Inflammation Research最新文献

{"title":"Multivariable genome-wide analysis elucidates the shared genetic architecture, immunosenescence features, and gut-origin therapeutic targets of ulcerative colitis-associated multisystem inflammation.","authors":"Shanneng Tang, Xin Yao, Shanshan Wang, Fanfan Zhu, Wenbin Zeng, Dongping Lai, Xiaobing Meng, Xinyue Zhang, Ziming Zhu, Tao Zhang, Ri'an Xu","doi":"10.1007/s00011-026-02257-y","DOIUrl":"https://doi.org/10.1007/s00011-026-02257-y","url":null,"abstract":"<p><strong>Background: </strong>Over 25% of patients with ulcerative colitis (UC) develop extraintestinal manifestations (EIMs), resulting in significant systemic morbidity. We define the shared genetic foundation of these manifestations as the UC-associated Multisystem Inflammatory Genetic Architecture (UC-MIGA). This study aims to identify shared genomic drivers and actionable immunosenescence therapeutic targets across the UC-EIM spectrum.</p><p><strong>Methods: </strong>We applied genomic structural equation modeling (SEM) to seven European-ancestry GWAS datasets (UC, deep vein thrombosis, ankylosing spondylitis, primary sclerosing cholangitis, pyoderma gangrenosum, interstitial lung disease, and erythema nodosum) to identify a shared latent genetic factor (F1). Post-SEM analyses included FUMA mapping, SuSIE/FINEMAP fine-mapping, FUSION/FOCUS transcriptome-wide studies, MAGMA enrichment, CELLECT deconvolution, LDSC partitioned heritability, and single-cell eQTL Mendelian randomization (MR). UC exhibited the highest standardized factor loading (0.9801) on F1, justifying its use as a representative proxy for UC-MIGA in downstream analyses. UC-telomere relationships were assessed via tissue-specific eQTL/sQTL enrichment across 49 GTEx tissues, spatial transcriptomics (gsMap), single-cell profiling (GSE214695, GSE163974), hdWGCNA, and colocalization analyses (eCAVIAR, fastENLOC).</p><p><strong>Results: </strong>SEM identified substantial genetic overlap (CFI = 1.0, SRMR = 0.17). Within the UC-MIGA framework, we identified 17,005 SNPs (P ≤ 1 × 10⁻2⁰⁰), 2,622 risk loci, and 152 high-confidence effector genes. Pathways implicated Th17/Treg imbalance and inflammasome signaling. Super-enhancer regions showed exceptional heritability enrichment (80.16%, fold = 4.79, p = 0.0007). MR identified 35 causal immune cell-gene associations. UC-telomere analyses revealed convergence in colon-specific DNA repair-mitochondrial energetics-telomere maintenance pathways, with B cells prioritized as the core cell type. Colocalization identified NKX2-3 and LINC01475 as high-confidence shared candidates. Embryonic intestinal enrichment supported the developmental origins of this systemic axis.</p><p><strong>Conclusion: </strong>UC-MIGA represents a genetically coherent architecture driven by super-enhancer-mediated epigenetic dysregulation, Th17/Treg imbalance, and immunosenescence features, including telomere dysfunction and B-cell exhaustion. The 'developmental vulnerability-environmental trigger' model explains the gut-origin inflammatory cascade underlying extraintestinal manifestations, with UC-telomere analysis providing a genomic foundation for systemic therapeutic strategies targeting the inflammation-aging nexus.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin improves osteogenic differentiation in a high-glucose environment by activating NRF2 to promote autophagy through the regulation of cross-talk between macrophages and bone marrow mesenchymal stem cells.","authors":"Jimei Zhang, Ling Zhu, Jianping Zhou, Qunying Yu, Guangyuan Yang, Chaoli Luo, Jianguo Meng, Kewang Mao, Jing Liu, Donggang Mou, Xuming Yang","doi":"10.1007/s00011-026-02267-w","DOIUrl":"https://doi.org/10.1007/s00011-026-02267-w","url":null,"abstract":"<p><strong>Background: </strong>Melatonin (MT) can regulate the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), but its effect on the osteogenic differentiation of BMSCs under high glucose (HG) conditions is unclear. Therefore, in this study, the effect of MT on the osteogenic differentiation of BMSCs under HG conditions was investigated.</p><p><strong>Methods: </strong>A mouse model of diabetic osteoporosis (DOP) was induced by the intraperitoneal injection of streptozotocin (STZ), and macrophages or BMSCs were cultured with 25 mM glucose to construct an in vitro cell model. Different doses of MT were used to treat the mice or cells. Genes and proteins were assessed through RT‒qPCR and Western blotting. ALP staining, alizarin red staining, and HE staining were used to assess the osteogenic differentiation of BMSCs and the advancement of DOP in mice.</p><p><strong>Results: </strong>Under normal conditions, MT could increase the expression of osteogenic differentiation-related proteins RUNX2, OCN, and OPN, and enhance differentiation and mineralization levels in BMSCs; however, MT failed to stimulate osteogenic differentiation in BMSCs under HG conditions. Furthermore, regardless of whether under HG conditions, in macrophages, MT suppressed the expression of the M1 phenotype markers CD86, iNOS, and CCR7 while increasing the expression of the M2 phenotype markers CD206, Arg1, and Ym1. Subsequent experiments revealed that under HG conditions, MT indirectly promoted the osteogenic differentiation of BMSCs through the enhancement of the M2 polarization of macrophages; however, MT was unable to directly influence the osteogenic differentiation of BMSCs. Additionally, in mouse experiments, administering high doses of MT effectively mitigated DOP by lowering blood glucose levels, ameliorating pathological damage in femoral tissues, and enhancing collagen accumulation and osteogenic markers expression. From a mechanistic standpoint, MT triggered autophagy by counteracting the suppressive effect of HG on NRF2, thus reducing HG-triggered ROS generation and inflammation in macrophage, promoting the M2 polarization of macrophages, and mitigating the suppressive effect of HG on the osteogenic differentiation of BMSCs.</p><p><strong>Conclusion: </strong>Our study indicates that under HG conditions, MT improves osteogenic differentiation by regulating the crosstalk between M2 macrophages and BMSCs.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of DAP12 in immune-related inflammatory diseases.","authors":"Jiaqi Lu, Lihao Shi, Guiyuan Jin, Yonghong Yang, Fengqin Zhu, Guangxi Zhou","doi":"10.1007/s00011-026-02256-z","DOIUrl":"https://doi.org/10.1007/s00011-026-02256-z","url":null,"abstract":"<p><p>DNAX-activated protein 12 (DAP12) is a key transmembrane adaptor protein containing an immunoreceptor tyrosine-based activation motif. DAP12 associates with a broad spectrum of cell surface receptors, including triggering receptors expressed on myeloid cells (TREM1 and TREM2), myeloid DAP12-associating lectin-1 (MDL-1), sialic acid-binding immunoglobulin-like lectin 15 (Siglec15), killer cell immunoglobulin-like receptor (KIR), NKG2C/CD94, and NKp44. They form a sophisticated signaling network that precisely regulates cellular activation, differentiation, and the balance between pro-inflammatory and anti-inflammatory responses. DAP12 is predominantly expressed in innate immune cells, including monocytes/macrophages, microglia, osteoclasts, and natural killer (NK) cells, where it governs key processes like cytokine production, cytoskeletal remodeling, and cytotoxic activity. Dysregulation of DAP12 signaling has been implicated in the pathogenesis of multiple immune-related inflammatory diseases, such as multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. In these conditions, DAP12 contributes to either protective or pathological outcomes depending on the receptor complex and microenvironment. This review provides a comprehensive overview of the structural characteristics of DAP12, its interaction with relevant receptors, and its specific functions in various cell types and immune-mediated inflammation.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Commentary: the TSP-1-CD47-integrin α4β1 axis-deciphering pathogenic mechanisms and therapeutic horizons in rheumatoid arthritis.","authors":"Jie Guo, Feng-Yi Mai, Xin-Yu Li, Yu Liu, Jing-Rong Liang, Xing-Long Li, Chen-Guang Li","doi":"10.1007/s00011-026-02233-6","DOIUrl":"https://doi.org/10.1007/s00011-026-02233-6","url":null,"abstract":"","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JAK/STAT inhibition reprograms T cell activation and metabolism in inflammatory arthritis patients.","authors":"Viviana Marzaioli, Aenea A I Brugman, Niamh O'Dowd, Achilleas Floudas, Aine Gorman, Carl Orr, Douglas J Veale, Ursula Fearon","doi":"10.1007/s00011-026-02242-5","DOIUrl":"https://doi.org/10.1007/s00011-026-02242-5","url":null,"abstract":"<p><strong>Objectives: </strong>Inflammatory arthritis (IA) is a group of autoimmune diseases characterised by joint inflammation and progressive damage, thus impairing the patient's quality of life. The JAK/STAT pathway inhibitor Tofacitinib has been successfully introduced into the clinic to treat patients with IA, however its direct effect on T cell responses is widely unknown. This study aims to assess the effect of Tofacitinib on T cell activation, polyfunctionality, proliferation and metabolism.</p><p><strong>Methods: </strong>The effect of Tofacitinib on T cells from peripheral blood, synovial fluid and synovial tissue was evaluated with multidimensional flow cytometric analysis. T cell proliferation was assessed by flow cytometry and T cell metabolism was examined by qPCR and Seahorse XF analyser. To investigate the effect of Tofacitinib on T cell polarisation, naïve T cells were differentiated into Th1, Th2 and Th17 with specific cytokine cocktails. Soluble mediators were evaluated by MSD multiplex analysis.</p><p><strong>Results: </strong>Tofacitinib significantly inhibited T helper cell activation as evidenced by a marked reduction in the frequency of PD-1/CD69/CD25-positive cells (p < 0.01). Reduced activation was consistent with impairment of pathogenic polyfunctionality of peripheral blood and synovial tissue-derived T cells. The impact of Tofacitinib on T cell plasticity was further substantiated by reduced T cell polarisation towards Th1 (p < 0.05), Th2 (p < 0.05), Th17 (p < 0.05) and a reduction in genes associated with T cell functions. The attenuation of pathogenic T cell responses is linked to metabolic adaptation, with Tofacitinib leading to a switch in metabolic capacity, mainly ascribed to the CD4^-CD8⁺ T cell compartment.</p><p><strong>Conclusions: </strong>Tofacitinib strongly alters T cell responses and potentially limits T cell pathogenicity by decreasing their activation, polyfunctionality, differentiation, and metabolic potential in both the circulation and the joints of patients with inflammatory arthritis.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucocorticoids combined with anticoagulation modulate the central NLRP3/NETosis inflammatory process in patients with severe cerebral venous thrombosis: a human mechanistic exploratory study.","authors":"Yu Li, Chao Ying, Xuemin Wang, Menglu Zhang, Shimin Hu, Yanning Cai, Jiangang Duan","doi":"10.1007/s00011-026-02260-3","DOIUrl":"https://doi.org/10.1007/s00011-026-02260-3","url":null,"abstract":"<p><strong>Objectives: </strong>Neutrophil-mediated neuroinflammation plays a crucial role in secondary brain injury following severe cerebral venous thrombosis (CVT). Although previous studies have reported that the combination of glucocorticoids (GCs) and anticoagulation is associated with improved clinical outcomes, its mechanism remains unknown. We hypothesized that the combination therapy may exert benefit by modulating neutrophil-driven inflammation.</p><p><strong>Methods: </strong>This study included a cohort of 50 patients diagnosed with severe CVT who were undergoing treatment with the combination therapy. We investigated the dynamic alterations in the NLRP3/NETosis inflammatory process by analyzing paired serum and cerebrospinal fluid (CSF) samples collected at baseline and 1 week post-treatment. Neurological function was systematically evaluated using the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS).</p><p><strong>Results: </strong>The combined therapy was associated with reduced CSF levels of key NLRP3/NETosis mediators, including NOD-like receptor family pyrin domain containing 3 (NLRP3), polymorphonuclear neutrophil elastase (PMN Elastase), myeloperoxidase (MPO), and citrullinated histone H3 (CitH3), while the corresponding serum levels were unchanged. Baseline CSF levels of NLRP3, PMN Elastase, and MPO strongly correlated with admission NIHSS and mRS. Early reductions in these central markers were associated with neurological improvement at discharge (ΔNIHSS). Moreover, patients with unfavorable outcomes (discharge mRS > 1) had significantly higher baseline NIHSS and CSF NLRP3 levels.</p><p><strong>Conclusions: </strong>The combined therapy may alleviate severe CVT by modulating the central NLRP3/NETosis inflammatory process.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulated cell death in sepsis: reframing NETosis within the spectrum of apoptosis and inflammatory lytic death.","authors":"Toshiaki Iba, Hideshi Okada, Isao Nagaoka, Ricard Ferrer, Jerrold H Levy","doi":"10.1007/s00011-026-02261-2","DOIUrl":"https://doi.org/10.1007/s00011-026-02261-2","url":null,"abstract":"<p><strong>Background: </strong>Sepsis is characterized by dysregulated inflammation leading to organ dysfunction. While immune activation and metabolic stress are central features, accumulating evidence suggests that regulated cell death programs actively influence inflammatory trajectories rather than serving as passive end-stage events. Apoptosis, pyroptosis, necroptosis, ferroptosis, and neutrophil extracellular trap (NET) formation have each been implicated in sepsis; however, their relative hierarchy, temporal dynamics, and compartment-specific relevance remain incompletely defined.</p><p><strong>Objective: </strong>To synthesize current evidence on regulated cell death pathways in sepsis and to propose a phase-specific and compartment-oriented framework that integrates apoptotic, inflammatory lytic, and NET-associated mechanisms within a unified inflammatory model.</p><p><strong>Methods: </strong>A narrative review of experimental, translational, and clinical studies examining apoptosis, pyroptosis, necroptosis, ferroptosis, PANoptosis, and NETosis in sepsis and related inflammatory states was conducted. Emphasis was placed on signaling dependency, inflammatory consequences, temporal phase distinctions, and cellular compartment heterogeneity.</p><p><strong>Results: </strong>Apoptosis remains the dominant leukocyte death program associated with late-phase immune depletion and immunosuppression. In contrast, inflammasome-mediated pyroptosis and RIPK1/RIPK3-dependent necroptosis amplify early hyperinflammatory responses by inducing membrane permeabilization and damage-associated molecular pattern release. Ferroptosis represents an emerging iron-dependent metabolic-inflammatory interface with potential organ-specific relevance, although clinical validation remains limited. NET formation, often interpreted as a distinct death program, is more appropriately understood as a context-dependent effector mechanism linking innate immunity to thromboinflammation rather than representing the predominant terminal fate of leukocytes in sepsis. Increasing evidence supports pathway crosstalk and PANoptotic integration, suggesting that regulated cell death programs function as overlapping inflammatory networks rather than isolated processes.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of neutrophils in the pathogenesis of abdominal aortic aneurysms.","authors":"Stephen A Addo, Kamila Wojnar-Lason, Amritha Sreekumar, Tamasi Roy, Douglas Sloan, Gábor Csányi","doi":"10.1007/s00011-026-02258-x","DOIUrl":"10.1007/s00011-026-02258-x","url":null,"abstract":"<p><strong>Background: </strong>Abdominal aortic aneurysm (AAA) is a progressive degenerative vascular disease characterized by structural weakening and pathological dilatation of the abdominal aortic wall. Currently, no effective pharmacological therapies are available, and treatment remains largely limited to surgical intervention. This underscores the urgent need to better understand the mechanisms driving disease development and progression. Among the cellular mediators implicated in AAA, neutrophils have emerged as key contributors to vascular inflammation and tissue destruction.</p><p><strong>Methods: </strong>We performed a comprehensive literature review of original research articles and relevant reviews addressing the role of neutrophils in AAA pathogenesis. Studies were identified through systematic searches of major databases, including PubMed and Google Scholar, using the keywords \"abdominal aortic aneurysm\", \"neutrophils\", \"vascular inflammation\", \"oxidative stress\", \"proteases\", and \"extracellular matrix degradation\". Both experimental and clinical studies were included to provide an integrated overview of current knowledge in the field.</p><p><strong>Results: </strong>Accumulating evidence indicates that neutrophils actively infiltrate the aortic wall during AAA development, where they release a diverse array of effector molecules, including reactive oxygen species, proteolytic enzymes, pro-inflammatory cytokines, chemotactic mediators, and granule proteins. Collectively, these mediators sustain chronic vascular inflammation, promote extracellular matrix degradation, and contribute to progressive structural weakening of the arterial wall. This review summarizes both established and emerging roles of neutrophils in AAA pathogenesis, with a particular focus on their contribution to vascular inflammation, thereby providing a conceptual framework for future diagnostic and therapeutic development.</p><p><strong>Conclusion: </strong>Neutrophils are central regulators of AAA pathogenesis through their multifaceted roles in vascular inflammation and extracellular matrix remodeling. Targeting neutrophil activation and downstream inflammatory pathways may represent a promising therapeutic strategy. A deeper mechanistic understanding of neutrophil-driven processes may facilitate the development of novel biomarkers and pharmacological approaches aimed at limiting AAA progression and preventing rupture.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ubiquitin ligase FBXW7 regulates epithelial pyroptosis in severe asthma.","authors":"Yixia Jiang, Tingfen Ji, Xuezhu Ren, Yangyang Gu, Xian Xu, Enguo Chen, Hequan Li","doi":"10.1007/s00011-026-02248-z","DOIUrl":"https://doi.org/10.1007/s00011-026-02248-z","url":null,"abstract":"<p><strong>Background: </strong>Severe asthma is characterized by persistent airway inflammation and epithelial injury. Pyroptosis, a Caspase-1-dependent inflammatory cell death pathway, has been implicated in airway inflammation. FBXW7, an E3 ubiquitin ligase involved in inflammatory regulation, may play a role in this process; however, its function in severe asthma remains unclear.</p><p><strong>Methods: </strong>Human microarray datasets from the Gene Expression Omnibus (GEO) were analyzed to identify differentially expressed genes and potential biomarkers using bioinformatics and machine learning approaches. Experimental validation was performed using murine asthma models, including ovalbumin (OVA)-induced and OVA/LPS-induced models. Airway epithelium-specific FBXW7 conditional knockout mice were generated to assess in vivo function. In vitro, murine lung epithelial (MLE12) cells with FBXW7 knockout or overexpression were used to evaluate pyroptosis and inflammatory responses following LPS/ATP stimulation. Cytokine levels, Caspase-1 expression, and signaling pathways were analyzed using ELISA, Western blotting, and immunofluorescence.</p><p><strong>Results: </strong>FBXW7 expression was significantly decreased in severe asthma compared with mild-to-moderate asthma, while Caspase-1 expression was increased. Machine learning analyses identified FBXW7 and Caspase-1 as potential biomarkers in severe asthma. In murine models, FBXW7 downregulation was more pronounced in severe asthma and was associated with increased inflammatory cell infiltration and cytokine production. FBXW7-deficient mice exhibited significantly elevated bronchoalveolar lavage fluid (BALF) inflammatory cell counts and increased IL-1β secretion compared with wild-type controls. In vitro experiments using MLE12 cell lines with FBXW7 overexpression, knockout, and wild-type backgrounds exhibited significant differences in Caspase-1 expression and altered secretion of inflammatory cytokines IL-18 and IL-1β under LPS/ATP-induced pyroptotic conditions, while pharmacological inhibition of Caspase-1 corrected aberrant cytokine secretion. However, mRNA levels of these cytokines remained stable, indicating that FBXW7 controls IL-18/IL-1β maturation/secretion via Caspase-1. Thus, the association among FBXW7, Caspase-1 and cGAS-STING was tested.</p><p><strong>Conclusions: </strong>FBXW7 suppresses airway epithelial pyroptosis and inflammation in severe asthma by regulating Caspase-1, potentially via the cGAS-STING pathway. These findings highlight FBXW7 as a potential biomarker for severe asthma.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic insights into natural product-driven modulation of NLRP3-inflammasome signalling in metabolic syndrome.","authors":"Prastuti Sahariah, Lunasmrita Saikia, Albert Bharali, Douglas Law, Saikat Sen, Lalita Ambigai Sivasamugham, Partha Pratim Dutta","doi":"10.1007/s00011-026-02253-2","DOIUrl":"https://doi.org/10.1007/s00011-026-02253-2","url":null,"abstract":"<p><strong>Introduction: </strong>Metabolic syndrome (MetS) comprises a cluster of interrelated metabolic abnormalities, including obesity, insulin resistance, dyslipidaemia and hypertension, mainly driven by chronic low-grade inflammation. Among innate immune pathways, the Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has emerged as a critical molecular link between metabolic stress and inflammatory signalling, promoting caspase-1 activation, interleukin (IL)-1β/IL-18 maturation and pyroptosis across metabolically active organs such as adipose tissue, liver and pancreas. Persistent NLRP3 activation, triggered by mitochondrial dysfunction, oxidative stress, ionic imbalance and impaired autophagy, contributes directly to insulin resistance, hepatic steatosis, β-cell dysfunction and cardiometabolic complications, highlighting natural products as promising multi-target modulators capable of attenuating NLRP3-driven metabolic inflammation.</p><p><strong>Methods: </strong>The literature search was conducted in PubMed and Scopus to identify recent studies investigating phytochemical-mediated modulation of NLRP3 inflammasome signalling in MetS from 2020 to December 2025. Eligible studies were screened for mechanistic relevance, with particular emphasis on NLRP3-centred pathways.</p><p><strong>Results and conclusion: </strong>The consolidated evidence demonstrates that diverse classes of natural products, including flavonoids, phenolic acids, terpenoids and other bioactive compounds, effectively attenuate NLRP3 activation by suppressing NF-κB-dependent priming, limiting mitochondrial ROS generation, stabilising lysosomal integrity, enhancing AMPK-SIRT signalling and promoting autophagy. Several plant extracts and complex formulations exhibit coordinated metabolic and anti-inflammatory benefits across adipose, hepatic, vascular, neural and renal models of MetS. In addition to summarising their regulatory effects on key inflammatory and metabolic pathways, the review also addresses available toxicity and safety data, thereby providing a more comprehensive perspective on their therapeutic relevance. Overall, this review presents an integrated synthesis of mechanistic and preclinical evidence highlighting natural products as multi-target modulators of NLRP3-mediated metabolic inflammation.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}