Frontiers in Immunology最新文献

{"title":"A high eosinophil proportion increases the risk of skin-related adverse events induced by apalutamide in patients with prostate cancer.","authors":"Yoshihiko Tasaki, Taku Naiki, Yoshihisa Mimura, Yosuke Sugiyama, Misato Tomita, Toshiharu Morikawa, Takashi Nagai, Rei Unno, Toshiki Etani, Shuzo Hamamoto, Yukihiro Umemoto, Takahiro Yasui, Yoko Furukawa-Hibi","doi":"10.3389/fimmu.2025.1681734","DOIUrl":"10.3389/fimmu.2025.1681734","url":null,"abstract":"<p><strong>Background: </strong>Skin-related adverse events (AEs) induced by apalutamide occur frequently in Japanese patients with prostate cancer. However, biomarkers for predicting these skin-related AEs have not yet been identified. Therefore, this study investigated whether the proportion of eosinophils could serve as a predictive biomarker for skin-related AEs in Japanese patients with prostate cancer treated with apalutamide.</p><p><strong>Methods: </strong>A total of 109 patients were enrolled in this study. Among them, 79 patients with prostate cancer who received apalutamide were categorized into two groups: the skin AE group (n = 45) and the non-skin AE group (n = 34), based on whether they experienced skin-related AEs of any grade. The eosinophil proportions in baseline samples collected before treatment were then analyzed.</p><p><strong>Results: </strong>The baseline eosinophil proportion was significantly higher in the skin AE group compared with the non-skin AE group (<i>P</i> < 0.05). The optimal cut-off value of the eosinophil proportion for predicting skin-related AEs of any grade was 1.8% (area under the receiver operating characteristic curve [AUC] = 0.768). In multivariate analysis, an eosinophil proportion ≥1.8% was identified as an independent factor associated with skin-related AEs of any grade (odds ratio, 13.3; 95% confidence interval, 3.82-46.4; <i>P</i> < 0.05).</p><p><strong>Conclusion: </strong>The baseline eosinophil proportion may serve as a predictive biomarker for skin-related AEs of any grade in Japanese patients with prostate cancer treated with apalutamide.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1681734"},"PeriodicalIF":5.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12536007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Administration of statins is correlated with favourable prognosis in lung cancer patients receiving immune checkpoint inhibitors.","authors":"Jingjing Yang, Jie Lin, Huaijuan Guo, Wenjuan Wu, Jiaxin Wang, Jingxian Mao, Wenbin Fan, Yang Lu, Ying Wang, Xuebing Yan","doi":"10.3389/fimmu.2025.1638677","DOIUrl":"10.3389/fimmu.2025.1638677","url":null,"abstract":"<p><strong>Objective: </strong>Statins are commonly used for cardiovascular diseases and recent studies have supported their anti-cancer role in numerous human malignancies. This study aims to investigate their prognostic impact in lung cancer patients receiving immune checkpoint inhibitors (ICIs).</p><p><strong>Methods: </strong>A retrospective analysis was performed based on the clinical data from 235 lung cancer patients who received ICI therapy between 2019 and 2024 in three hospitals. The correlation of statin use with overall survival (OS) or progression-free survival (PFS) was analyzed. Then, a comprehensive bioinformatics analysis was used to identify prognostic target genes of statins and investigate their correlation with immune infiltration, followed by validation in an independent cohort and cellular experiments.</p><p><strong>Results: </strong>In the whole cohort, 80 patients (34.0%) received statins. The statin users had a significantly better OS and PFS than the non-statin users. Statin use was an independent favorable prognostic factor for ICI-treated lung cancer patients. Transcription factor RAR-related orphan receptor alpha (RORA) was identified as a favorable prognostic target gene of statins. RORA was found to be downregulated in lung cancer tissues and correlated with infiltration of some immune cells. In the validation cohort, RORA expression was positively correlated with CD8⁺ T cell infiltration in lung cancer tissues, and improved prognosis in lung cancer patients receiving ICIs. Atorvastatin treatment increased RORA expression and RORA knockdown partly antagonized the inhibitory role of Atorvastatin on the malignant characteristics of lung cancer cells <i>in vitro</i>.</p><p><strong>Conclusion: </strong>Statin use was significantly correlated with improved prognosis in lung cancer patients receiving ICIs. Statins may enhance ICI efficacy partly through RORA. Due to study limitations, the actual role of statins and their target genes in anti-cancer immunity needs further investigations.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1638677"},"PeriodicalIF":5.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12535986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic value of neutrophil to lymphocyte ratio in patients with esophagus cancer receiving neoadjuvant therapy: a systematic review and meta-analysis.","authors":"Longwei Ma, Jiaxing He, Ping Li, Long Ma, He Wang, Yanchao Deng","doi":"10.3389/fimmu.2025.1615962","DOIUrl":"10.3389/fimmu.2025.1615962","url":null,"abstract":"<p><strong>Background: </strong>Growing research reveals a relation of the neutrophil-to-lymphocyte ratio (NLR) to clinical outcomes of the esophageal cancer (EC) population undergoing neoadjuvant therapy. However, current findings remain inconclusive and somewhat controversial.</p><p><strong>Methods: </strong>PubMed, Embase, Web of Science, and the Cochrane Library were thoroughly retrieved until April 22, 2025 to collect studies on the link of NLR to prognosis among the EC population following neoadjuvant therapy. Eligible studies were selected as per predefined eligibility criteria. The primary outcomes encompassed overall survival (OS), recurrence-free survival (RFS), and pathological complete response (pCR). Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were pooled for prognostic significance assessment along with subgroup analyses. The evidence was graded via the GRADE method.</p><p><strong>Results: </strong>11 cohort studies involving 2,220 patients were included in the analysis. The results demonstrated a notable link of risen NLR to less favorable OS (HR = 1.99, 95% CI: 1.43-2.76, P < 0.0001; I² = 88%), shorter RFS (HR = 2.69, 95% CI: 1.77-4.08, P < 0.00001; I² = 47%), and lower pCR rates (OR = 0.67, 95% CI: 0.47-0.94, P = 0.02; I² = 62%). Subgroup analyses by sample size, follow-up length, age, treatment modality, and NLR cut-off value consistently demonstrated a strong correlation between elevated NLR and shortened RFS across all subgroups. Notably, in patients receiving neoadjuvant chemoradiotherapy (NCRT), the link of increased NLR to OS and RFS appeared more robust compared to those receiving neoadjuvant chemotherapy (NCT) alone.</p><p><strong>Conclusion: </strong>In patients with EC undergoing neoadjuvant therapy, a higher pre-treatment NLR is significantly linked to worse OS and RFS, as well as a lower likelihood of achieving pCR. Therefore, NLR can be a valuable prognostic biomarker in this patient population, potentially aiding clinicians in risk stratification and treatment decision-making.</p><p><strong>Systematic review registration: </strong>https://www.crd.york.ac.uk/prospero/, identifier CRD42024610088.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1615962"},"PeriodicalIF":5.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12535995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroinflammation: targeting microglia for neuroprotection and repair after spinal cord injury.","authors":"Roberta Ramos Cavalcanti, Fernanda Martins Almeida, Ana Maria Blanco Martinez, Camila Marques Freria","doi":"10.3389/fimmu.2025.1670650","DOIUrl":"10.3389/fimmu.2025.1670650","url":null,"abstract":"<p><p>Neuroinflammation is a tightly regulated process essential for central nervous system (CNS) homeostasis, debris clearance, and defense against pathogens. Microglia, the resident immune cells of the CNS, are central to this response, supporting plasticity and repair under normal conditions. Following spinal cord injury (SCI), however, this response becomes amplified and dysregulated. Early microglial activation can be protective, but prolonged activation drives the release of pro-inflammatory and cytotoxic mediators that exacerbate secondary injury and hinder repair. Microglia also engage in complex crosstalk with astrocytes, oligodendrocytes, neurons, and infiltrating immune cells, orchestrating both protective and damaging processes. This dual and dynamic nature underscores their importance as both targets and modulators in SCI therapies. This review aims to examine the roles of microglia in SCI, summarizes SCI pathology, the specific roles of microglia and macrophages, and outlines translational efforts to modulate their activation, while also highlighting the barriers to clinical application. Evidence from preclinical studies and emerging therapeutic strategies, including pharmacological, cell-based, and exosome-based interventions, demonstrates the potential to reduce harmful inflammation, promote neuroprotection, and support functional recovery. Despite these advances, clinical translation remains limited, constrained by the heterogeneity of microglial responses, narrow therapeutic windows, and patient-specific variability. These challenges often lead to modest or inconsistent clinical outcomes. Future strategies will require precision, multi-targeted approaches that integrate microglial modulation with the preservation of the blood-brain barrier (BBB) and the regulation of peripheral immune infiltration. Harnessing the regenerative potential of microglia, guided by biomarker-based patient stratification and a deeper understanding of their dynamic roles, offers the most promising path toward meaningful recovery after SCI.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1670650"},"PeriodicalIF":5.9,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12535890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Case Report: Mevalonate kinase deficiency: an underdiagnosed cause of ischemic stroke-characterization of a novel genetic variant.","authors":"Lyna-Nour Hamidi, Jack Christopher Drda, Meriem Belhocine, Hannah-Laure Elfassy, Stéphanie Ducharme-Bénard, Maxime Chayer-Lanthier, Bushra Sultana, Sylvain Lanthier","doi":"10.3389/fimmu.2025.1651819","DOIUrl":"10.3389/fimmu.2025.1651819","url":null,"abstract":"<p><p>Mevalonate kinase deficiency (MKD) is an inherited autoinflammatory syndrome resulting from impaired isoprenoid biosynthesis due to biallelic mevalonate kinase (<i>MVK</i>) mutations. This metabolic defect leads to dysregulated innate immunity, particularly excessive interleukin-1β release. While typically presenting in childhood with periodic fevers, expanding evidence links MKD to heterogeneous adult phenotypes with immune-mediated end-organ damage. We report an adult male presenting with leg pain and finger cyanosis followed by acute ischemic stroke, macular rash, and lymphadenopathies. He exhibited classical markers of innate immune activation, including persistent elevation of C-reactive protein. Genetic testing identified compound heterozygosity for the known <i>MVK</i> pathogenic variant c.1129G>A (V377I) and a novel missense variant, c.1049A>C (Q350P). Structural modeling of Q350P revealed disruption of the GHMP kinase domain, predicted to destabilize mevalonate kinase conformation and impair its function. The measurement of mevalonate kinase activity in lymphocytes was at 55% (normal >60%). Interleukin-1β blockade with canakinumab was initiated, and the blood markers of inflammation normalized, further supporting a central role for innate immune dysregulation. This case highlights a novel <i>MVK</i> missense variant (Q350P) with subnormal mevalonate kinase activity. The patient's compound heterozygous state with partially preserved mevalonate kinase activity may explain the attenuated systemic features and the delayed clinical onset. Remarkably, ischemic stroke was part of the initial presentation, suggesting that mevalonate kinase deficiency can manifest primarily through thrombo-inflammatory complications in adulthood, even in the absence of recurrent febrile episodes. This expands the phenotypic spectrum of MKD and underscores the need to consider adult-onset autoinflammatory syndromes in the differential diagnosis of cryptogenic ischemic strokes with markers of systemic inflammation. It also supports the utility of cytokine-targeted therapies in such contexts.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1651819"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12531262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming resistance to PD-1 and CTLA-4 blockade mechanisms and therapeutic strategies.","authors":"Xiaodong Wang, Jing He, Gouping Ding, Yixuan Tang, Qianqian Wang","doi":"10.3389/fimmu.2025.1688699","DOIUrl":"10.3389/fimmu.2025.1688699","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 have achieved groundbreaking clinical success in multiple cancers; however, a large proportion of patients experience primary or acquired resistance. This review synthesizes the complex mechanisms underlying resistance to PD-1/CTLA-4 blockade and surveys emerging strategies to overcome them. Resistance arises from multifaceted interactions among tumor-intrinsic alterations (e.g., epigenetic silencing of antigen presentation machinery via EZH2/PRC2, oncogenic pathway-driven upregulation of PD-L1, genetic loss of IFNγ pathway components such as JAK1/2 or B2M), immune cell dysfunction (e.g., T cell exhaustion with co-expression of inhibitory receptors including PD-1, TIM-3, and LAG-3, metabolic and epigenetic T cell reprogramming, suppressive regulatory T cells), and stromal microenvironmental factors (e.g., hypoxia-inducible factors, immunosuppressive metabolites like IDO-mediated kynurenine, tumor-associated macrophages and MDSCs, aberrant angiogenesis). To counteract these diverse resistance mechanisms, a spectrum of novel therapeutic approaches is under development. Mechanism-targeted monotherapies include agents that restore tumor immunogenicity (e.g., epigenetic modulators to upregulate MHC expression), reinvigorate exhausted T cells (e.g., blockade of alternative checkpoints such as LAG-3), and reprogram the suppressive tumor microenvironment (e.g., inhibitors of immunosuppressive myeloid pathways). In parallel, rational combination therapies are being explored, pairing ICIs with chemotherapy (to induce immunogenic cell death and enhance T cell infiltration), molecularly targeted drugs (to disrupt oncogenic immune-evasion signals), or immune modulators (e.g., IL-2 or IL-18 variants to boost effector T cell function). Furthermore, emerging predictive biomarkers and machine learning-based signatures (e.g., soluble checkpoint levels, inflammatory indices, tumor transcriptomic scores) are improving the ability to anticipate ICI resistance and guide personalized escalation of therapy. Overall, this synthesis highlights the recent insights into resistance biology and promising avenues to extend the durable benefits of PD-1/CTLA-4 blockade to a larger proportion of patients.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1688699"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12531160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HMGB1-dependent signaling in the regulation of mast cell activity during inflammation.","authors":"Justyna Agier, Sylwia Różalska, Magdalena Wiktorska, Elżbieta Kozłowska, Magdalena Jurczak, Monika Nowak, Paulina Żelechowska","doi":"10.3389/fimmu.2025.1643427","DOIUrl":"10.3389/fimmu.2025.1643427","url":null,"abstract":"<p><strong>Background: </strong>Damaged cells release endogenous molecules known as alarmins into the extracellular space following cellular injury. Alarmins may function as adjuvants by interacting with PRRs to indicate danger and initiate a localized sterile inflammatory response, which facilitates tissue regeneration. A pivotal alarmin is HMGB1, which is internalized through the RAGE to notify adjacent cells about compromised homeostasis. Given the significant role of mast cells (MCs) in inflammatory processes and the critical nature of alarmins as indicators of danger, this study evaluates the hypothesis that MCs serve as essential sensors of cellular injury. The present study investigates whether HMGB1 affects the expression levels of specific PRRs in mature MCs. These receptors include Dectin-1 and Dectin-2, TLR2, NOD1, and RIG-I. Furthermore, this study aims to determine whether HMGB1 modulates the inflammatory response of these cells, which encompasses the production of cytokines, chemokines, ROS, histamine, and cysLTs, as well as their migration patterns. Moreover, the research aims to investigate the role of RAGE and the involvement of signaling molecules in the activation of MCs mediated by HMGB1.</p><p><strong>Methods: </strong>All experiments were carried out using <i>in vivo</i> differentiated, mature tissue MCs freshly isolated from the rat peritoneal cavity. The potency of HMGB1 to provoke MC PRR expression, generation, and/or release of a panel of mediators and migration was investigated.</p><p><strong>Results: </strong>HMGB1 markedly enhances the expression of Dectin-1, RIG-I, and NOD1, while simultaneously stimulating MCs to produce CCL3, IL-1β, TNF, cysLTs, histamine, and ROS. This protein acts as a potent chemoattractant for MCs. The administration of RAGE antagonist to MCs significantly attenuated the generation of mediators and the migratory response, thereby confirming the receptor's involvement in the response of HMGB1-treated cells. Intracellular signaling in MCs activated by HMGB1 involves ERK1/2, p38 MAPK, PI3K, NF-κB, and, in part, JAK2.</p><p><strong>Conclusions: </strong>The data robustly support the notion that HMGB1 is an important endogenous alarmin that promotes and enhances MC activity in inflammatory processes. These insights highlight HMGB1 as a potential therapeutic target for regulating MC-driven inflammatory disorders, which encompass allergy, autoimmune diseases, and chronic conditions.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1643427"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12531030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating immune landscape and immune signatures in spontaneous HIV controllers.","authors":"Adriana Navas, Jéssica C Dos Santos, Bram van Cranenbroek, Nadira Vadaq, Albert L Groenendijk, Wilhelm A J W Vos, Marc J T Blaauw, Louise van Eekeren, Casper Rokx, Janneke E Stalenhoef, Marvin A H Berrevoets, Mihai G Netea, Leo A B Joosten, Andre J A M van der Ven, Hans J P M Koenen","doi":"10.3389/fimmu.2025.1642482","DOIUrl":"10.3389/fimmu.2025.1642482","url":null,"abstract":"<p><p>A subset of people with HIV, termed HIV controllers (HIC), maintain low viral loads without antiretroviral therapy. To identify the immune cell architecture of HIV control, we profiled peripheral blood from 54 HIC (including 21 elite controllers, EC) and 1,044 non-controllers (non-HIC) in the 2000HIV study (NCT03994835) using high-dimensional cytometry and confounder-adjusted regression analysis. Both HIC and EC exhibited distinct innate immune profiles compared to non-HIC, marked by reduced frequencies of CCR5⁺ NKT and TCRγδ1⁺ cells. EC further showed increased neutrophils and TCRγδ2⁺ cells, and reduced eosinophils. Unsupervised clustering revealed elevated CD11c and CD1c expression on TCRγδ2⁺ cells in EC, correlating with IFNγ production, suggesting a proinflammatory γδ T cell program unique to EC. Adaptive immune profiling showed shared features between HIC and EC: increased CD4⁺ naïve and Th1/17 cells, reduced Th17 and Tfh cells, and higher CD8⁺ TEMRA and Tc1/17 cells with reduced memory subsets. Both groups showed increased naïve and immature B cells and decreased switched memory and plasma cells. EC uniquely exhibited increased IgA⁺ memory B cells -a feature consistent with enhanced mucosal immunity- and decreased IgG⁺ memory B cells and CD307d expression, suggestive of mucosal imprinting and reduced exhaustion. Comparison of HIC and EC revealed divergent CCR5 and CXCR4 expression: EC had higher frequencies of CCR5⁺ and CXCR4⁺ CD4⁺ and CD8⁺ T cells. These elevations correlated with circulating chemokines, notably MIF for CXCR4, implying protective ligand occupancy. HIC instead showed overall lower co-receptor expression and ligand correlations. In conclusion, while HIC and EC share a core immune phenotype linked to viral control, EC-specific features- γδ T cell activation, IgA⁺ memory enrichment, and chemokine receptor regulation-may underlie more robust or distinct immune control mechanisms. This profiling resource offers new avenues for HIV cure-focused strategies.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1642482"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12532132/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Caspase-1 in osteoarthritis: multi-omics insights into the effects of VX-765 on human chondrocyte function and phenotype.","authors":"Jian Mei, Nicole Schäfer, Penghui Wei, Zhiheng Kong, Shushan Li, Patrick Pann, Marianne Ehrnsperger, Brian Johnstone, Eva Matalova, Susanne Grässel","doi":"10.3389/fimmu.2025.1677801","DOIUrl":"10.3389/fimmu.2025.1677801","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA) progression involves chronic inflammation, chondrocyte senescence, and extracellular matrix (ECM) degradation affecting all synovial joint tissues. To date, no regenerative OA drugs have been approved. Caspase-1, a core effector of the inflammasome, may contribute to OA via both canonical inflammatory and non-canonical functions, but its therapeutic value remains unclear.</p><p><strong>Methods: </strong>We combined transcriptomic, proteomic, functional, and Mendelian randomization (MR) approaches. Using GSE168505 data, we analyzed CASP1, CARD gene family members (CARD16/17/18/8), and OA-related genes in OA- versus non-OA chondrocytes. We established an <i>in vitro</i> OA model by treating human chondrocytes with TNF-α ± VX-765 and assessed Caspase-1 activity, cell metabolism, and MMP secretion. We further conducted LC-MS/MS proteomic profiling, molecular docking, and MR analysis to identify molecular mechanisms and causal links.</p><p><strong>Results: </strong>CASP1 and inflammatory/ECM-degrading genes (e.g., IL1B, MMP13) were upregulated in OA chondrocytes, whereas SOX9 was downregulated. CASP1 gene expression correlated positive with genes involved in senescence, inflammation, oxidative stress and ECM remodeling. Inhibitor VX-765 significantly inhibited Caspase-1 activity, reduced senescence, and enhanced migration in non-OA- and OA chondrocytes, with donor-dependent effects in OA chondrocytes. It also suppressed MMP13 secretion in OA chondrocytes. Integrated transcriptomic and proteomic analysis showed that VX-765 reprogrammed OA-activated signaling, significantly downregulating pathways related to senescence, inflammation, complement activation, and ECM organization, while upregulating interferon-α/γ responses. Moreover, in silico performed molecular docking analyses suggest that caspase-1 may directly bind MMP13, CTSD, ABL1, MRPS11, POLR21, SMAD2 and SOX9. MR analysis supported a causal link between increased CARD17/18/8 gene expression and reduced OA risk; several CASP1 SNPs (e.g., rs61751523) showed negative OA associations, suggesting a protective role.</p><p><strong>Conclusions: </strong>This study demonstrates that Caspase-1 contributes to OA pathogenesis through both canonical and non-canonical mechanisms, and that VX-765 can alleviate chondrocyte dysfunction. The combined evidence supports VX-765 as a potential disease-modifying target for OA therapy. However, further investigation is warranted to clarify Caspase-1's physiological roles, including possible off-target effects of its inhibitors, in cartilage and other joint tissues and the clinical relevance of inter-individual variability, with genomic variants (e.g., rs61751523) as one potential contributor, for therapeutic application.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1677801"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12532135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"What is the relationship between microorganisms in the human body and upper tract urothelial carcinoma?","authors":"Xin Pei, Minghui Yu, Yijia Wang, Shi Zong, Fei Qi, Kaichen Wang","doi":"10.3389/fimmu.2025.1636782","DOIUrl":"10.3389/fimmu.2025.1636782","url":null,"abstract":"<p><p>Upper Tract Urothelial Carcinoma (UTUC) is a highly malignant tumor originating from the epithelium of the upper urinary tract with diverse pathogenesis, but currently available diagnostic and therapeutic strategies have some limitations. In recent years, human microbiome-related studies have provided new ideas for the exploration of the pathogenesis and treatment of UTUC. In this paper, we review the research progress of human microbiome related to UTUC. Focusing on the urinary microbiome, the role of the microbiome in the pathogenesis of UTUC is investigated through the mechanisms of chronic inflammation, genotoxic damage, immune microenvironmental imbalance and metabolic reprogramming. The pyelo-ureteric microbiome of healthy populations is dominated by commensal bacteria such as Lactobacillus and Streptococcus, whereas pathogenic bacteria such as Escherichia coli (E. coli) and Enterococcus faecalis are significantly enriched in patients with UTUC, which results in the development of DNA damage, inflammatory response and immunosuppression. In addition, microbiome metabolites (e.g., short-chain fatty acids, tryptophan derivatives) can influence tumor progression by modulating immune checkpoints (e.g., PD-1/PD-L1, B7-H4) and metabolic pathways (e.g., Warburg effect). In diagnostic and therapeutic applications, urinary microbial markers (e.g., E. coli-specific gene clusters) can be combined with circulating tumor DNA (ctDNA) assays to improve diagnostic sensitivity and specificity, and indices of intestinal flora diversity (e.g., Simpson's index) are significantly correlated with the response rate to chemotherapy and prognostic course. In the future, we need to overcome the challenges of difficult sample acquisition, unknown causal mechanisms, and etiologic heterogeneity interference, and promote multi-omics joint modeling as well as cross-ethnicity and geographic research, and bidirectional regulation mechanisms of the gut-kidney axis in order to develop more accurate UTUC diagnosis and treatment strategies.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1636782"},"PeriodicalIF":5.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12531182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145328852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}