Cell Biology and Toxicology最新文献

{"title":"Dissecting the METTL3/STC2 axis in colorectal cancer: implications for drug resistance and metastasis.","authors":"Qiang Su, Kaiyue Wang, Ruohan Liao, Hanyu Zhang, Bochu Wang","doi":"10.1007/s10565-025-10043-5","DOIUrl":"10.1007/s10565-025-10043-5","url":null,"abstract":"<p><p>In recent years, the role of epigenetic modifications, especially N6-methyladenosine (m6A) modifications, in the occurrence and development of cancer has received increasing attention. This study aims to elucidate the role of m6A modification in colorectal cancer (CRC), focusing on the effect of METTL3 on STC2 expression and its effects on cell proliferation, drug resistance and metastasis. Using MeRIP-seq, mRNA-seq, EdU staining, CCK-8 (Cell Counting Kit-8) assay, Transwell assay, Western blot and flow cytometry, this study confirmed that RNA methylation was predominantly located in the CDS region and that STC2 was overexpressed in advanced cancer and 5-FU (5-Fluorouracil)-resistant cell lines. Knockdown of STC2 increased the sensitivity of cells to 5-FU, reduced cell proliferation and metastatic capacity, and indicated that METTL3 positively regulates STC2 m6A modification. Further experiments showed that METTL3 knockdown reduced the IC50 (Half Maximal Inhibitory Concentration) of 5-FU-resistant CRC cells, inhibited cell proliferation, ERS (Endoplasmic Reticulum Stress) and oxidative stress, and reduced KRAS G12 and G13 mutations, and these effects were reversed by STC2 overexpression. In vivo, METTL3 knockdown enhanced the efficacy of 5-FU and inhibited tumor metastasis, whereas STC2 overexpression counterbalanced these benefits. Overall, our findings suggest the METTL3/STC2 axis as a promising therapeutic target to combat drug resistance and metastasis in colorectal cancer.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"100"},"PeriodicalIF":5.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265330","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":"SENP3 alleviates osteoporosis via promoting SIRT3 transcription through the increase of DLX2 stability via SUMO2/3.","authors":"Jie Bu, Xuezheng Xu, Yi Luo, Jianfan Liu, Feng Zhou","doi":"10.1007/s10565-025-10052-4","DOIUrl":"10.1007/s10565-025-10052-4","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have indicated a close relationship between SENP3 and osteoporosis. However, the detailed molecular mechanism of SENP3 mediating osteoporosis has not been well studied. The goal of this work was to study the specific mechanism by which SENP3 regulates downstream genes through deSUMOylation and thus affects the progression of osteoporosis.</p><p><strong>Methods: </strong>Osteogenic differentiation was evaluated through osteogenic marker genes, mineralization, and ALP activity, which were detected by qPCR, western blot, and ALP staining assays. Osteoporosis was assessed in OVX mice assessed using qPCR, Micro-CT, and H&E staining assays. The levels of SENP3, DLX2, and SIRT3 were monitored using qPCR and western blot assays. The SUMOylated modification of DLX2 was evaluated using Co-IP and IP assays. The binding of DLX2 to the SIRT3 promoter was confirmed with ChIP, qPCR, dual-luciferase reporter and western blot assays.</p><p><strong>Results: </strong>SENP3, DLX2, and SIRT3 expressions were decreased in tissues of OVX mice. Mechanically, SENP3 inhibited SUMOylated modification of DLX2 and augmented DLX2 stability. Addition of SENP3 accelerated osteogenic differentiation via regulating DLX2. Moreover, DLX2 bound to SIRT3 promoter and accelerated SIRT3 transcription. DLX2 depletion-induced impeditive effects on osteogenic differentiation were reversed by SIRT3 overexpression. Moreover, DLX2 addition counteracted sh-SENP3-induced inhibitory effect on osteogenic differentiation, which was partially reversed by SIRT3 knockdown. Furthermore, SENP3 alleviated osteoporosis in OVX mice by regulating DLX2/SIRT3 axis.</p><p><strong>Conclusion: </strong>Addition of SENP3 accelerated osteogenic differentiation and relieved osteoporosis via increasing SIRT3 transcription by the enhance of DLX2 stability via SUMO2/3.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"99"},"PeriodicalIF":5.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257433","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":"Loss of YTHDF1 suppresses the progression of malignant rhabdoid tumor of the kidney by regulating Glutathione S-transferase Mu 2 (GSTM2).","authors":"Qian-Wen Xiong, Yuntao Liu, Min He, Xiao-Die Shen, Manli Zhao, Shuang-Ai Liu, Gensheng Zhang, Qian Liu, Jinhu Wang, Wan-Xin Peng","doi":"10.1007/s10565-025-10049-z","DOIUrl":"10.1007/s10565-025-10049-z","url":null,"abstract":"<p><strong>Background: </strong>Malignant rhabdoid tumor of the kidney (MRTK) is a rare renal tumor with poor prognosis. While germline mutations of SMARCB1 are considered to be the primary cause of MRTK, emerging evidence suggests that somatic epigenetic changes also play a vital role in the development and progression of MRTK. YTHDF1, an m6A reader protein, has been implicated in regulation of tumorigenesis by influencing RNA translation and stability in several adult cancers. However, the exploration of the role of YTHDF1 in pediatric cancer, especially MRTK, remains limited.</p><p><strong>Methods: </strong>In this study, CRISPR/Cas9 was employed to knockout (KO) YTHDF1 in G401 cells. The impact of YTHDF1 on the cell growth and chemoresistance were assessed using CCK-8 assays. Western blot and qRT-PCR were used to determine the changes in ferroptosis marker gene expression. Additionally, 4D-label free quantitative proteomics was conducted to uncover alterations by YTHDF1 deletion.</p><p><strong>Results: </strong>We observed that the deletion of YTHDF1 in the MRTK cell line led to a significant reduction in malignancy-associated characteristics, including decreased cell motility, invasive growth, and chemoresistance. Quantitative proteomic analysis revealed that the glutathione-related signaling pathway was notably affected by YTHDF1 KO. Specifically, YTHDF1 KO resulted in a reduction of both mRNA and protein levels of Glutathione S-Transferase Mu 2 (GSTM2), a phase II metabolizing enzyme responsible for conjugating glutathione to electrophilic compounds. The decrease in GSTM2 levels following YTHDF1 KO increased the susceptibility of MRTK cells to ferroptosis. Notably, overexpression of GSTM2 in YTHDF1 KO cells partially restored the oncogenic phenotype of MRTK cells, underscoring its role in MRTK progression.</p><p><strong>Conclusions: </strong>In summary, our findings provide new insights into the molecular mechanisms driving MRTK progression, highlighting YTHDF1 and GSTM2 as potential therapeutic targets for this aggressive pediatric renal tumor.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"96"},"PeriodicalIF":5.3,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246643","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":"Annexin A1-FPR1 Interaction in dendritic cells promotes immune microenvironment modulation in Thyroid Cancer.","authors":"Hongwei Jiang, Lirun Kuang, Tianyi Zhang, Xupeng Zhao","doi":"10.1007/s10565-025-10042-6","DOIUrl":"10.1007/s10565-025-10042-6","url":null,"abstract":"<p><p>Thyroid cancer (THCA) is profoundly influenced by its immune microenvironment, with dendritic cells (DCs) serving as key mediators of tumor-immune interactions. This study leveraged single-cell RNA sequencing and transcriptome RNA sequencing to analyze DC populations in THCA tissues. The results revealed significant disparities in DC distribution and function, with formyl peptide receptor 1 (FPR1) emerging as a crucial factor associated with patient prognosis. Meta-analysis further validated the differential expression of FPR1, reinforcing its significance in THCA progression. Investigations into the TME highlighted the relationship between FPR1 and DC maturation and activation, elucidating the mechanistic basis for immune regulation. Experimental validation confirmed that Annexin A1 (ANXA1) interacts with FPR1 in DCs, promoting tumor progression through immune modulation. These findings advance the understanding of THCA immune mechanisms and underscore the potential of targeting the ANXA1-FPR1 axis as a novel approach for immunotherapy in THCA.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"97"},"PeriodicalIF":5.3,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246642","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":"Exosomal POU5 F1 derived from TNBC promotes cancer progression by regulating M2 macrophage polarization via inhibiting TRAF6 ubiquitination and activating AKT in macrophage.","authors":"Yimeng Chai, Yao Shi","doi":"10.1007/s10565-025-10041-7","DOIUrl":"10.1007/s10565-025-10041-7","url":null,"abstract":"<p><p>Exosomes are pivotal in triple-negative breast cancer (TNBC) development, and accumulating evidence underscores their potential as therapeutic targets and diagnostic indicators. In this study, we revealed a significant enrichment of the POU domain, class 5, transcription factor 1 (POU5F1) in TNBC cells-derived exosomes. Functionally, silencing endogenous POU5F1 in TNBC cells substantially inhibited their aggressive phenotypes. Moreover, exosomes derived from TNBC cells contributed to macrophage M2 polarization by transferring POU5F1 to the recipient macrophages. Mechanistically, POU5F1 within these exosomes prevented the tumor necrosis factor receptor-associated factor 6 (TRAF6) degradation in macrophages, thereby activating the protein kinase B (AKT) signaling cascade and driving M2 polarization. Furthermore, in vivo experiments provided evidence that POU5F1 knockdown significantly reduced tumor growth and macrophage M2 polarization in a mouse model of TNBC cells by modulating the TRAF6/AKT signaling axis. Our study concludes that POU5F1 in TNBC cells-derived exosomes is vital for promoting macrophage M2 polarization by inhibiting TRAF6 ubiquitination and activating AKT signaling, thereby contributing to TNBC progression.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"95"},"PeriodicalIF":5.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215026","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":"Lipidomics reveals effect of EHHADH in lung squamous cell.","authors":"Jianan Huang, Linlin Zhang, Wanxin Duan, Liyang Li, Xiaoxia Liu, Xiangdong Wang","doi":"10.1007/s10565-025-10044-4","DOIUrl":"10.1007/s10565-025-10044-4","url":null,"abstract":"<p><p>Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are two major pathological types of non-small cell lung cancer (NSCLC), characterized by distinct patterns of lipid metabolism. However, the molecular mechanisms underlying lipid metabolism reprogramming specific to LUSC remain poorly understood. This study aims to fill this gap by identifying and characterizing EHHADH (enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase) as a key regulator of medium-chain fatty acid metabolism in LUSC. The peroxisomal L-bifunctional enzyme is one of the important elements to control the peroxisomal fatty acid beta-oxidation pathway. Through high-expression genes related to lipid metabolism were identified by data mining, the expression and regulatory effects of EHHADH in different cell lines were investigated. EHHADH was highly expressed in LUSC cells and exhibited different expression patterns from those in LUAD cells. Knockdown of EHHADH in LUSC cell lines led to a marked reduction in cell proliferation. RNA sequencing following EHHADH silencing demonstrated significant changes in the expression of lipid metabolism-related genes in different cell lines, such as AZGP1, CAV1, CYP3A4, NR2F2, NR3C2, and RARG. Lipidomics analysis further demonstrated that EHHADH plays a crucial role in regulating intracellular and extracellular lipid profiles. EHHADH knockdown resulted in increased levels of long-chain fatty acids and storage lipids, while decreased levels of medium-chain fatty acids. Conversely, overexpression of EHHADH reduced long-chain fatty acids and storage lipids, while increasing specific medium-chain fatty acids. These metabolic alterations were consistent with changes in lipid metabolism-related protein expression, supporting the molecular mechanistic role of EHHADH in lipid regulation. In conclusion, EHHADH functions as an important regulator of lipid metabolism in LUSC and plays a key role in the occurrence, progression, and treatment of lung cancer. The important impact of EHHADH in lipid metabolism disorders suggests potential utility as a biomarker for diagnosis and a target for personalized treatment strategies in lung cancer.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"94"},"PeriodicalIF":5.3,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191560","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":"cIAP2-mediated IGF2BP2 ubiquitination and degradation regulate cardiomyocyte apoptosis via stabilizing m⁶A-modified BAX mRNA in myocardial infarction.","authors":"Cong Wang, Jijia Liu, Xuyang Hou, Qing Guan, Huiling Zhou, Yong Luo, Wancun Jin, Fan Bai, Lijun Liu, Jian Wang, Li Xie, Feng Li, Haidan Liu","doi":"10.1007/s10565-025-10045-3","DOIUrl":"10.1007/s10565-025-10045-3","url":null,"abstract":"<p><p>Ubiquitin-proteasome system (UPS) is a major degradation system that maintains cardiac proteostasis, thus displaying an indispensable role in coronary artery disease, including myocardial infarction (MI). However, the function and mechanism of ubiquitin ligases in MI remain unclarified. In this study, we reported that cIAP2 protein, an E3 ubiquitin ligase, was downregulated in MI tissue and oxygen-glucose deprivation (OGD)-treated cardiomyocytes (CMs). cIAP2 depletion promoted OGD-induced injury and apoptosis in CMs, while adeno-associated virus (AAV) serotype 9 mediated-cardiac specific cIAP2 overexpression inhibited myocardial injury in MI mice. Moreover, we identified IGF2BP2 as a novel substrate of cIAP2. Mechanistically, cIAP2 downregulation inhibited IGF2BP2 ubiquitination and proteasomal degradation, leading to the upregulation of IGF2BP2 protein, which subsequently enhanced OGD-induced injury and apoptosis by stabilizing BAX mRNA in an m⁶A-dependent manner. In addition, our results showed that CWI1-2, a small molecule inhibitor of IGF2BP2, alleviated myocardial injury in MI mice by inhibiting cardiomyocyte apoptosis. Altogether, our results indicate that cIAP2 is a ubiquitin E3 ligase of IGF2BP2. The downregulation of cIAP2 protein aggravates OGD-induced apoptosis and oxidative damage in CMs via IGF2BP2/BAX axis. These findings provide a potential therapeutic target for reducing cardiomyocyte loss in MI.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"92"},"PeriodicalIF":5.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186651","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":"Integrated machine learning survival framework develops a prognostic model based on macrophage-related genes and programmed cell death signatures in a multi-sample Kidney renal clear cell carcinoma.","authors":"Xuefei Liu, Min Deng, Xing Luo, Tingting Li, Yanan Ge, Jianong Li, Jiang Zhao, Limin Yang","doi":"10.1007/s10565-025-10023-9","DOIUrl":"10.1007/s10565-025-10023-9","url":null,"abstract":"<p><strong>Background: </strong>Macrophages are closely associated with the progression of Kidney renal clear cell carcinoma (KIRC) and can influence programmed cell death (PCD) of tumour cells. To identify prognostic biomarkers for KIRC, it is essential to investigate the association between macrophage-related genes and PCD characteristics.</p><p><strong>Methods: </strong>Clinical details and transcriptome data from 693 KIRC samples were obtained from multiple databases, including TCGA and GEO. Genes associated with macrophages and programmed cell death (PCD) were identified and key regulatory genes and PCD patterns were analyzed. The relationship between macrophages and 18 types of cell death is under investigation with a powerful computational framework. Ten machine learning algorithms, 101 unique combinations of algorithms were utilized to build a macrophage-associated programmed cell death (MacPCD) model to predict KIRC patient survival. Immunohistochemistry and RT-qPCR were used for genetic analysis of MacPCD models.</p><p><strong>Results: </strong>The MacPCD model is made up of six genes which showed strong predictive power for the prognosis of patients with KIRC. Immunohistochemistry and RT-qPCR showed that among the MacPCD model genes, BID, SLC25A37 and BNIP3L were highly expressed in tumour tissues, whereas ACSL1, SDHB and ALDH2 were highly expressed in normal tissues. Biologically, the high MacPCD group showed higher tumor mutation burden and increased immune cell infiltration and high expression of immunomodulators. In particular, MacPCD was an independent prognostic indicator of KIRC and was the best predictor of KIRC survival (AUC = 0.920) compared with multiple clinical variables (Age, M, and Stage).</p><p><strong>Conclusion: </strong>We used a powerful machine learning framework to highlight the great potential of MacPCD in providing personalised risk assessment and immunotherapy intervention recommendations for KIRC patients.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"93"},"PeriodicalIF":5.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186652","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 key regulator circPDE3B promotes arsenic-induced bladder carcinogenesis by affecting STAT3 and NF-κB stability.","authors":"Yihong Gao, Haotian Xu, Qingyun Zhao, Dunyu Cai, Xiaodong Zhou, Xingcai Chen, Shengyi Yuan, Deqing Li, Taoran Ning, Xiangyu Dong, Mengyao Li, Gang Li, Aruo Nan","doi":"10.1007/s10565-025-10038-2","DOIUrl":"10.1007/s10565-025-10038-2","url":null,"abstract":"<p><p>Long-term exposure to arsenic (As), which is a ubiquitous environmental contaminant, significantly enhances the risk of multiple cancers, including bladder and lung cancers. In recent years, the important roles of circular RNAs (circRNAs) in tumorigenesis and development have attracted widespread attention. However, the specific molecular mechanisms by which circRNAs promote bladder cancer development following exposure to arsenic remain incompletely understood. This study is the first to demonstrate that circPDE3B is significantly upregulated in a cell model of transformation triggered by arsenic and that it promotes this transformation process. Our study elucidated the biological function of circPDE3B in vitro, in SV-HUC-1 cells, showing that it accelerates the malignant transformation from arsenic via increasing cell proliferation and inhibiting apoptosis. Furthermore, we delineated a novel molecular mechanism whereby circPDE3B directly binds to NF-κB and STAT3, inhibiting their ubiquitination and increasing their stability. This, in turn, affects downstream HIF-1α expression, promoting the malignant transformation of SV-HUC-1 cells and eventually resulting in bladder carcinogenesis. Our research reveals the critical regulatory role of circPDE3B in the arsenic-triggered malignant transformation within SV-HUC-1 cells. This study offers broader perspectives on the molecular mechanisms driving bladder cancer progression, while also identifying potential targets for early diagnosis and treatment of bladder tumour.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"91"},"PeriodicalIF":5.3,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172796","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":"IFI204 in microglia mediates traumatic brain injury-induced mitochondrial dysfunction and pyroptosis via SENP7 interaction.","authors":"Ting Guo, Yongxing Lai, Shuguang Wu, Chunjin Lin, Xinyu Zhou, Peiqiang Lin, Mouwei Zheng, Jianhao Chen, Fan Lin","doi":"10.1007/s10565-025-10032-8","DOIUrl":"10.1007/s10565-025-10032-8","url":null,"abstract":"<p><strong>Objectives: </strong>Traumatic brain injury (TBI) is a primary contributor to chronic functional impairment in human populations, initiating complex neuroinflammatory cascades and neurodegeneration. Despite extensive research efforts, the precise pathophysiological pathways remain incompletely characterized. This investigation aims to establish a novel therapeutic strategy that targets critical molecular pathways post-injury, potentially addressing the current limitations in the clinical management of TBI patients.</p><p><strong>Methods: </strong>The single-cell data of cortical tissue from mice with TBI were obtained from public databases (GSE160763), which was utilized to identify alterations in in the composition of disease-associated cells and related molecules as the disease progresses. Functional and pathway enrichment analyses were conducted to elucidate the functional characteristics of microglia and astrocyte subpopulations. Trajectory analysis was employed to investigate cell differentiation characteristics. Subsequently, we examined the expression and function of microglia-specific molecules, such as IFI204, along with their underlying molecular mechanisms using Western blotting, immunofluorescence, co-immunoprecipitation (CO-IP), histopathology, behavioral tests, and molecular docking to assess binding status, as well as molecular dynamics simulations. Finally, we used molecular docking technology to find small molecule compounds that IFI204 can stably bind to.</p><p><strong>Results: </strong>We identified nine major cell populations, most of which undergo dynamic changes following TBI. Astrocytes and microglia were the predominant populations in each group, and further cluster analysis revealed that the proportions of interferon (IFN) and axonogenesis-related microglial subtypes increased after TBI. Trajectory inference analysis indicated that the expression of Ifi204 is upregulated in microglia during disease progression. Conditional microglial knockdown of IFI204 significantly improved neurological deficits in mice, and alleviated mitochondrial dysfunction and microglial pyroptosis. Mechanistically, SENP7, identified as a novel molecule, interacts with IFI204 in microglia, catalyzes the deSUMOylation of IFI204, and promotes STING signal activation, ultimately driving microglial pyroptosis and mitochondrial dysfunction.</p><p><strong>Conclusions: </strong>The interaction between IFI204 and SENP7 promotes microglial pyroptosis and related mitochondrial dysfunction. Furthermore, in the case of TBI, we hypothesize that targeting IFI204 might yield therapeutic benefits.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"89"},"PeriodicalIF":5.3,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12102124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126804","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}