Clinical and Translational Medicine最新文献

{"title":"Targeting Zfp36 to combat cardiac hypertrophy: Insights into ferroptosis pathways","authors":"Mingyu Zhang,&nbsp;Xiaoxiang Guan,&nbsp;Zheng Dong,&nbsp;Chenxu Yang,&nbsp;Chao Xiong,&nbsp;Wenzheng Cheng,&nbsp;Aijing Shang,&nbsp;Yaru Liu,&nbsp;Xiaofei Guo,&nbsp;Bowen Zhang,&nbsp;Bo Zhang,&nbsp;Saidi Jin,&nbsp;Wenyi Qi,&nbsp;Berezhnova Tatjana Alexandrovna,&nbsp;Yuan Jiang,&nbsp;Zhimin Du,&nbsp;Chaoqian Xu","doi":"10.1002/ctm2.70247","DOIUrl":"https://doi.org/10.1002/ctm2.70247","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cardiac hypertrophy is a precursor to heart failure and represents a significant global cause of mortality, thereby necessitating timely and effective therapeutic interventions. Zinc finger protein 36 (Zfp36) is recognised as a critical regulator of ferroptosis; however, its role and underlying mechanisms in cardiac hypertrophy remain largely unexplored. This study aims to investigate the regulatory function of Zfp36 in ferroptosis within the context of cardiac hypertrophy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and results</h3>\u0000 \u0000 <p>Single-cell sequencing analysis demonstrated a reduction in Zfp36 expression associated with cardiac hypertrophy. Zfp36 was observed to mitigate ferroptosis and reduce hypertrophic phenotypes in cardiomyocytes subjected to Angiotensin II (Ang II) and in myocardial tissues induced by transverse aortic constriction. The ferroptosis inhibitor Ferrostatin-1 was shown to alleviate hypertrophy when co-incubated with si-Zfp36 and Ang II. Mechanistically, Zfp36 binds to the 3′ untranslated region (3′UTR) of Ythdc2 mRNA, facilitating its degradation. Ythdc2 subsequently binds to SLC7A11 mRNA, enhancing its decay, which leads to a reduction in glutathione (GSH) levels, thereby exacerbating ferroptosis and cardiac hypertrophy. Furthermore, overexpression of Ythdc2 reversed the protective effects conferred by Zfp36, while silencing of Ythdc2 counteracted the effects of Zfp36 knockdown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study elucidates the role of Zfp36 in cardiac hypertrophy, specifically detailing its modulatory mechanism via the Ythdc2/SLC7A11/GSH ferroptosis pathway. These insights lay the groundwork for innovative approaches to understanding the pathological mechanisms underlying cardiac hypertrophy and enhancing clinical interventions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Zfp36 was initially demonstrated to attenuate cardiac hypertrophy through the inhibition of ferroptosis in cardiomyocytes, providing a new target for therapeutic strategies targeting ferroptosis.</li>\u0000 \u0000 <li>Zfp36 facilitated the degradation of Ythdc2 mRNA by binding to it, subsequently inhibiting Ythdc2-mediated degradation of SLC7A11 mRNA, and maintaining GSH levels. This elucidates a previously unrecognized regulatory pathway in the context of cardiac hypertrophy.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70247","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143489747","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":"Genome-wide profiling of N6-methyladenosine-modified pseudogene-derived long noncoding RNAs reveals the tumour-promoting and innate immune-restraining function of RPS15AP12 in ovarian cancer","authors":"Jie Xu,&nbsp;Yifei Ren,&nbsp;Jiayi Lu,&nbsp;Fengjiang Qin,&nbsp;Dan Yang,&nbsp;Chunyan Tang,&nbsp;Yu Yang,&nbsp;Jing Xu,&nbsp;Tao Liu,&nbsp;Ping Yi","doi":"10.1002/ctm2.70249","DOIUrl":"https://doi.org/10.1002/ctm2.70249","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;Pseudogene-derived lncRNAs are widely dysregulated in cancer. Technological advancements have facilitated the functional characterization of increasing pseudogenes in cancer progression. However, the association between pseudogenes and RNA N6-methyladenosine (m&lt;sup&gt;6&lt;/sup&gt;A) modification in cancer, as well as the underlying mechanisms, remains largely unexplored.&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;We analyzed the expression of 12 146 pseudogenes and comprehensively examined the m&lt;sup&gt;6&lt;/sup&gt;A modification of RNAs derived from them and their paralogs. Through integrative analysis of multi-omics data, we explored the associations between pseudogene dysregulation and m&lt;sup&gt;6&lt;/sup&gt;A, identifying critical pseudogenes involved in HGSOC progression. Tumour promotion role of RPS15AP12 and its cognate parent gene was characterized by cell proliferation, transwell assays, and scratch assays in ovarian cells and xenograft nude mice. RNA decay assays were used to reveal the participation of m&lt;sup&gt;6&lt;/sup&gt;A in decreasement of RPS15AP12 lncRNA stability. Luciferase reporter assays were performed to verify that RPS15AP12 enhances RPS15A expression by competitively binding to miR-96-3p. Western blot and phosphorylation assays were performed to investigate the impairment of RPS15AP12 towards the sensors of MAVS (RIG-I and MDA5), and downstream p-TBK1 and p-IRF3. Finally, ELISA assays were performed to explore the regulatory role of RPS15AP12 in IFN-β expression.&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;M&lt;sup&gt;6&lt;/sup&gt;A is distributed across over a thousand pseudogenes, and hypomethylation leads to their upregulation in HGSOC. We identified a processed pseudogene, RPS15AP12, upregulated by FTO-mediated m&lt;sup&gt;6&lt;/sup&gt;A demethylation. RPS15AP12 enhances the growth ability and metastatic capabilities of ovarian cancer (OC) cells via functioning as a competitive endogenous RNA (ceRNA) for its host gene, RPS15A, through the sequestration of miR-96-3p. Importantly, the deletion of RPS15AP12 diminishes the expression of RPS15A, leading to the upregulation of anti-tumour immune responses by activating RIG-I and MDA5 and downstream p-TBK1 and p-IRF3 as well as IFN-β levels.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our findings expand the understanding of m&lt;sup&gt;6&lt;/sup&gt;A-modulated pseudogenes in tumour growth and anti-tumour innate immunity in OC.&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;","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70249","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143489756","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":"An adoptive cell therapy with TREM2-overexpressing macrophages mitigates the transition from acute kidney injury to chronic kidney disease","authors":"Yating Zhang,&nbsp;Yu Liu,&nbsp;Siweier Luo,&nbsp;Hanzhi Liang,&nbsp;Chipeng Guo,&nbsp;Yufei Du,&nbsp;Hongyu Li,&nbsp;Le Wang,&nbsp;Xiaohua Wang,&nbsp;Chun Tang,&nbsp;Yiming Zhou","doi":"10.1002/ctm2.70252","DOIUrl":"https://doi.org/10.1002/ctm2.70252","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;Macrophages have been shown to contribute to renal injury and fibrosis as well as repair. Recently, Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)-positive macrophages have been shown to play important roles in regulating tissue inflammation and repair. However, it remains unclear whether they can mitigate the transition from acute kidney injury to chronic kidney disease (the AKI–CKD transition).&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;The AKI–CKD transition was generated by unilateral ischaemia–reperfusion injury (UIRI) in wild-type (WT) and Trem2 knockout mice. F4/80 magnetic beads were used to isolate renal macrophages. Flow cytometry was used to determine the levels of TREM2 and CD11b levels. Quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blotting and histological staining were performed to determine the expression of cytokines and fibrotic markers. RNA-seq was used to investigate transcriptomic changes between WT and Trem2 knockout bone marrow-derived macrophages (BMDMs). TREM2-overexpressing macrophages were generated using lentivirus and transferred intravenously to UIRI mice.&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;TREM2 macrophages exhibited a strong renal protective effect on the AKI–CKD transition. Genetic deletion of Trem2 resulted in increased renal inflammation and exacerbated renal injury and fibrosis in UIRI mice. Interestingly, we found that hypoxia could increase TREM2 expression in macrophages via HIF-1α. Upregulated TREM2 expression enhanced macrophage phagocytosis and suppressed the expression of pro-inflammatory cytokines, resulting in lower levels of apoptosis and fibrosis in tubular epithelial cells. Using RNA-seq analysis, we showed that the regulatory effects of TREM2 were orchestrated by the PI3K-AKT pathway. Pharmacological regulation of the PI3K-AKT pathway could modulate the macrophage-mediated inflammation and phagocytosis. In addition, an adoptive cell therapy using TREM2-overexpressing macrophages effectively reduced the immune cell infiltration, renal injury and fibrosis in UIRI mice.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our study not only provides valuable mechanistic insights into the role of Trem2 in the AKI–CKD transition but also offers a new avenue for TREM2-overexpressing macrophage-based adoptive cell therapy to treat kidney diseases.&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 3","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70252","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143489888","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":"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,&nbsp;Qin Zhang,&nbsp;Xia Fang,&nbsp;Ling Li,&nbsp;Gangyi Yang,&nbsp;Xiaohui Xu,&nbsp;Mengliu Yang","doi":"10.1002/ctm2.70233","DOIUrl":"https://doi.org/10.1002/ctm2.70233","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 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.&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;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.&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 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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;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.&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;MAFLD is associated with increased hepatocytes NRF2 expression.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;NRF2 alleviates MAFLD by suppressing pyroptosis.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;NRF2 directly inhibits GSDMD expression to regulate pyroptosis.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;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}