Molecular Medicine最新文献

{"title":"Hydrogen sulfide-mediated protein s-persulfidation: a regulatory mechanism in cardiovascular homeostasis.","authors":"Luzheng Zhang, Ziyi Gu, Song Xue, Yongyi Wang","doi":"10.1186/s10020-026-01517-1","DOIUrl":"10.1186/s10020-026-01517-1","url":null,"abstract":"<p><strong>Background: </strong>Cardiovascular diseases represent a primary cause of global mortality. Hydrogen sulfide operates as a major endogenous gasotransmitter that contributes to cardiovascular homeostasis through multiple biochemical mechanisms, among which protein S-persulfidation, represents a major redox-sensitive post-translational mechanism. This dynamically reversible modification converts cysteine sulfhydryl groups into highly nucleophilic persulfide groups to prevent irreversible oxidative damage.</p><p><strong>Aim of review: </strong>This review aims to systematically synthesize the current molecular understanding of S-persulfidation in cardiovascular biology. We evaluate the methodological evolution of site-specific detection technologies, delineate the regulatory mechanisms of sulfur signaling across distinct physiological axes, and assess the clinical translational potential of reactive sulfur species delivery systems.</p><p><strong>Key scientific concepts of review: </strong>The manuscript outlines the evolution of detection methodologies from early biotin-switch assays to Quantitative Thiol Reactivity Profiling. Mechanistically, S-persulfidation modulates membrane potential and vascular tone by altering the open probability of ion channels including K_ATP and Ca_v1.2. At the intracellular level, this modification regulates kinase cascades, redox sensors such as the Keap1/Nrf2 pathway, and metabolic enzymes to preserve mitochondrial bioenergetics. S-persulfidation also orchestrates genomic and post-transcriptional programs by directly modifying transcription factors and RNA-binding proteins. Furthermore, it reinforces the cellular protein quality control system to alleviate endoplasmic reticulum stress, optimize autophagy, and establish inhibitory checkpoints against apoptosis and pyroptosis. The review also evaluates systemic delivery vectors, including S-persulfidated albumin and engineered biomaterial scaffolds. Overcoming current translational barriers requires integrating spatial multi-omics with site-specific genetic validation to advance S-persulfidation biology toward precise cardiovascular therapeutics.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148176249","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":"Colchicine attenuates kidney injury by modulating the NLRP3 inflammasome pathway.","authors":"Gyuri Kim, Ga Young Heo, Bo Young Nam, YooJin Cho, Je Wook Yu, Cheol Ho Park, Hyung Woo Kim, Jung Tak Park, Tae-Hyun Yoo, Shin-Wook Kang, Seung Hyeok Han","doi":"10.1186/s10020-026-01511-7","DOIUrl":"10.1186/s10020-026-01511-7","url":null,"abstract":"<p><strong>Background: </strong>Colchicine, a well-known anti-inflammatory drug, has emerged as a therapeutic option in various inflammatory diseases. However, its role in chronic kidney disease (CKD) remains unclear. This study aims to investigate the reno-protective effects of colchicine in an experimental CKD model and its potential role in modulating the NOD-like receptor, pyrin domain containing protein 3 (NLRP3) inflammasome pathway.</p><p><strong>Methods: </strong>A CKD animal model was established in C57BL/6 mice by feeding a 0.2% adenine-containing diet. Colchicine (0.3 mg/kg/day) or saline was administered intraperitoneally for 4 weeks. RNA sequencing of kidney tissue was performed to capture molecular signatures associated with the therapeutic mechanism of colchicine in CKD. In vitro, renal tubular epithelial cells (RTECs) were treated with transforming growth factor-β (TGF-β, 10 ng/ml) and bone marrow-derived macrophages (BMDMs) were exposed to p-cresol sulfate (PCS, 0.5 mM). Colchicine (0.1 μM for RTECs and 1.0 μM for BMDMs) was administered to evaluate its protective effects.</p><p><strong>Results: </strong>Colchicine treatment significantly reduced systemic inflammatory markers including tumor necrosis factor-α, interleukin-6, and interleukin-1β. In the kidney tissues of adenine-fed mice, prominent fibrotic change and macrophage infiltration were observed, both of which were significantly attenuated by colchicine treatment. These improvements were accompanied by reduced albuminuria and improved kidney function. RNA sequencing revealed that colchicine modulated key inflammatory pathways, including the nuclear factor-κB and NOD-like receptor signaling pathway. Notably, colchicine treatment significantly decreased the expression levels of NLRP3 inflammasome components in adenine-fed mice, TGF-β-treated RTECs and PCS-treated BMDMs. Mechanistically, colchicine inhibited the interaction between NLRP3 and apoptosis-associated speck-like protein containing a CARD in TGF-β-treated RTECs and PCS-treated BMDMs, resulting in decreased NLRP3 inflammasome assembly, as demonstrated by oligomerization cross-linking assay and proximity-ligation assay.</p><p><strong>Conclusions: </strong>We demonstrated that colchicine can attenuate kidney injury and fibrosis in adenine-induced CKD mice by inhibiting NLRP3 inflammasome assembly and activation.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13449497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148157429","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":"The roles of cytoplasmic dynein complex in various ocular disorders.","authors":"Xuebin Zhou, Jianan Xie, Wanqing Tong, Jinling Fu","doi":"10.1186/s10020-026-01523-3","DOIUrl":"10.1186/s10020-026-01523-3","url":null,"abstract":"<p><strong>Background: </strong>The cytoplasmic dynein complex mediates retrograde transport of various intracellular components and plays a critical role in mitosis, nuclear migration, organelle positioning, vesicle trafficking, misfolded protein clearance, and intercellular signaling.</p><p><strong>Main body: </strong>Mutations in human cytoplasmic dynein subunits and regulators have been directly linked to various neurological diseases and are increasingly recognized as contributors to ocular degenerative diseases. However, the precise mechanisms underlying ocular morphogenesis and degeneration remain poorly understood. Various animal models, including Drosophila, mouse, and zebrafish, have been established to investigate the pathogenesis of cytoplasmic dynein complex-related ocular disorders. Findings from these models indicate that dynein complex-related ocular pathologies often involve endoplasmic reticulum stress, impaired Notch signaling, and disrupted Sonic Hedgehog pathways. Systematically integrating gene functional data and molecular mechanism clues derived from different models can help refine the \"gene-phenotype-mechanism\" correlation network and may ultimately advance precision diagnosis and targeted therapy.</p><p><strong>Conclusion: </strong>Emerging evidence has highlighted the cytoplasmic dynein complex as a key factor in ocular development and disease. Integrating findings across model systems may enable more precise diagnosis and the development of targeted interventions for dynein-related ocular disorders.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13445693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148150363","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":"Neutrophilic asthma: advances in experimental models from pathogenesis to therapeutic translation.","authors":"Jialin Yao, Jingjing Lu, Jing Gao, Ximing Liao, Di Wu, Muyun Wang, Qiang Li, Wei Gao","doi":"10.1186/s10020-026-01507-3","DOIUrl":"10.1186/s10020-026-01507-3","url":null,"abstract":"<p><strong>Background: </strong>Neutrophilic asthma (NA) is a severe and therapy-resistant asthma endotype marked by persistent airway inflammation, neutrophil infiltration, and limited response to glucocorticoids. The development of targeted therapies has been hampered by insufficient mechanistic insight and the lack of physiologically relevant experimental models.</p><p><strong>Main body: </strong>This review comprehensively synthesizes current in vivo and in vitro models for NA, discussing their methodologies, mechanistic fidelity, and translational potential. Murine systems provide flexible genetic and induction platforms; rat models reliably replicate steroid resistance; and equine models spontaneously mimic chronic human disease. Advanced in vitro approaches including air-liquid interface cultures, patient-derived organoids and lung-on-a-chip devices, enable precise study of epithelial barrier dysfunction, immune crosstalk, and personalized drug responses.</p><p><strong>Conclusion: </strong>By critically evaluating these tools, our review establishes a foundation for model standardization and underscores their collective role in elucidating NA pathogenesis and advancing precision medicine.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13436277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148138529","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":"Slfn4-mediated Stat3 signaling promotes suppressive bone marrow monocytes in a murine second-hit sepsis model.","authors":"Xiaoyan Meng, Huawei Wei, Jiao Cai, Yiman Han, Haowei Wang, Yutong Yang, Lei Peng, Xingying He, Hongbin Yuan","doi":"10.1186/s10020-026-01515-3","DOIUrl":"10.1186/s10020-026-01515-3","url":null,"abstract":"<p><strong>Background: </strong>Sepsis survivors who develop recurrent or secondary infections often exhibit prolonged immunosuppression and impaired pathogen clearance, yet the underlying mechanisms remain poorly defined and targeted therapies are limited.</p><p><strong>Methods: </strong>We established a murine second-hit sepsis model to examine immune remodeling during the immunosuppressive phase after an initial inflammatory insult. Bone marrow immune remodeling was characterized by flow cytometry and single-cell RNA sequencing. Purified myeloid subsets were subjected to functional assays, transcriptomic analyses, and molecular studies to define how Slfn4 regulates the suppressive program of monocytic myeloid-derived suppressor cell-like (M-MDSC-like) cells.</p><p><strong>Results: </strong>We found that Slfn4 marks an immunosuppressive M-MDSC-like subset in the bone marrow during second-hit sepsis, and our data support a role for the Slfn4-Stat3 axis in maintaining its suppressive phenotype. Genetic silencing of Slfn4 or pharmacologic inhibition of Stat3 was associated with reduced M-MDSC-like cell abundance, partially restored T-cell function, and improved survival. Mechanistically, our data supports a model in which SLFN4 enhances Stat3 activation in association with post-transcriptional repression of Socs3, potentially through interaction with an AU-rich element within the Socs3 3'-UTR. In addition, sildenafil, a PDE5 inhibitor, decreased M-MDSC-like cell abundance and enhanced bacterial clearance in vivo.</p><p><strong>Conclusions: </strong>These findings implicate the Slfn4-Stat3 axis in bone marrow-associated immunosuppression in this murine second-hit sepsis model and support further investigation of this pathway in the late immunosuppressive phase of sepsis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148143959","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":"DCLK1 mediates airway epithelial barrier disruption through NF-κB activation in severe asthma.","authors":"Wun-Hao Cheng, Mei-May Neoh, Kuan-Yuan Chen, Kang-Yun Lee, Po-Hao Feng, Yu-Chih Wu, Lee-Yuan Lin, Fara Silvia Yuliani, Yan-An Wang, Chien-Huang Lin, Bing-Chang Chen","doi":"10.1186/s10020-026-01513-5","DOIUrl":"10.1186/s10020-026-01513-5","url":null,"abstract":"<p><strong>Background: </strong>Severe asthma is characterized by epithelial barrier dysfunction, airway remodeling, and chronic inflammation. Doublecortin-like kinase 1 (DCLK1), a kinase initially identified as a cancer stem cell marker, has been linked to NF-κB-mediated inflammatory responses. However, its role in TGF-β-induced epithelial barrier disruption in severe asthma remains unclear.</p><p><strong>Methods: </strong>The expression of DCLK1 and junctional proteins was examined in bronchial epithelial tissue biopsies and air-liquid interface (ALI) cultures derived from patients with severe asthma and healthy controls. The role of DCLK1 was investigated in vitro using TGF-β-treated BEAS-2B cells and in vivo using ovalbumin (OVA)- and house dust mite (HDM)-induced murine asthma models. Global DCLK1 knockout mice were employed to assess epithelial integrity, airway remodeling, and inflammatory responses in murine asthma.</p><p><strong>Results: </strong>DCLK1 expression was increased in bronchial epithelial cells from patients with severe asthma. DCLK1 siRNA reversed TGF-β-induced epithelial dysfunction by restoring E-cadherin expression and reducing fibronectin and N-cadherin levels in BEAS-2B cells. Moreover, DCLK1 silencing improved epithelial barrier function, as evidenced by increased transepithelial electrical resistance (TEER) and E-cadherin expression. Mechanistically, DCLK1 mediates TGF-β-induced EMT via activation of the NF-κB signaling pathway. DCLK1 knockout mice exhibited improved lung function and reduced airway inflammatory cell infiltration compared with wild-type mice under both OVA and HDM exposure.</p><p><strong>Conclusions: </strong>DCLK1 promotes airway epithelial barrier dysfunction in severe asthma through NF-κB activation. Targeting DCLK1 may represent a novel therapeutic strategy to restore epithelial integrity in severe asthma.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13412315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148055812","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":"Lactylation and lactate: insights into muscle cell epigenetic regulators in exercise.","authors":"Bo Chen, Jingbo Xia, Chaoge Wang, Min Hu, Jingwen Liao","doi":"10.1186/s10020-026-01506-4","DOIUrl":"10.1186/s10020-026-01506-4","url":null,"abstract":"<p><p>Lactate was once regarded as a metabolic waste. However, recent studies have established its dual role as both a versatile signaling molecule and a substrate for a novel post-translational modification (PTMs)-lysine lactylation. Exercise, as a primary physiological stimulus for lactate production, provides an ideal context for exploring lactate-mediated epigenetic regulation. This regulatory mechanism is particularly relevant in muscle cells, which serve as both the main producers and consumers of lactate. This review focuses on three core muscle cell types: skeletal muscle cells, cardiomyocytes and vascular smooth muscle cells (VSMCs). We systematically elucidate the functional roles of the lactate-lactylation in these cells, examining how lactate can regulate cellular adaptation and pathological processes both independently and in concert with other PTMs. Furthermore, we analyze the distinct effects of diferent exercise modalities (ranging from moderate training to overtraining) on the lactylation dynamics, revealing its the dual functions of lactylation in exercise physiology and pathology. By integrating these mechanisms, this review provides a novel theoretical framework for understanding exercise-mediated muscle cell function and offers fresh perspectives for intervention strategies targeting metabolic and cardiovascular diseases.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13403442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148055760","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":"Systematic functional evaluation of CNGA1 missense variants associated with retinitis pigmentosa.","authors":"Peggy Reuter, Jennifer Schroeder, Marc Sturm, Mathieu Quinodoz, Veronika Vaclavik, Miriam Bauwens, Marieke De Bruyne, Bart Leroy, Joseph van Aerschot, Katarina Stingl, Susanne Kohl","doi":"10.1186/s10020-026-01518-0","DOIUrl":"10.1186/s10020-026-01518-0","url":null,"abstract":"<p><strong>Background: </strong>Missense variants are frequently classified as variants of uncertain significance (VUS) according to the guidelines of the American College of Medical Genetics and Genomics and the Association of Molecular Pathology (ACMG/AMP). Consequently, disease relevance remains elusive, impeding molecular genetic diagnostics, patients` and family genetic counseling, and identification of patients eligible for clinical trials. Functional studies are critical for resolving the clinical significance of VUS. CNGA1 encodes the main subunit of the rod cyclic nucleotide-gated (CNG) channel, a vital component of the phototransduction cascade. Variants in CNGA1 are a rare cause of autosomal recessive retinitis pigmentosa and a phase I/II gene augmentation trial (NCT06291935) is currently ongoing highlighting the necessity to differentiate benign from pathogenic variants.</p><p><strong>Methods: </strong>CNGA1 missense variants compiled from retinal disease patient cohorts, public databases and literature were functionally investigated using a medium-throughput aequorin-based assay and in vitro minigene splice assays for predicted exonic spliceogenic variants. Functional data were correlated with the in silico prediction of five variant effect predictors (VEPs) and applied to support or revise variants' ACMG/AMP classification.</p><p><strong>Results: </strong>Data mining revealed 86 missense CNGA1 variants - including three novel - most of them lacking functional data; 65.1% of the variants were initially classified as VUS. The aequorin-based assay showed that 72.1% of tested variants significantly impaired CNG channel function and were classified as functionally abnormal, while 23.3% were functionally normal and 5% remained functionally uncertain. Correlation of the functional data with in silico predictions identified AlphaMissense and CPT-1 to be the most suitable tools for assessing CNGA1 missense variants. Using in vitro minigene splice assays, two putative missense variants were shown to induce missplicing. Based on the functional findings, 62.1% of the variants initially classified as VUS were re-categorized as likely pathogenic or likely benign. Furthermore, 93.3% of the variants initially classified as likely pathogenic showed an effect on CNGA1 channel function, confirming their disease relevance and supporting their reclassification as pathogenic.</p><p><strong>Conclusion: </strong>This study represents the first comprehensive functional assessment of disease-associated CNGA1 missense variants, thus significantly advancing the understanding of their disease relevance and improving molecular genetic diagnostics in patients.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"32 1","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13214374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148033137","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":"Machine learning, whole genome sequencing, and Mendelian randomization support a role of CRP on COVID-19 severity.","authors":"Francesca Lantieri, Stefania Croci, Sergio Decherchi, Marta Rusmini, Giada Recchi, Martina Bonacini, Ilaria Ferrigno, Alessandro Rossi, Yeraldin Chiquinquira Castillo De Spelorzi, Edoardo Henzen, Francesca Rosamilia, Davide Cangelosi, Fabio Landuzzi, Andrea Angius, Vincenzo Rallo, Pamela Mancuso, Annamaria Pezzarossi, Paolo Giorgi Rossi, Mariagrazia Catanoso, Marco Gattorno, Andrea Cavalli, Pier Luigi Meroni, Diego Vozzi, Paolo Uva, Isabella Ceccherini, Carlo Salvarani","doi":"10.1186/s10020-026-01512-6","DOIUrl":"10.1186/s10020-026-01512-6","url":null,"abstract":"<p><strong>Background: </strong>The coronavirus disease 2019 (COVID-19) ranges from asymptomatic to very severe infection and death, largely depending on host factors, including genetics. We have investigated clinical and genetic data from 200 COVID-19 patients to search for factors predisposing to increased disease severity.</p><p><strong>Methods: </strong>Patients were divided into non-hospitalized mild/pauci-symptomatic and hospitalized severe. An interpretable Machine Learning approach was applied to blood biomarkers while genome-wide associations were performed for COVID-19 severity. Finally, a possible causal role of chronic low-grade inflammation on COVID-19 severity was searched by Mendelian Randomization.</p><p><strong>Results: </strong>A high severity predictive role was observed in our sample by Machine Learning for the C-Reactive Protein measured in the course of SARS-CoV-2 infection (iCRP). This was also suggested by evidence of association with variants known to be involved in the CRP levels in the general population (pCRP). Finally, a possible causal role of chronic low-grade inflammation on COVID-19 severity could be shown by Mendelian Randomization using publicly available summary statistics of two COVID-19 Genome-Wide Association Studies.</p><p><strong>Conclusions: </strong>Consistent with previous results, a predictive role of CRP levels on COVID-19 severity was detected in our sample. Furthermore, Mendelian Randomization supported a causal role of genetically predicted chronic CRP levels.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148033148","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":"STUB1-mediated ubiquitination regulates Fli-1 stability and CD4⁺T cell activation during inflammation.","authors":"Pengfei Li, Liu Liu, Yan Wu, Meng Liu, Maria Trojanowska, Hongkuan Fan","doi":"10.1186/s10020-026-01494-5","DOIUrl":"10.1186/s10020-026-01494-5","url":null,"abstract":"<p><strong>Background: </strong>Fli-1, a member of the ETS transcription factor family, has been implicated in multiple inflammatory and immune-related disorders, including sepsis, lupus, Alzheimer's disease, and post-traumatic stress disorder (PTSD). Recent studies further suggest a critical role for Fli-1 in CD4⁺ T cells in graft-versus-host disease, systemic sclerosis, and PTSD; however, its precise function and regulation during inflammatory CD4⁺ T cell responses remain incompletely understood.</p><p><strong>Methods: </strong>Wild-type and CD4⁺ T cell-specific Fli-1 knockout mice were administered LPS via intraperitoneal injection. Survival rates and splenic T cell activation were subsequently assessed. In vitro, cultured Jurkat and HEK cells were utilized to investigate the STUB1/Fli-1-related signaling pathway.</p><p><strong>Results: </strong>Here, we demonstrate that Fli-1 expression is markedly upregulated in splenic CD4⁺ T cells in a murine model of endotoxemia. CD4⁺ T cell-specific deletion of Fli-1 significantly improves survival and attenuates splenic CD4⁺ T cell activation. Mechanistically, we identify STUB1 as a novel E3 ubiquitin ligase for Fli-1 that promotes K27-linked ubiquitination and proteasomal degradation under basal conditions. Inflammatory stimulation disrupts the STUB1/HSP70 interaction, reducing STUB1-mediated ubiquitination and enhancing Fli-1 protein stability. Consistent with these findings, Fli-1 knockout reduces TNFα, IFNγ, and IL-10 expression, whereas STUB1 knockout enhances their expression in Jurkat cells. Gain- and loss-of-function studies further reveal that Fli-1 modulates NFκB signaling, a key pathway in T cell activation.</p><p><strong>Conclusions: </strong>Collectively, our results identify the STUB1/Fli-1 axis as a previously unrecognized regulator of CD4⁺ T cell function and a potential therapeutic target for inflammatory diseases.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":8.3,"publicationDate":"2026-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13386852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148033112","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}