Clinical and Translational Medicine最新文献

{"title":"Nuclear factor erythroid 2-related factor 2 ameliorates disordered glucose and lipid metabolism in liver: Involvement of gasdermin D in regulating pyroptosis","authors":"Xuyun Xia, Qin Zhang, Xia Fang, Ling Li, Gangyi Yang, Xiaohui Xu, Mengliu Yang","doi":"10.1002/ctm2.70233","DOIUrl":"https://doi.org/10.1002/ctm2.70233","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The epidemic of metabolic dysfunction-associated fatty liver disease linked to excessive high-fat diet (HFD) consumption has sparked widespread public concern. Nuclear factor erythroid 2-related factor 2 (NRF2) has been reported to improve glucose/lipid metabolism, liver lipid degeneration and alleviate HFD-induced inflammation. However, its pathways and mechanisms of action are not fully understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To confirm the effect of NRF2 on glucose/lipid metabolism in the liver, Nrf2-/- mice as well as liver-specific Nrf2 knockout mice, and AAV-TBG-Nrf2 were employed. The hyperinsulinemic-euglycemic clamp was utilized to determine the effect of NRF2 on glucose metabolism. To elucidate the effect of NRF2 on pyroptosis, we performed western blots, immunofluorescence, quantitative real-time PCR, and Flow cytometry experiments. Finally, chromatin immunoprecipitation-seq and dual-luciferase reporter assay was used to underscore the transcriptional regulatory effect of NRF2 on Gsdmd.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that overexpression of Nrf2 inhibited the expression of inflammatory cytokines and pyroptosis markers, including cle-Caspase1, NLRP3 and the N-terminus of gasdermin D (N-GSDMD) both in vivo and in vitro, while Nrf2 deficiency was the opposite. Specifically, with NRF2 expression up-regulated, GSDMD expression decreased and Gsdmd overexpression partially reversed the effect of Nrf2 overexpression on pro-inflammatory phenotype. Mechanistically, we demonstrate that NRF2 binds to the Gsdmd promoter at the −2110 - 1130 bp site, inhibiting the GSDMD expression and thereby improving glucose/lipid metabolism and liver steatosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our data indicate that NRF2 is an effective inhibitor of pyroptosis and has a multi-target effect in the treatment of obesity-related metabolic diseases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>MAFLD is associated with increased hepatocytes NRF2 expression.</li>\u0000 \u0000 <li>NRF2 alleviates MAFLD by suppressing pyroptosis.</li>\u0000 \u0000 <li>NRF2 directly inhibits GSDMD expression to regulate pyroptosis.</li>\u0000 \u0000 <li>Targeting the NRF2–pyroptosis (GSDMD) axis offers a potential therapeutic strate","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70233","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive transcriptome, miRNA and kinome profiling identifies new treatment options for personalized lung cancer therapy","authors":"Shen Zhong,&nbsp;Yvonne Börgeling,&nbsp;Patrick Zardo,&nbsp;Danny Jonigk,&nbsp;Jürgen Borlak","doi":"10.1002/ctm2.70177","DOIUrl":"https://doi.org/10.1002/ctm2.70177","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Basic research identified oncogenic driver mutations in lung cancer (LC). However, &lt;10% of patients carry driver mutations. Thus, most patients are not recommended for first-line kinase inhibitor (KI)–based therapies. Through enabling technologies and bioinformatics, we gained deep insight into patient-specific signalling networks which permitted novel KI-based treatment options in LC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed molecular pathology, transcriptomics and miRNA profiling across 95 well-characterized LC patients. We confirmed results based on cross-linked immunoprecipitation-sequencing data, and used <i>N</i> = 524 adeno- and 497 squamous cell carcinomas as validation sets. We employed the PamGene platform to identify aberrant kinases, validated the results by evaluating independent siRNA and CRISPR-mediated mRNA knockdown studies in human LC cell lines.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Transcriptomics revealed 439, 1240, 383 and 320 significantly upregulated genes, respectively, for adeno-, squamous, neuroendocrine and metastatic cases, and there are 1092, 1477, 609 and 1267 downregulated DEGs. Based on gene enrichment analysis and experimentally validated miRNA–gene interactions, we constructed regulatory networks specific for adeno-, squamous, neuroendocrine and metastatic LC. Molecular profiling discovered 137 significantly upregulated kinases (range 2–26-fold) of which 65 and 72, respectively, are tyrosine and serine-threonine kinases while 6 kinases carry driver mutations. Meanwhile, there are 21 kinases commonly upregulated irrespective of the histological type of LC. Bioinformatics decoded networks in which kinases function as master regulators. Typically, the networks consisted of 14, 9, 16 and 19 highly regulated kinases in adeno-, squamous, neuroendocrine and metastatic LC. Inhibition of kinases which function as master regulators disrupted the signalling networks, and their gene knock-down studies confirmed inhibition of cell proliferation in a panel of human LC cell lines. Additionally, the proposed molecular profiling enables KI-based therapies in patients with acquired drug resistance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study broadens the perspective of KI-based therapies in LC, and we propose a framework to overcome acquired drug resistance.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70177","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kibra knockdown inhibits the aberrant Hippo pathway, suppresses renal cyst formation and ameliorates renal fibrosis in nphp1KO mice","authors":"Yichen Yang,&nbsp;Zhihe Xue,&nbsp;Jiayong Lai,&nbsp;Jinglan Zhang,&nbsp;Changmiao Pang,&nbsp;Jinglin Zhong,&nbsp;Zhanpeng Kuang,&nbsp;Baojuan Zou,&nbsp;Yaqing Liu,&nbsp;Liangzhong Sun","doi":"10.1002/ctm2.70245","DOIUrl":"https://doi.org/10.1002/ctm2.70245","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Introduction&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Nephronophthisis (NPH) is an autosomal recessive interstitial cystic kidney disease, which is the most common genetic cause of end-stage renal disease (ESRD) in childhood. The Hippo pathway is regulated by the cilium and has been suggested to be linked to NPH. The aim of the study was to investigate the involvement of Hippo pathway in the pathogenesis of &lt;i&gt;nphp1&lt;/i&gt; defect-associated NPH (NPH1).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Method&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;&lt;i&gt;Nphp1&lt;/i&gt; knockout (&lt;i&gt;nphp1&lt;/i&gt;&lt;sup&gt;KO&lt;/sup&gt;) Madin-Darby Canine Kidney (MDCK) cells and &lt;i&gt;nphp1&lt;/i&gt;&lt;sup&gt;KO&lt;/sup&gt; C57BL/6J mice were generated via CRISPR gene editing strategy. The siRNAs targeting &lt;i&gt;Kibra&lt;/i&gt;, &lt;i&gt;MST1&lt;/i&gt; and &lt;i&gt;LATS1&lt;/i&gt; were designed. An AAV9 vector was designed for &lt;i&gt;Kibra&lt;/i&gt; knockdown. The expression and phosphorylation of core Hippo pathway molecules were evaluated. Pathological renal changes were evaluated via light microscopy respectively with haematoxylin–eosin and Masson staining.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In &lt;i&gt;nphp1&lt;/i&gt;&lt;sup&gt;KO&lt;/sup&gt; MDCK cells, &lt;i&gt;nphp1&lt;/i&gt;&lt;sup&gt;KO&lt;/sup&gt; mice and NPH1 patients’ kidneys, Kibra, p-MST1/2, p-LATS and p-YAP exhibited a notable increase in levels, with an even greater elevation observed in renal cyst cells, indicating the Hippo pathway activated in these &lt;i&gt;nphp1&lt;/i&gt;-deficient contexts. &lt;i&gt;Nphp1&lt;/i&gt; re-expression reversed the Hippo pathway activation in cells, indicating that the Hippo pathway activation is related to &lt;i&gt;nphp1&lt;/i&gt; deficiency in vitro. Meanwhile, in vitro, &lt;i&gt;MST1&lt;/i&gt; knockdown downregulated LATS1 and YAP phosphorylation, &lt;i&gt;LATS1&lt;/i&gt; knockdown downregulated YAP phosphorylation, suggesting the activation of the canonical Hippo pathway in &lt;i&gt;nphp1&lt;/i&gt;-deficient contexts. Knockdown of the upstream regulator &lt;i&gt;Kibra&lt;/i&gt; inhibited the Hippo pathway activation in both &lt;i&gt;nphp1&lt;/i&gt;&lt;sup&gt;KO&lt;/sup&gt; MDCK cells and mice. Following &lt;i&gt;Kibra&lt;/i&gt; knockdown, the organisation of &lt;i&gt;nphp1&lt;/i&gt;&lt;sup&gt;KO&lt;/sup&gt; MDCK cells became more compact, the intensity of the actin fibres increased. Besides, decreased renal fibrosis and cyst formation were observed in &lt;i&gt;nphp1&lt;/i&gt;&lt;sup&gt;KO&lt;/sup&gt; mice.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The canonical Hippo pathway is aberrantly activated in &lt;i&gt;nphp1&lt;/i&gt;-deficient conditions. &lt;i&gt;Kibra&lt;/i&gt; may serve as a crucial upstream regulator of &lt;i&gt;nphp1&lt;/i&gt; deficiency-related Hippo pathway activation. &lt;i&gt;Kibra&lt;/i&gt; upregulation and activation of the Hippo pathway are involved in the pathogenesis of NPH1.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70245","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial genomics uncovers cytokines promoting ovarian tumour heterogeneity and immunotherapy resistance","authors":"Gurkan Mollaoglu,&nbsp;Brian D. Brown,&nbsp;Alessia Baccarini","doi":"10.1002/ctm2.70248","DOIUrl":"https://doi.org/10.1002/ctm2.70248","url":null,"abstract":"&lt;p&gt;Ovarian cancer (OvCa) is a leading cause of cancer-related deaths among women, with a five-year survival rate of less than 50%.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Despite a woman's lifetime risk of developing OvCa being as high as one in 91, the lack of effective screening methods and the disease's subtle, nonspecific symptoms—often mistaken for benign conditions—result in most cases being diagnosed at advanced stages. Standard treatment for advanced OvCa includes a combination of debulking surgery and chemotherapy, with some patients also receiving targeted therapies such as Bevacizumab (a vascular endothelial growth factor inhibitor) or Olaparib (a poly[ADP-ribose] polymerase inhibitor). However, even with optimal surgery and chemotherapy, most tumours recur within 18–24 months, often developing resistance to further treatment.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; To date, immunotherapies have shown limited success in OvCa, with clinical trials using immune checkpoint inhibitors reporting objective response rates below 10%.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; This is despite the moderate tumour mutation burden and PD-L1 positivity observed in OvCa. Increasing evidence from preclinical and clinical studies suggests that OvCa's highly immunosuppressive tumour microenvironment is responsible for the failure of immunotherapy.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Ovarian cancer is a prime example of intratumoral heterogeneity (ITH), a key driver of treatment failure across many cancers.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Ovarian tumours almost universally exhibit &lt;i&gt;TP53&lt;/i&gt; loss, along with frequent somatic and germline mutations in homologous recombination repair pathway genes—most notably &lt;i&gt;BRCA1&lt;/i&gt; and &lt;i&gt;BRCA2&lt;/i&gt;—leading to homologous recombination deficiency in approximately half of the cases. Without proper DNA repair mechanisms, these tumours accumulate extensive chromosomal abnormalities, including copy number variations and structural alterations, resulting in profound genomic instability.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; The long latency of tumour development, coupled with widespread metastatic dissemination to peritoneal organs, provides fertile ground for OvCa to grow with significant ITH, which in turn promotes immune evasion and treatment resistance.&lt;/p&gt;&lt;p&gt;Understanding how ITH drives immune evasion and immunotherapy resistance is therefore of paramount importance. Notably, ITH is not confined to cancer cells but also manifests within the tumour microenvironment (TME), influencing immune cell abundances, functional states, and cellular interactions.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; A fundamental question is how tumour clones establish their distinct TMEs and to what extent clonal TME influences clonal selection. Sequencing and imaging-based studies of clinical samples have identified certain genomic correlates of ovarian TME phenotypes, such as genetic alterations affecting angiogenesis, antigen presentation, oxidative phosphorylation, and inflammatory signalling pathways.&lt;span&gt;&lt;sup&gt;7-10&lt;/sup","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70248","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CLINICAL AND TRANSLATIONAL MEDICINE","authors":"","doi":"10.1002/ctm2.70259","DOIUrl":"https://doi.org/10.1002/ctm2.70259","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70259","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitin-specific protease 25 improves myocardial ischemia–reperfusion injury by deubiquitinating NLRP3 and negatively regulating NLRP3 inflammasome activity in cardiomyocytes","authors":"Bozhi Ye,&nbsp;Diyun Xu,&nbsp;Lingfeng Zhong,&nbsp;Yi Wang,&nbsp;Wei Wang,&nbsp;Haowen Xu,&nbsp;Xue Han,&nbsp;Julian Min,&nbsp;Gaojun Wu,&nbsp;Wenhai Huang,&nbsp;Guang Liang","doi":"10.1002/ctm2.70243","DOIUrl":"https://doi.org/10.1002/ctm2.70243","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Myocardial ischemia/reperfusion injury (MI/RI) restricts the effect of myocardial reperfusion therapy and lacks effective prevention and treatment methods. Deubiquitinating enzymes (DUBs), especially members of the ubiquitin-specific protease (USP) family of DUBs, are key proteins in the ubiquitination modification process and play a vital role in MI/RI. Therefore, we aimed to investigate the role of USP25, as a member of the USP family, in MI/RI and its molecular mechanism.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Transcriptome sequencing was applied to evaluate the differential expression of USP families during hypoxia/reoxygenation (H/R) and validated in human and mouse heart samples and cardiomyocytes by performing quantitative polymerase chain reaction. Wild-type or USP25&lt;sup&gt;−/−&lt;/sup&gt; mice were used to develop the MI/RI model. Co-immunoprecipitation (Co-IP) combined with liquid chromatography–tandem mass spectrometry analysis was used to screen the potential substrate protein of USP25 in H/R-induced cardiomyocyte injury. TUNEL and Hoechst/propidium iodide staining and western blot were used to detect the level of pyroptosis. In addition, cardiomyocyte-specific USP25 overexpression in NLRP3&lt;sup&gt;−/−&lt;/sup&gt; mice with AAV9 vectors was used to validate the biological function of USP25 and NLRP3 interaction.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We found that the expression level of USP25 was significantly decreased in I/R-induced mouse heart tissues and primary cardiomyocytes in a time-dependent manner. USP25 deficiency exacerbated MI/RI and aggravated I/R-induced cardiac remodelling in mice. Mechanistically, USP25 directly binds to NLRP3 protein and K63-linkedly deubiquitinates NLRP3 at residue K243 via its active site C178, thus hindering NLRP3–ASC interaction and ASC oligomerization to inhibit NLRP3 activation and pyroptosis in cardiomyocytes. We further showed that the overexpression of USP25 in cardiomyocytes ameliorated MI/RI in mice, whereas this protective effect disappeared when NLRP3 is knocked out.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our study demonstrated that USP25 ameliorates MI/RI by regulating NLRP3 activation and its mediated pyroptosis. This finding extends the protective role of USP25 in cardiovascular disease and provides an experimental basis for future USP25-based drug development for the treatment of MI/RI.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70243","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143466142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SHP2 inhibition and adjuvant therapy synergistically target KIT-mutant GISTs via ERK1/2-regulated GSK3β/cyclin D1 pathway","authors":"Chunxiao He,&nbsp;Jiaying Yu,&nbsp;Shuang Mao,&nbsp;Shaohua Yang,&nbsp;Xianming Jiang,&nbsp;Lei Huang,&nbsp;Mingzhe Li,&nbsp;Yulong He,&nbsp;Xinhua Zhang,&nbsp;Xi Xiang","doi":"10.1002/ctm2.70231","DOIUrl":"https://doi.org/10.1002/ctm2.70231","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Most gastrointestinal stromal tumours (GISTs) are driven by KIT proto-oncogene, receptor tyrosine kinase (KIT). Targeted treatment with imatinib has been successful in primary GIST patients. However, resistance and relapse gradually develop due to secondary KIT mutations. Identifying novel therapeutic targets for advanced GIST with KIT mutants is critical.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 gene editing, immunoblotting, immunoprecipitation and cell-based assays were used to characterise the role of Src homology region 2 domain-containing phosphatase 2 (SHP2) in GIST. Immunoblotting, cell cycle analysis, transcriptome analysis and rescue experiments were performed to investigate the molecular mechanisms underlying SHP2 inhibition. Synergistic effects of SHP2 inhibition with approved KIT tyrosine kinase inhibitors (TKIs) were demonstrated using cell proliferation assay, spheroid formation assay, cell cycle analysis and immunoblotting. The combination of SHP2 inhibition and imatinib was further evaluated in GIST mouse models.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In KIT-mutant GIST, SHP2 was hyperactive and coprecipitated with KIT. Activated SHP2 transduced signals from KIT to the downstream MAPK/ERK pathway. SHP2 inhibition significantly reduced cell viability and arrested cell at G0/G1 phase in GIST cells. Mechanistically, SHP2 regulated the MAPK/ERK, GSK3β/cyclin D1 and mTORC1 pathways in GIST. Specifically, SHP2 inhibition relieved GSK3β self-inhibition, leading to a reduction in cyclin D1 via phosphorylation at Thr286 and subsequent G0/G1 cell cycle arrest. Rescue experiments confirmed that cyclin D1 is functional and critical for cell proliferation. Additionally, SHP2 inhibition synergised with approved KIT TKIs in inhibiting GIST cells. In GIST mouse models, SHP2 inhibitor (SHP099) combined with imatinib significantly inhibited proliferation of imatinib-sensitive and -insensitive GIST cells.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;SHP2 functioned as a key signal transducer for the MAPK/ERK signalling pathway and regulated the cell cycle through GSK3β/cyclin D1/Rb pathway. SHP2 inhibition demonstrates significant efficacy towards GIST cells and synergises with approved TKIs. Therefore, SHP2 represents a promising therapeutic target for advanced GIST.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70231","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143455862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipose tissue deficiency impairs transient lipid accumulation and delays liver regeneration following partial hepatectomy in male Seipin knockout mice","authors":"Qianqian Dong,&nbsp;Ziwei Liu,&nbsp;Yidan Ma,&nbsp;Xin Chen,&nbsp;Xiaowei Wang,&nbsp;Jinye Tang,&nbsp;Kexin Ma,&nbsp;Chenxi Liang,&nbsp;Mengyu Wang,&nbsp;Xiaoqin Wu,&nbsp;Yang Liu,&nbsp;Yaru Zhou,&nbsp;Hongyuan Yang,&nbsp;Mingming Gao","doi":"10.1002/ctm2.70238","DOIUrl":"https://doi.org/10.1002/ctm2.70238","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Liver diseases pose significant health challenges, underscoring the importance of understanding liver regeneration mechanisms. Systemic adipose tissue is thought to be a primary source of lipids and energy during this process; however, empirical data on the effects of adipose tissue deficiency are limited. This study investigates the role of adipose tissue in liver regeneration, focusing on transient regeneration-associated steatosis (TRAS) and hepatocyte proliferation using a Seipin knockout mouse model that mimics severe human lipodystrophy. Additionally, the study explores therapeutic strategies through adipose tissue transplantation.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Male Seipin knockout (&lt;i&gt;Seipin&lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt;) and wild-type (WT) mice underwent 2/3 partial hepatectomy (PHx). Liver and plasma samples were collected at various time points post-surgery. Histological assessments, lipid accumulation analyses and measurements of hepatocyte proliferation markers were conducted. Additionally, normal adipose tissue was transplanted into &lt;i&gt;Seipin&lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; mice to evaluate the restoration of liver regeneration.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;&lt;i&gt;Seipin&lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; mice exhibited significantly reduced liver regeneration rates and impaired TRAS, as evidenced by histological and lipid measurements. While WT mice demonstrated extensive hepatocyte proliferation at 48 and 72 h post-PHx, characterised by increased mitotic cells, elevated proliferating cell nuclear antigen and Ki67 expression, &lt;i&gt;Seipin&lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; mice showed delayed hepatocyte proliferation. Notably, adipose tissue transplantation into &lt;i&gt;Seipin&lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; mice restored TRAS and improved liver regeneration and hepatocyte proliferation. Conversely, liver-specific overexpression of Seipin in &lt;i&gt;Seipin&lt;sup&gt;−/−&lt;/sup&gt;&lt;/i&gt; mice did not affect TRAS or liver regeneration, indicating that the observed effects are primarily due to adipose tissue deficiency rather than hepatic Seipin itself.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Systemic adipose tissue is essential for TRAS and effective liver regeneration following PHx. Its deficiency impairs these processes, while adipose tissue transplantation can restore normal liver function. These findings underscore the critical role of adipose tissue in liver recovery and suggest potential therapeutic strategies for liver diseases associated with lipodystrophies.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70238","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143455905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 secret codes in N7-methylguanosine modification: Context-dependent function of methyltransferase-like 1 in human diseases","authors":"Huan Fang,&nbsp;Jing He,&nbsp;Dan Du,&nbsp;Xue Wang,&nbsp;Xinyu Xu,&nbsp;Linping Lu,&nbsp;Yefan Zhou,&nbsp;Yangyang Wen,&nbsp;Fucheng He,&nbsp;Yingxia Li,&nbsp;Hongtao Wen,&nbsp;Mingxia Zhou","doi":"10.1002/ctm2.70240","DOIUrl":"https://doi.org/10.1002/ctm2.70240","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>N⁷-methylguanosine (m⁷G) is one of the most prevalent post-transcriptional modifications of RNA and plays a critical role in RNA translation and stability. As a pivotal m⁷G regulator, methyltransferase-like 1 (METTL1) is responsible for methyl group transfer during the progression of m⁷G modification and contributes to the structure and functional regulation of RNA. Accumulating evidence in recent years has revealed that METTL1 plays key roles in various diseases depending on its m⁷G RNA methyltransferase activity. Elevated levels of METTL1 are typically associated with disease development and adverse consequences. In contrast, METTL1 may act as a disease suppressor in several disorders. While the roles of m⁷G modifications in disease have been extensively reviewed, the critical functions of METTL1 in various types of disease and the potential targeting of METTL1 for disease treatment have not yet been highlighted. This review describes the various biological functions of METTL1, summarises recent advances in understanding its pathogenic and disease-suppressive functions and discusses the underlying molecular mechanisms. Given that METTL1 can promote or inhibit disease processes, the possibility of applying METTL1 inhibitors and agonists is further discussed, with the goal of providing novel insights for future disease diagnosis and potential intervention targets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>METTL1-mediated m7G modification is crucial for various biological processes, including RNA stability, maturation and translation.</li>\u0000 \u0000 <li>METTL1 has emerged as a critical epigenetic modulator in human illnesses, with its dysregulated expression correlating with multiple diseases progression and presenting opportunities for both diagnostic biomarker development and molecular-targeted therapy.</li>\u0000 \u0000 <li>Enormous knowledge gaps persist regarding context-dependent regulatory networks of METTL1 and dynamic m7G modification patterns, necessitating mechanistic interrogation to bridge basic research with clinical translation in precision medicine.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70240","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143455906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E2F1/CDK5/DRP1 axis mediates microglial mitochondrial division and autophagy in the pathogenesis of cerebral ischemia-reperfusion injury","authors":"Ya-Jing Yuan,&nbsp;Tingting Chen,&nbsp;Yan-Ling Yang,&nbsp;Hao-Nan Han,&nbsp;Li-Ming Xu","doi":"10.1002/ctm2.70197","DOIUrl":"https://doi.org/10.1002/ctm2.70197","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The integrity of brain function is at stake due to cerebral ischemia-reperfusion injury (CIRI), which encompasses mitochondrial dysfunction, autophagy, and neuroinflammation. The role of E2F1 in mediating these processes in microglia during CIRI remains unclear.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A CIRI mouse model was utilized for single-cell RNA transcriptome sequencing of brain tissues. The research comprised diverse gene expression, gene ontology (GO), and the enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Experimental techniques included oxygen-glucose deprivation (OGD/R) cell models, RT-qPCR, Western Blot, ChIP assays, and microglia-neuron co-cultures.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A significant aspect highlighted in the study was the involvement of CDK5 in the induction of mitochondrial abnormalities associated with CIRI. Upregulation of E2F1 and CDK5 in post-CIRI microglia was observed. E2F1 facilitated CDK5 transcription, leading to DRP1 phosphorylation, exacerbating neurotoxic effects. Silencing E2F1 improved neurobehavioral outcomes in CIRI mice.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Activation of E2F1-mediated CDK5 drives mitochondrial division while inhibiting mitophagy in microglia, triggering inflammation, neuronal apoptosis, and exacerbating CIRI damage. Targeting this pathway could offer novel therapeutic strategies for mitigating CIRI-induced brain injury.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Identification of the E2F1/CDK5/DRP1 Axis in CIRI This study reveals that the E2F1 transcription factor upregulates CDK5 expression, which in turn phosphorylates DRP1, promoting excessive mitochondrial fission and inhibiting mitophagy in microglia. This mechanism plays a critical role in cerebral ischemia-reperfusion injury (CIRI).&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Mitochondrial Dysfunction and Neuroinflammation The activation of DRP1 leads to mitochondrial fragmentation and excessive ROS accumulation, triggering microglial activation and inflammatory responses, exacerbating neuronal apoptosis and brain injury in CIRI.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Therapeutic Potential of E2F1 Silencing Knockdown of E2F1 in microglia effectively reduces mitochondrial damage, restores mitophagy, suppresses inflammation, and improves ne","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 2","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70197","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143438795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}