome data from patients with brucellosis and healthy controls (GSE69597) were integrated with 1793 immune-related genes from ImmPort. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) identified candidate genes, which were further screened using three machine-learning algorithms (LASSO, random forest, and SVM-RFE). Immune pathway enrichment, immune-cell infiltration (CIBERSORT), and molecular docking with first-line drugs (doxycycline and rifampicin) were performed. qRT-PCR was used to validate hub gene expression in PBMCs from clinical cohorts.</div></div><div><h3>Results</h3><div>RFX5, FYN, IL12RB2, and LGR6 demonstrated high diagnostic value in ROC analysis. Enrichment analyses indicated that brucellosis-related IRGs are primarily involved in immune recognition, activation of immune responses, and regulation of inflammatory processes, and were significantly correlated with levels of various immune cell infiltrates. Exploratory molecular docking suggested potential binding propensities between standard anti-Brucella antibiotics (doxycycline and rifampicin) and the candidate host proteins. Clinical sample validation further confirmed significant expression changes of IL12RB2 and FYN in patients with brucellosis.</div></div><div><h3>Conclusion</h3><div>IL12RB2 and FYN serve as robust immune biomarkers for human brucellosis and may represent therapeutic candidates linked to Th1 signaling and T-cell activation. This integrative computational-experimental framework provides a foundation for precision diagnosis and immunomodulatory strategies in brucellosis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116268"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unrevealing role of TLRs/NLRP receptors in halting Alzheimer's neuroinflammation: Current progress and existing therapies","authors":"Shubham Upadhayay","doi":"10.1016/j.intimp.2026.116285","DOIUrl":"10.1016/j.intimp.2026.116285","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116285"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GDF11 protects against sepsis-induced myocardial injury and cardiac dysfunction by targeting the Nrf2 signaling pathway-dependent ferroptosis","authors":"Haibo Zhang ,&nbsp;Yutian Mi ,&nbsp;Chunling Kong ,&nbsp;Xiaotian Gao ,&nbsp;Chennian Xu ,&nbsp;Zhiming Song ,&nbsp;Fangfang Wang","doi":"10.1016/j.intimp.2026.116318","DOIUrl":"10.1016/j.intimp.2026.116318","url":null,"abstract":"<div><div>Sepsis, a systemic inflammatory response syndrome caused by infection, can lead to life-threatening multi-organ dysfunction. Among its complications, sepsis-induced cardiomyopathy (SIC) represents one of the most severe conditions with poor prognosis. Currently, pharmacological options for clinical management of SIC are limited and often yield suboptimal outcomes, necessitating the urgent exploration of novel therapeutic strategies. Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β (TGF-β) superfamily, possesses a variety of biological properties. Importantly, recent studies have highlighted the crucial protective role of GDF11 in various cardiovascular diseases. However, to date, there have been no reports on the alterations and effects of GDF11 in SIC. In this study, we initially observed a significant downregulation of GDF11 expression in both myocardium and serum of C57BL/6 J mice treated with lipopolysaccharide (LPS). Subsequently, through endogenous overexpression of GDF11 or exogenous supplementation with recombinant GDF11, we found that GDF11 mitigated lipid peroxidation-dependent ferroptosis by inhibiting iron accumulation and ameliorating mitochondrial dysfunction, thereby alleviating cardiac dysfunction and myocardial injury in septic mice. Additionally, our cellular experiments demonstrated that GDF11 could also inhibit LPS-induced ferroptosis in neonatal mouse cardiomyocytes. Nevertheless, blocking the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway using ML385 in vivo or Nrf2 siRNA in vitro abrogated the above protective effects of GDF11 against SIC. Taken together, our findings show that GDF11 may alleviate SIC by inhibiting cardiomyocyte ferroptosis through activation of the Nrf2 signaling pathway, suggesting GDF11 as a potential therapeutic target for treating patients with sepsis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116318"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}