Journal of Cellular and Molecular Medicine最新文献

{"title":"Isoimperatorin Reduces Synovial Inflammation and Fibrosis in Knee Osteoarthritis via the cAMP Signalling Pathway.","authors":"Lishi Jie, Junnan Liu, Zaishi Zhu, Zeling Huang, Yujiang Liu, Guanhong Liu, Xiaofeng Shen, Yuwei Li, Xiaoqing Shi","doi":"10.1111/jcmm.70880","DOIUrl":"https://doi.org/10.1111/jcmm.70880","url":null,"abstract":"<p><p>To explore the mechanism of pharmacological action of Isoimperatorin (ISO), a small molecule compound with anti-inflammatory properties extracted from the rhizome of Notopterygium incisum, in attenuating synovial inflammation in knee osteoarthritis (KOA). By establishing a rat model of KOA and using histopathology and molecular biology methods, we evaluated the pharmacological effect of ISO on synovitis. Synovial fluid from the knee joint was collected for transcriptomic and metabolomic analyses. Fibroblast-like synoviocytes were cultured in vitro, and calcium fluorescence imaging and mitochondrial membrane potential assays were performed to assess the effects of ISO on the cAMP signalling pathway and KOA-related synovial inflammation. Preliminary pharmacodynamic observations showed that ISO was able to reduce synovial inflammation in KOA rats. Further transcriptomic findings in synovial tissues indicated that the mechanism of action of ISO was related to the cAMP signalling pathway and calcium ion signalling pathway. The results of metabolomics showed that the progression of synovial fibrosis was related to the abnormal metabolism of glycerophospholipids, and the intervention of ISO could significantly promote the metabolism of glycerophospholipids in synovial tissues. Finally, the results of in vitro experiments showed that ISO improved the level of inflammation and the degree of fibrosis in synovial cells, activated the cAMP signalling pathway and promoted PPAR expression, whereas inhibition of the activation of the cAMP signalling pathway attenuated the effects of ISO. ISO promotes PPAR function by upregulating the cAMP signalling pathway to modulate glycerophospholipid metabolism, thereby alleviating synovial inflammation and slowing fibrosis progression in KOA.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"29 19","pages":"e70880"},"PeriodicalIF":4.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zerumbone Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Suppressing the NLRP3/Caspase-1/GSDMD Signalling Pathway.","authors":"Yun-Jie Xu, Fei-Fei Fang, Guo-Qiang Zhao, Wei-Yan Yu, Hong-Yan Han, Hong Teng, Jun-Ning Lyu, Jian-Feng Wang","doi":"10.1111/jcmm.70873","DOIUrl":"https://doi.org/10.1111/jcmm.70873","url":null,"abstract":"<p><p>A cyclic sesquiterpene with 11 carbon atoms is the primary component of essential oils from the wild ginger species, Zingiber zerumbet. It exhibits pharmacological effects, including anti-inflammatory and antioxidant properties. However, limited information exists regarding its role in pyroptosis during acute lung injury (ALI). Herein, we investigated how zingerone affects pyroptosis in a murine lipopolysaccharide (LPS)-induced ALI model established via intraperitoneal zerumbone (Zer) administration. Bronchoalveolar lavage fluid, serum, and lung tissue samples were collected after 24 h. Haematoxylin and eosin staining was performed to assess lung tissue damage. Western blot analysis and real-time quantitative polymerase chain reaction (qRT-PCR) were used to quantify protein expression levels associated with pyroptosis. Before LPS exposure, mouse alveolar epithelial (MLE)-12 cells were pretreated with 10 μM Zer for 2 h and then incubated with 1 ng/mL LPS for an additional 24 h. Zer treatment reduced lung tissue injury, inflammation, and oxidative stress in model mice. Zer counteracted pyroptosis in the alveolar epithelial cells of these mice. In MLE-12 cells, Zer significantly inhibited oxidative stress and inflammation. Zer suppressed NLRP3/Caspase-1/GSDMD signalling, pivotal in pyroptosis, mitigating ALI progression. A potential novel therapeutic agent for ALI inhibited the NLRP3/GSDMD signalling pathway involved in pyroptosis.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"29 19","pages":"e70873"},"PeriodicalIF":4.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Flavonoid Kaempferol Mitigates Periprosthetic Osteolysis by Regulating the NLRP3 Inflammasome and Balancing Bone Metabolism.","authors":"Cheng Huang, Chenhui Zhang, Yongjun Luo, Lujun Guo, Yanglin Wu, Qingyan Shi, Yazhong Zhang, Chengyuan Yang, Bo Wang, Junjie Niu, Jun Lin","doi":"10.1111/jcmm.70878","DOIUrl":"https://doi.org/10.1111/jcmm.70878","url":null,"abstract":"<p><p>Total joint arthroplasty (TJA) is an effective intervention for end-stage arthritis; however, its long-term success is often compromised by wear particle-induced osteolysis, leading to aseptic loosening and implant failure. This study investigates the potential of kaempferol (Ka), a natural flavonoid with anti-inflammatory properties, to alleviate osteolysis by modulating NLRP3 inflammasome activation. In a murine calvarial osteolysis model, Ka administration significantly attenuated bone loss induced by CoCrMo alloy particles. Mechanistically, Ka dose-dependently inhibited NLRP3 inflammasome activation in macrophages, as evidenced by reduced IL-1β secretion, decreased ASC oligomerisation and suppressed GSDMD cleavage, ultimately leading to decreased pyroptosis. These effects were found to be partially mediated via GPR109a. Furthermore, Ka markedly suppressed osteoclast differentiation and activity both in vivo and in vitro while promoting osteoblast differentiation, thereby contributing to the restoration of bone remodelling balance. Taken together, our findings suggest that Ka exerts a protective effect against wear particle-induced osteolysis by targeting the NLRP3 inflammasome and modulating osteoimmune responses, which may offer a novel therapeutic strategy to manage periprosthetic osteolysis and prolong implant longevity.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"29 19","pages":"e70878"},"PeriodicalIF":4.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Integrative Genotyping and Gene Expression Profiling of the Mutated Human FAM111B Gene and Fibrosis-Associated Pathway in the POIKTMP Syndrome.","authors":"Nadine Tambwe, Musalula Sinkala, Oluwafemi G Oluwole, Nonhlanhla P Khumalo, Afolake Arowolo","doi":"10.1111/jcmm.70871","DOIUrl":"https://doi.org/10.1111/jcmm.70871","url":null,"abstract":"<p><p>Poikiloderma with tendon contracture, myopathy and pulmonary fibrosis (POIKTMP) is a rare hereditary disorder caused by mutations in the FAM111B gene, characterised by multi-organ fibrosis, particularly affecting the lungs. This study investigates the molecular mechanisms of fibrosis in POIKTMP through genotyping and gene expression profiling of FAM111B and associated fibrotic pathways. Post-mortem formalin-fixed paraffin-embedded (FFPE) tissues from a POIKTMP patient and healthy controls were analysed. Genomic DNA was extracted, confirming the FAM111B Y621D mutation via Sanger sequencing. RT-qPCR and the RT² Profiler PCR Array were used to evaluate fibrosis-related gene expression in lung and skin tissues. Disease and pathway enrichment analyses were conducted using Metascape, GeneMANIA and Enrichr tools. The FAM111B Y621D mutation was validated, and gene expression profiling revealed significant upregulation of fibrotic markers, such as TGFβ-3, PDGFA, ITGB1, MMP3, MMP13 and CCN2 in the lungs, and COL3A1 and THBS2 in the skin. Pathway enrichment analysis linked FAM111B to extracellular matrix remodelling, cell adhesion, and cancer. These findings suggest that FAM111B mutations drive fibrosis through dysregulated gene networks, highlighting potential therapeutic targets for POIKTMP and related fibrotic diseases. Further research is required to understand FAM111B's role in fibrosis fully.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"29 19","pages":"e70871"},"PeriodicalIF":4.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IFI16 Induced by p53 Activates the NF-κB Pathway to Counteract Cisplatin-Induced Apoptosis in Cervical Cancer Cells.","authors":"Lili Zhong, Jiaxin Li, Jianfeng Zhong, Yifan Zhang, Hang Qi, Huimei Yu, Xin Li","doi":"10.1111/jcmm.70728","DOIUrl":"10.1111/jcmm.70728","url":null,"abstract":"<p><p>Cervical cancer ranks as the second most prevalent cancer among women worldwide, and the primary treatment for advanced cases involves cisplatin-based chemotherapy. However, the duration of cisplatin treatment is typically short, with a median survival rate of approximately 1 year. This highlights the urgent need to enhance our understanding of cisplatin's mechanism of action in cervical cancer treatment. Our findings demonstrate that p53 induces the nuclear translocation of IFI16, leading to activation of the NF-κB signalling pathway. This activation plays a crucial role in protecting cervical cancer cells against cisplatin-induced apoptosis. The activation of NF-κB is independent of STING, which is a downstream molecule of IFI16. STING signalling activation by cisplatin may not be associated with cisplatin-induced apoptosis. To further validate this tumour-promoting effect of IFI16 during cisplatin therapy, we established a subcutaneous implantation tumour model using mouse cervical cancer (U14) cells and conducted additional in vitro experiments. We examined the role and mechanism of IFI16 in cisplatin treatment of cervical cancer. The role of IFI16 in cervical cancer progression deserves further study. Targeted inhibition of IFI16 may be a new way to increase cisplatin sensitivity of cervical cancer cells.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"29 15","pages":"e70728"},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12328537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794576","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":"Ischemia-Reperfusion Injury in Free Flaps: Molecular Mechanisms and Protective Effects of Remote Ischemic Preconditioning.","authors":"Marius Drysch, Alexander Fiedler, Tabea Kurbacher, Sonja Verena Schmidt, Felix Reinkemeier, Flemming Puscz, Mustafa Becerikli, Maria Fueth, Pia Weskamp, Marcus Lehnhardt, Christoph Wallner, Alexander Sogorski","doi":"10.1111/jcmm.70739","DOIUrl":"10.1111/jcmm.70739","url":null,"abstract":"<p><p>Ischemia-reperfusion injury remains a major challenge in free flap surgery, contributing to oxidative stress, inflammation, and cell death that impair tissue viability and outcomes. Remote ischemic preconditioning (RIPC) has emerged as a potential protective strategy by modulating cellular stress responses, but its molecular mechanisms in free flaps remain incompletely understood. We prospectively enrolled 36 female patients undergoing autologous breast reconstruction with mainly deep inferior epigastric perforator (DIEP) free flaps, randomised into three groups: No RIPC, Early RIPC (24 h preconditioning), and Late RIPC (1 h preconditioning). Tissue samples were collected pre-ischemia and post-reperfusion for immunohistochemical and multiplex protein analyses. RIPC did not reduce oxidative stress markers, as 4-hydroxynonenal (4-HNE) levels were comparable across groups, while 3-nitrotyrosine levels paradoxically increased after RIPC. Early RIPC selectively modulated cell death pathways, with decreased expression of mitochondrial apoptotic marker caspase 9 and reduced necroptotic activation of mixed lineage kinase domain-like protein (MLKL) after reperfusion. Caspase 8 showed a transient modulation, suggesting effects on apoptosis-necroptosis crosstalk. Cyclophilin A levels were elevated after reperfusion in RIPC groups, indicating an adaptive stress response. These findings suggest that early RIPC exerts selective protection by modulating apoptosis and necroptosis, rather than broadly reducing oxidative stress. RIPC may represent a targeted strategy to improve free flap survival in reconstructive surgery.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"29 15","pages":"e70739"},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12329344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794577","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":"Deciphering the Proteomic Landscape of Circulating Extracellular Vesicles in Human Abdominal Aortic Aneurysm.","authors":"Chaoyang Yu, Ge Zhang, Shaotong Pei, Yifei Zhang, Peiyu Yuan, Renying Miao, Kaisaierjiang Kadier, Pengpeng Zhang, Tianshu Gu, Ruhao Wu, Haonan Zhang, Shiqian Zhang, Bo Yang, Han Wu, Yudi Xu, Ke Hu, Qingfei Xu, Yaxin Chen, Jinliang Wang, Zongao Cai, Junnan Tang, Teng Li, Yan Song","doi":"10.1111/jcmm.70725","DOIUrl":"10.1111/jcmm.70725","url":null,"abstract":"<p><p>Abdominal aortic aneurysm (AAA) is the most prevalent and lethal form of arterial aneurysm, frequently manifesting asymptomatically until a catastrophic rupture occurs. While various diagnostic imaging tools and several potential biomarkers have been explored for the purpose of early AAA screening, the usage of liquid biopsy such as extracellular vesicles (EVs)-carried protein for the early diagnosis of AAA is still being overlooked. In this study, we enrolled 18 AAA patients and nine healthy normal controls, including data from the National Drug Clinical Trial Organisation-Vascular Surgery (NDCTO) (in-house cohort) and the Second Clinical Medical College, Jinan University (Shenzhen People's Hospital) (external cohort). We employed Olink's proximity extension assay (PEA) technology based on the plasma EV proteins and first comprehensively characterised the proteomics landscape in circulating EV underlying AAA disease development. A complex profile of differential EV proteins and EV protein-protein interactions network in AAA patients was identified. The differentially expressed EV proteins in AAA patients were found to be significantly associated with several enriched pathways, including the cellular response to cytokine stimuli, inflammatory response, and the regulation of the glucocorticoid receptor (GR) pathway. Moreover, five hub proteins were identified as being of particular significance: these were Interleukin-4, Interleukin-6, MCP-1, Neurturin, and Oncostatin-M. The Olink proteomics technique was utilised in order to identify these proteins. The significance of these proteins was further validated through Western blotting and enzyme-linked immunosorbent assay (ELISA) in the external cohort. The five EV proteins displayed reliable performance and robustness for distinguishing AAA from healthy people, revealing high accuracy with AUC values of 0.760, 0.840, 0.800, 0.840, and 0.900, respectively. The present study has revealed the plasma EV proteins landscape within AAA and further uncovered their potential roles in the pathogenesis of the disease. This presents a new direction for clinical diagnosis and management of AAA. Consequently, these five EV proteins have the potential to serve as useful biomarkers for the diagnosis and prediction of AAA. Further research is warranted to explore their potential as therapeutic targets.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"29 15","pages":"e70725"},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12328994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794575","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":"Obesity-Induced Loss of Function of Bone Marrow Mesenchymal Stromal Cells Is Linked to Cellular Stress and Irreversible at Advanced Stages.","authors":"Ece Gizem Polat, Mehmet Emin Şeker, Burcu Pervin, Barış Ulum, Fatima Aerts-Kaya","doi":"10.1111/jcmm.70776","DOIUrl":"10.1111/jcmm.70776","url":null,"abstract":"<p><p>Obesity increases the likelihood of metabolic diseases and can affect stem cell function negatively. Here, we aimed to elucidate the mechanisms involved in the loss of stem cell function induced by obesity by assessing levels of oxidative stress (OS) and endoplasmic reticulum stress (ERS) in bone marrow-derived mesenchymal stromal cells (BM-MSCs) from healthy donors with a body mass index (BMI) of 25-30 (obese) and BMI > 30 (morbid obese). We assessed base levels of OS and ERS, activation of cellular response mechanisms, and the effects of Melatonin (MT), which is known to decrease OS, and TUDCA, which is known to decrease ERS. Loss of BM-MSC differentiation was correlated with the degree of obesity and associated with upregulation of OS and ERS. Increased BMI was accompanied by elevated intracellular ROS and accelerated senescence of BM-MSCs. Although treatment with MT and TUDCA was able to decrease OS and ERS in BM-MSCs from obese donors, cellular stress in BM-MSCs from morbid obese donors was irreversible. Therefore, it is imperative to treat and prevent obesity before the negative effects on stem cells become permanent and irreversible. Early treatment of obesity may not only prevent metabolic diseases; it may also protect tissue resident stem cells.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"29 15","pages":"e70776"},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12331444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799205","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":"Molecular Subtypes and Risk Prediction Model Based on Malignant Cell Differentiation Trajectories in Breast Cancer.","authors":"Penghui Yan, Hanlin Sun, Siqiao Wang, Runzhi Huang, Chaofeng Shi, Qihang Yang, Yibo Qiao, Haonan Wang, Deqian Kong, Jiwen Zhu, Yunqing Yang, Zongqiang Huang","doi":"10.1111/jcmm.70680","DOIUrl":"10.1111/jcmm.70680","url":null,"abstract":"<p><p>Breast cancer (BRCA) is characterised by complex cellular heterogeneity and differentiation hierarchies, which play a crucial role in bone metastasis and therapeutic resistance. However, existing classification systems remain inadequate in capturing these complexities, limiting their effectiveness in guiding treatment strategies. To address this gap, we integrated single-cell RNA-seq profiles, spatial transcriptomes, along with 1097 bulk RNA-seq profiles of TCGA-BRCA cohort to dissect the molecular landscape of BRCA. By performing UMAP analysis, we identified nine tumour clusters and three spatially distinct spot types (immune, stromal and malignant spots) and further delineated 11 differentiation states from 2493 malignant spots. Through clustering, monocle 2 pseudo-time and prognostic analyses, we identified the prognostic BRCA cell fate-related genes, then constructed a novel BRCA stratification system (four subtypes) with differential prognosis, biological plausibility and clinical significance. Also, least absolute shrinkage and selection operator (LASSO) regression analysis was performed for the BRCA cell fate-related genes in constructing a prognostic model. The model has modest accuracy and accordance (AUC = 0.708), which could distinguish BRCA patients into high-risk or low groups. With correlation analysis, regulation networks were constructed for different subtypes based on the key cell fate-related genes, transcription factors, metastasis-related pathways, immune components and so on, to investigate the regulatory relationships between primary BRCA and BRCA bone metastasis. Afterwards, we identified the most significant inhibitors (puromycin, MS-275, megestrol, aesculetin) for bone metastatic BRCA, which might have potential translational significance. In all, we developed a novel molecular stratification system for BRCA based on the cell fate-related markers of malignant cells, which offered strong translational potential for diagnosis, prognosis and personalised therapeutic interventions.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"29 15","pages":"e70680"},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12332891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799204","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":"TNFSF14-HVEM/LTβR Exacerbates Keratinocyte Abnormalities and IMQ-Induced Psoriatic Skin Inflammation via Activating NF-κB/TWIST1 Signalling Pathway.","authors":"Sheng-Jie Long, Quan-You Zheng, Feng Xu, Gui-Qing Li, Jian Chen, Wen-Jie Chen, Jiang-Mei Xu, Xiao-Lin Gao, Shen-Ju Liang, Gui-Lian Xu","doi":"10.1111/jcmm.70774","DOIUrl":"10.1111/jcmm.70774","url":null,"abstract":"<p><p>Psoriasis (PS) is a chronic autoimmune skin disease that poses a serious threat to over 100 million patients worldwide. An increasing number of studies have indicated that keratinocytes (KCs) play an essential role in the inflammatory progression of PS. The present study found that tumour necrosis factor superfamily member 14 (TNFSF14) and its two receptors were up-regulated in IMQ-primed KCs and psoriatic skin sections. It also revealed that blocking TNFSF14 signalling (via gene knockout or injections) with its receptors' soluble fusion proteins lymphotoxin beta receptor (LTβR)-immunoglobulin G Fc domain (LTβR-IgGFc) and herpesvirus entry mediator-IgGFc (HVEM-IgGFc) significantly alleviated imiquimod (IMQ)-induced psoriatic skin inflammation by attenuating epidermal hyperplasia, decreasing cellular proliferation, keratinisation, apoptosis, and inflammatory response. Accordingly, direct stimulation with recombinant TNFSF14 markedly enhanced KC abnormalities as evidenced by aggravated cell proliferation and keratinisation, increased cellular apoptosis, and up-regulated inflammatory cytokine expression. Mechanistic studies demonstrated that TNFSF14 mediates KC abnormalities via the nuclear factor-kappa B (NF-κB)/TWIST1 pathway. Taken together, our study findings indicate that TNFSF14-HVEM/LTβR promotes KC dysfunction and IMQ-induced psoriatic skin inflammation via enhancing NF-κB/TWIST1 signalling and suggest that TNFSF14 is a promising therapeutic strategy for the clinical treatment of PS.</p>","PeriodicalId":15215,"journal":{"name":"Journal of Cellular and Molecular Medicine","volume":"29 15","pages":"e70774"},"PeriodicalIF":4.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12327566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794578","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}