Inflammation Research最新文献

{"title":"ADAM19: biological characteristics and implications in disease pathology and clinical applications.","authors":"Yichun Hu, Xuehan Wang, Yang Qu, Deyuan Li, Shujin Li, Dejun Hu, Hanmeng Liu, Yongkang Wu","doi":"10.1007/s00011-026-02340-4","DOIUrl":"10.1007/s00011-026-02340-4","url":null,"abstract":"<p><strong>Purpose of review: </strong>This article critically examines ADAM19-mediated inflammatory remodeling within five distinct subtypes of solid tumors prone to inflammation, employing non-neoplastic inflammatory states strictly as a comparative reference. As a transmembrane protease belonging to the ADAM family, ADAM19 undergoes maturation through plasmin-dependent cleavage, with its expression tightly regulated by both transcriptional and epigenetic controls. Although dysregulated ADAM19 levels are evident in various inflammatory lesions and malignancies, its context-specific dual biological roles necessitate a systematic synthesis.</p><p><strong>Recent findings: </strong>ADAM19 modulates signal transduction pathways by processing pro-inflammatory cytokines. While it generally expedites progression in the majority of solid tumors, it paradoxically suppresses tumor growth in prostate cancer and specific osteosarcoma subsets; this functional dichotomy is orchestrated by intricate non-coding RNA networks and interconnected signaling cascades. Preclinical evidence indicates that ADAM19 holds promise as both a biomarker and a therapeutic target, yet robust clinical validation remains lacking. Consequently, this review delineates ADAM19 structural characteristics, contrasts its tissue-specific regulatory mechanisms across different malignancies, and integrates exosomal and immune-related signaling axes to reconcile contradictory research findings. We highlight pivotal translational challenges, notably tissue-dependent functional heterogeneity and the scarcity of selective ADAM19 inhibitors, while proposing targeted research directions to advance future precision oncology strategies centered on ADAM19.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069067","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":"Interferon-mediated regulation of the neurovascular unit in diabetic retinopathy.","authors":"Haoyang Yu, Liqing Xie, Wenjian Lin","doi":"10.1007/s00011-026-02369-5","DOIUrl":"10.1007/s00011-026-02369-5","url":null,"abstract":"<p><strong>Background: </strong>Diabetic retinopathy (DR) is an important complication of diabetes mellitus (DM) and one of the leading causes of preventable blindness. The onset and progression of DR involve multiple molecular mechanisms, among which inflammatory responses and immune dysregulation play important roles. Interferons (IFNs), as key mediators of the immune system, exhibit complex regulatory effects during the progression of DR. Type I IFNs generally exert protective effects by suppressing inflammation, inhibiting pathological angiogenesis, and maintaining endothelial barrier integrity; however, certain IFN-α subtypes may also induce the production of pro-inflammatory factors. In contrast, type II IFN can promote inflammatory responses, induce apoptosis, and facilitate aberrant angiogenesis, while under specific conditions it may also inhibit abnormal cell proliferation. IFNs regulate multiple cell types within the retinal neurovascular unit (NVU) through diverse signaling pathways, thereby affecting blood-retinal barrier (BRB) homeostasis, neurodegeneration, and neovascularization.</p><p><strong>Conclusions: </strong>IFNs exert both protective and detrimental effects in DR. Elucidating the differential regulatory roles of IFNs across various cell types and their functional changes at different stages of disease progression may facilitate precise modulation of the retinal microenvironment and provide a theoretical basis for personalized treatment of DR.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069172","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":"MLN4924 suppresses kidney renal clear cell carcinoma progression through coordinated inhibition of Cullin1 neddylation and PSMB10-associated NF-κB inflammatory signaling.","authors":"Dequan Liu, Jing Su, Feng Chen, Lei Liu, Xiaochen Qi, Qifei Wang, Guangzhen Wu, Huijun Sun, Zhanmeng Zhu, Xiangyu Che","doi":"10.1007/s00011-026-02363-x","DOIUrl":"10.1007/s00011-026-02363-x","url":null,"abstract":"<p><strong>Background: </strong>Kidney renal clear cell carcinoma (KIRC) is characterized by malignant progression, inflammatory signaling, and therapeutic resistance. This study investigated whether MLN4924, a selective NEDD8-activating enzyme inhibitor, suppresses KIRC progression through coordinated regulation of Cullin1 neddylation, PSMB10 expression, and NF-κB signaling.</p><p><strong>Methods: </strong>KIRC cells were treated with MLN4924, followed by Western blotting, transcriptomic sequencing, pathway enrichment analysis, PSMB10 knockdown, and NF-κB pathway assessment. Complementary PSMB10 overexpression rescue experiments, together with colony formation and Transwell assays, were performed to test whether restoration of PSMB10 could reverse MLN4924-induced NF-κB inhibition and associated malignant phenotypes. A 786-O nude mouse xenograft model was used to evaluate the in vivo antitumor effects, tolerability, histological alterations, and molecular mechanisms of MLN4924.</p><p><strong>Results: </strong>MLN4924 inhibited renal cancer cell growth and markedly reduced Cullin1-NEDD8 and PSMB10 protein levels. Transcriptomic analysis revealed extensive remodeling of lipid and sterol metabolism, extracellular matrix organization, cytokine and inflammatory signaling, growth factor-related pathways, and DNA replication-associated processes. MLN4924 treatment and PSMB10 knockdown both suppressed p65 phosphorylation, while combined intervention further inhibited phosphorylation of p65, IKKα/β, and IκBα. Conversely, PSMB10 overexpression partially restored p65 phosphorylation in MLN4924-treated ACHN and 786-O cells and significantly recovered colony formation, migration, and invasion. In vivo, MLN4924 significantly reduced tumor volume and weight, with an inhibition rate exceeding 30% and acceptable tolerability. Treated tumors showed increased apoptosis and necrosis, decreased Cullin-NEDD8, PSMB10, phospho-p65, TNF-α, IL-6, EMT/ECM remodeling markers, and proliferation-related proteins, and enhanced apoptotic signaling.</p><p><strong>Conclusion: </strong>MLN4924 suppresses KIRC progression through inhibition of neddylation and attenuation of PSMB10-associated IKK/IκB/p65 NF-κB inflammatory signaling.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069140","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":"Multi-omics characterization of Yao syndrome identifies three pathophysiological axes and disease-specific divergence from Blau syndrome.","authors":"Jingyuan Zhang, Xin Huang, Guishan Liu, Xuan Zhou, Chunlei Li, Min Shen","doi":"10.1007/s00011-026-02355-x","DOIUrl":"10.1007/s00011-026-02355-x","url":null,"abstract":"<p><strong>Objectives: </strong>Yao syndrome (YAOS, OMIM #617321) is a NOD2-associated systemic autoinflammatory disease whose molecular pathophysiology remains uncharacterized, with no patient-level omics data reported. We performed the first integrated multi-omics characterization of YAOS.</p><p><strong>Methods: </strong>Peripheral blood mononuclear cell (PBMC) transcriptomics (RNA-seq; DESeq2), quantitative plasma proteomics (7352 proteins; DIA-MS/DIA-NN), and untargeted metabolomics (1051 MS2-annotated metabolites) were performed on six YAOS patients carrying NOD2 variants across all four functional domains (CARD, NBD, NBD-LRR junction, LRR) and healthy controls (HC). Analyses included transcription factor (TF) activity inference, CIBERSORTx immune deconvolution, co-expression network analysis, drug target mapping, and parallel transcriptomic comparison with Blau syndrome (n = 3).</p><p><strong>Results: </strong>Despite >100-fold C-reactive protein (CRP) variation (0.31-36.34 mg/L) and regimens ranging from no treatment to quadruple immunosuppression, 600 differentially expressed genes (DEGs) were identified (|log₂FC|> 1, false discovery rate [FDR] < 0.05). NF-κB was the dominant transcriptional program (TF activity P= 0.008). Cross-platform integration identified three convergent pathophysiological axes: NF-κB/pyroptosis-driven innate immune activation (7/7 effectors directionally concordant between transcriptome and proteome), metabolic reprogramming linked to acylcarnitine accumulation (log₂FC = +0.75 to +1.42, nominal P<0.05), and gut-immune axis disruption. This inflammatory architecture persisted across all regimens examined. Drug target mapping indicated that none of the six currently targeted gene products reached transcriptomic significance, whereas three untargeted nodes-RELA, gasdermin D (GSDMD), and tyrosine kinase 2 (TYK2)-were among the most significantly upregulated (all FDR < 0.001). Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) emerged as the top co-expression hub. Parallel comparison with Blau syndrome (BS, OMIM #186580) revealed qualitatively distinct effector programs-pyroptosis execution with M1 polarization in YAOS versus inflammasome activation without pyroptosis in BS.</p><p><strong>Conclusions: </strong>This first patient-level multi-omics characterization of a NOD2-associated autoinflammatory disease identifies a convergent, YAOS-specific inflammatory architecture and a treatment-target mismatch, generating mechanistic and therapeutic hypotheses that require validation in adequately powered cohorts.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038367","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":"Loss of C3 and CD14 reduces region-specific neuroinflammation in a murine polytrauma model.","authors":"Florian Olde Heuvel, Marica Pagliarini, Fan Sun, Ludmila Lupu, Zongren Zhao, Likun Cui, Jin Zhang, Rebecca Halbgebauer, Marco Mannes, Tobias Maria Boeckers, Bernd Knöll, Egil Lien, Tom Eirik Mollnes, Markus Huber-Lang, Francesco Roselli","doi":"10.1007/s00011-026-02367-7","DOIUrl":"10.1007/s00011-026-02367-7","url":null,"abstract":"<p><strong>Background: </strong>TBI-polytrauma (P-TBI) is associated with acute neurological deterioration, delirium, and poor prognosis. Systemic inflammatory mediators are thought to amplify the cerebral neuroimmune response, particularly microglial activation, with detrimental consequences.</p><p><strong>Methods: </strong>We investigated the roles of complement factor C3 and the TLR co-receptor CD14 in a murine polytrauma model combining mild TBI with femur fracture, blunt thorax trauma, and resuscitated haemorrhagic shock, using mice lacking C3, CD14, or both.</p><p><strong>Results: </strong>P-TBI induced a rapid, brain-wide increase in inflammatory cytokines with region-specific patterns. TNF and CCL2 mRNA were upregulated in microglia in the cortex, hippocampus, and striatum, and this response was abolished in C3^-/-CD14^-/- mice. Analysis of single knockouts showed that cytokine induction depended on CD14 in the cortex, C3 in the striatum, and both in the hippocampus. In contrast, neither C3 nor CD14 influenced cytokine induction at the cortical lesion site. Interestingly, neuronal cFOS responses showed an inverse regional C3/CD14 dependency compared with inflammatory cytokine responses, with a cortical C3 dependency and striatal CD14 dependency.</p><p><strong>Conclusion: </strong>Thus, C3 and CD14 are dispensable for the acute response at the injury site but differentially regulate microglial and neuronal activation in remote brain regions, representing potential targets to reduce P-TBI-associated encephalopathy.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038428","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":"UBE2L6 drives ulcerative colitis progression by promoting BIRC2 degradation and activating non-canonical NF-κB signalling.","authors":"Zhiyi Cheng, Chao Yu, Guiyuan Liu, Bingbing Su, Longfei Dai, Xiaojun Zhao, Chuanjiang Huang","doi":"10.1007/s00011-026-02364-w","DOIUrl":"10.1007/s00011-026-02364-w","url":null,"abstract":"<p><strong>Background: </strong>Post-translational modifications (PTMs) have been increasingly recognized as important regulators of ulcerative colitis (UC) progression. However, the specific PTM type and key enzyme driving UC remain largely undefined.</p><p><strong>Methods: </strong>Genes related to 21 PTM types were intersected with differentially expressed genes (DEGs) in UC and screened using 113 machine learning algorithms. Functional validation was performed in lipopolysaccharide (LPS) stimulated NCM460 and HT29 cells. Immunoprecipitation-mass spectrometry (IP-MS) combined with data-independent acquisition (DIA) proteomics was used to identify downstream targets and pathways.</p><p><strong>Results: </strong>UBE2L6 was identified as a key PTM-related gene in UC. In LPS stimulated intestinal epithelial cells, UBE2L6 downregulation was found to markedly attenuate inflammatory responses and barrier dysfunction. BIRC2 was identified as a downstream target of UBE2L6, and the non-canonical NF-κB pathway was determined to be the principal signalling axis involved. Mechanistically, UBE2L6 was shown to facilitate the transfer of K48 linked ubiquitin chains to BIRC2, thereby promoting BIRC2 autoubiquitination and degradation. Consequently, NIK degradation was impaired, leading to NIK accumulation, enhanced p100 processing to p52, and activation of non-canonical NF-κB signalling.</p><p><strong>Conclusions: </strong>UBE2L6 promotes UC progression through BIRC2 degradation-dependent activation of the non-canonical NF-κB pathway and may serve as a potential therapeutic target in UC.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038356","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":"Retraction Note: N‑Pyrazoloyl and N‑thiopheneacetyl hydrazone of isatin exhibited potent anti‑inflammatory and anti‑nociceptive properties through suppression of NF‑κB, MAPK and oxidative stress signaling in animal models of inflammation.","authors":"Sara Zeeshan, Muhammad Naveed, Adnan Khan, Ayesha Atiq, Maryam Arif, Muhammad Naeem Ahmed, Yeong Shik Kim, Salman Khan","doi":"10.1007/s00011-026-02382-8","DOIUrl":"https://doi.org/10.1007/s00011-026-02382-8","url":null,"abstract":"","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030361","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 IL-4/IL-4R/STAT6 signaling axis regulates macrophage efferocytosis in osteoarthritis.","authors":"Haiping Zhang, Ziliang Yu, Dagong Gao, Fei Xia, Yixuan Li, Jiafeng He, Wei Liu, Xiaozhong Zhou","doi":"10.1007/s00011-026-02376-6","DOIUrl":"10.1007/s00011-026-02376-6","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA) is a leading cause of global disability, with no available therapies that effectively halt disease progression. Impairment of macrophage efferocytosis, the clearance of apoptotic cells, is implicated in OA pathogenesis, yet the underlying mechanisms remain poorly understood. This study investigates the role of the anti‑inflammatory cytokine interleukin‑4 (IL‑4) in regulating macrophage efferocytosis during OA.</p><p><strong>Methods: </strong>Public single‑cell and bulk RNA‑seq datasets were analyzed to identify key cell populations and pathways. An OA model was established by destabilizing the medial meniscus (DMM) in C57BL/6 mice, followed by intra‑articular delivery of AAV‑IL‑4. Joint integrity was evaluated using micro‑CT, histology (H&E, Safranin O-Fast Green), immunohistochemistry, and immunofluorescence. Cytokine levels were measured by ELISA. Macrophage proliferation, polarization, phagocytosis, and efferocytosis were assessed by flow cytometry and fluorescence imaging. Molecular mechanisms were examined via Western blot, transcriptomic sequencing, and STAT6 knockdown. Pharmacological inhibition of AKT was used to assess the contribution of AKT signaling.</p><p><strong>Results: </strong>IL‑4 expression was reduced in OA tissues, and low macrophage efferocytosis correlated with OA severity. In mice, IL‑4 supplementation attenuated cartilage degradation, bone loss, and synovial inflammation. In vitro, IL‑4 promoted macrophage proliferation, M2 polarization, IL‑10 secretion, and enhanced both phagocytosis and efferocytosis in both RAW264.7 cells and primary bone marrow-derived macrophages (BMMs). Mechanistically, IL‑4 increased phosphorylated STAT6 (pSTAT6) in macrophages, and STAT6 knockdown abolished the IL‑4‑induced functional enhancements. Transcriptomics and Western blotting revealed that IL-4/STAT6 signaling activates the PI3K/AKT pathway. Pharmacological inhibition of AKT reversed IL-4-enhanced efferocytosis and phagocytosis.</p><p><strong>Conclusion: </strong>The IL-4/IL-4R/STAT6 axis sustains macrophage function by activating the PI3K/AKT pathway, thereby boosting efferocytosis and mitigating OA progression. These findings provide a novel immunomodulatory framework for OA therapy, highlighting macrophage-directed strategies as a potential therapeutic avenue.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008388","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":"Targeting USP47 reprograms macrophage polarization to ameliorate septic peritonitis and promote cutaneous wound healing.","authors":"Hu Lei, Li Yang, Hanzhang Xu, Yingying Wang, Yingli Wu","doi":"10.1007/s00011-026-02380-w","DOIUrl":"10.1007/s00011-026-02380-w","url":null,"abstract":"<p><strong>Objective: </strong>Dysregulation of M1/M2 macrophage polarization drives sepsis and impaired wound healing. Deubiquitinases (DUBs) are promisingdrug targets, but the role of ubiquitin-specific protease 47 (USP47) in macrophage plasticity remains unclear. This study investigated the regulatoryfunction of USP47 in macrophage polarization and its therapeutic potential for inflammatory disorders.</p><p><strong>Methods: </strong>In vitro, human THP-1 and mouse bonemarrow-derived macrophages were polarized, with USP47 modulated via genetic manipulation or the inhibitor P22077. In vivo, LPS-induced septicperitonitis and cutaneous wound models were used to evaluate the effects of Usp47 deficiency or P22077 treatment. Mechanistically, protein interactionand ubiquitination assays were performed to verify the USP47-YAP axis and downstream signaling.</p><p><strong>Results: </strong>USP47 was upregulated in M1 macrophagesand downregulated in M2 macrophages. USP47 inhibition skewed macrophages toward the M2 phenotype. In vivo , Usp47 knockout or P22077 treatmentimproved survival in septic mice, reduced systemic inflammation, and accelerated wound healing, accompanied by increased M2 infiltration at lesion sites.Mechanistically, USP47 directly deubiquitinated and stabilized YAP protein; stabilized YAP drove M1 polarization via two parallel axes: nucleartranslocation to promote pro-inflammatory cytokine transcription, and promotion of NLRP3 inflammasome stabilization.</p><p><strong>Conclusions: </strong>USP47 is a critical regulator of macrophage polarization via the USP47-YAP-NLRP3 axis. Targeting USP47 exerts anti-inflammatory and pro-repair effects, representing a promising therapeutic strategy for sepsis and wound healing disorders.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008430","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":"Identification of immune cell mitochondrial dysfunction characteristics and clinical predictive biomarkers in sepsis via multi-cohort machine learning and single-cell RNA sequencing.","authors":"Xin Le, Youfen Fan, Sida Xu, Jiliang Li, Shengyong Cui, Guoying Jin, Neng Huang, Yaohua Yu, Pei Xu","doi":"10.1007/s00011-026-02366-8","DOIUrl":"10.1007/s00011-026-02366-8","url":null,"abstract":"<p><strong>Background: </strong>Sepsis involves dysregulated host responses with mitochondrial dysfunction as a key mechanism, yet its immune cell landscape and clinical utility are unclear.</p><p><strong>Methods: </strong>We integrated five GEO datasets (GSE65682, GSE95233, GSE54514, GSE26440, GSE26378) comprising 1,256 samples. Mitochondrial dysfunction-related genes were identified through differential expression analysis and WGCNA. Ten machine learning algorithms were compared to construct an optimal diagnostic model. NMF clustering defined sepsis subtypes, and a mitochondrial dysfunction score (MAS) was developed. Single-cell RNA sequencing (GSE167363, 59,731 cells) validated cell-type-specific expression patterns. Furthermore, Western blotting was performed to confirm the protein-level expression of selected hub genes in PBMC samples.</p><p><strong>Results: </strong>438 differentially expressed genes were identified (224 upregulated, 214 downregulated), with upregulated genes enriched in oxidative phosphorylation and downregulated genes in T cell receptor signaling. Elastic net achieved optimal diagnostic performance (AUC = 0.9156), yielding a 12‑gene signature with robust external validation (AUC up to 0.918). NMF stratified patients into two subtypes (Cluster 1, n = 412; Cluster 2, n = 511) with distinct immune profiles; Cluster 2 exhibited elevated NLRP3/IL1B expression and enhanced innate immune infiltration. MAS significantly correlated with sepsis status (p = 7.56e‑27) and showed superior diagnostic performance (AUC up to 0.969). Single‑cell analysis revealed MAS enrichment in monocytes and dendritic cells, with positive correlation to monocyte function (rho = 0.443). Notably, protein-level validation confirmed that TXN, CTSZ, SLPI, PSMC5, and DNM2 were significantly upregulated, while FLI1 was downregulated in sepsis patients, consistent with the transcriptomic findings. Furthermore, clinical correlation analysis revealed that the signature score was significantly positively correlated with SOFA and APACHE II scores, and patients with high signature scores exhibited significantly worse 28-day survival. Pseudotime trajectories showed distinct differentiation patterns (P < 0.001).</p><p><strong>Conclusions: </strong>This comprehensive multi-omics analysis, further supported by experimental protein-level validation and clinical correlation with severity scores and survival outcomes, establishes mitochondrial dysfunction-immunity crosstalk as a central axis in sepsis pathogenesis. The identified 12-gene signature and MAS score provide robust diagnostic tools with translational potential for clinical sepsis management.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008419","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}