Clinical and Translational Medicine最新文献

{"title":"Neuroimmune interactions: The bridge between inflammatory bowel disease and the gut microbiota","authors":"Jinxia Zhai,&nbsp;Yingjie Li,&nbsp;Jiameng Liu,&nbsp;Cong Dai","doi":"10.1002/ctm2.70329","DOIUrl":"https://doi.org/10.1002/ctm2.70329","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The multidimensional regulatory mechanism of the gut–brain–immune axis in the context of inflammatory bowel disease (IBD) has garnered significant attention, particularly regarding how intestinal microbiota finely regulates immune responses through immune cells and sensory neurons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main Body</h3>\u0000 \u0000 <p>Metabolites produced by intestinal microbiota influence the phenotype switching of immune cells via complex signalling pathways, thereby modulating their anti-inflammatory and pro-inflammatory functions during intestinal inflammation. Furthermore, sensory neurons exhibit heightened sensitivity to microbial-derived signals, which is essential for preserving intestinal balance and controlling pathological inflammation by integrating peripheral environmental signals with local immune responses. The dynamic equilibrium between immune cells and the neuroimmunoregulation mediated by sensory neurons collectively sustains immune homeostasis within the intestine. However, this coordination mechanism is markedly disrupted under the pathological conditions associated with IBD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>An in-depth exploration of the interactions among immune cells, gut microbiota and sensory neurons may yield significant insights into the pathological mechanisms underlying IBD and guide the creation of new treatment approaches.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The gut microbiota regulates the gut-brain-immune axis, modulating neuroimmune interactions in IBD.</li>\u0000 \u0000 <li>Microbiota-derived metabolites influence immune cells, thereby affecting neurons.</li>\u0000 \u0000 <li>Neurons secrete mediators, enabling bidirectional neuroimmune communication essential for intestinal homeostasis.</li>\u0000 \u0000 <li>Disruptions contribute to IBD, offering therapeutic targets.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70329","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144108990","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":"Comparative impact of proton versus photon irradiation on triple-negative breast cancer: Role of VEGFC in tumour aggressiveness","authors":"Saharnaz Sarlak,&nbsp;Delphine Marotte,&nbsp;Arthur Karaulic,&nbsp;Jessy Sirera,&nbsp;Alessandra Pierantoni,&nbsp;Meng-Chen Tsai,&nbsp;Roxane Sylvestre,&nbsp;Clement Molina,&nbsp;Arthur Gouraud,&nbsp;Aurélien Bancaud,&nbsp;Paraskevi Kousteridou,&nbsp;Marie Vidal,&nbsp;Joël Hérault,&nbsp;Jérôme Doyen,&nbsp;Maeva Dufies,&nbsp;Florent Morfoisse,&nbsp;Barbara Garmy-Susini,&nbsp;Frédéric Luciano,&nbsp;Gilles Pagès","doi":"10.1002/ctm2.70330","DOIUrl":"https://doi.org/10.1002/ctm2.70330","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;In this study, we demonstrated that proton (P) and photon (X) radiotherapies (RT) lead to different molecular changes in triple-negative breast cancer (TNBC) cells. P-irradiated tumours tended to make larger tumours, while X-irradiated ones exhibited increased aggressiveness. Both types of radiation increased gene expression related to angiogenesis (blood vessel formation) and lymphangiogenesis (lymph vessel formation), which are associated with more aggressive cancer behaviour. We also found that targeting the lymphangiogenesis-related gene, vascular endothelial growth factor C (VEGFC), alongside either type of RT, could improve the prognosis for TNBC patients.&lt;/p&gt;&lt;p&gt;Breast cancer (BC) is the most common type of cancer among women.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Its aggressive forms, like TNBC, tend to be highly vascularized and often have an increased network of lymphatic vessels, which allows the cancer to metastasize more rapidly.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Standard treatment involves with a combination of surgery, chemotherapy and RT to target both local and systemic diseases. Despite these treatments, recurrence remains a significant challenge in aggressive forms of BC.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Proton therapy, a newer form of RT, offers more precise targeting than conventional X-RT, potentially reducing side effects by narrowing the radiation field.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Ongoing clinical trials are investigating whether P-RT might offer advantages over conventional X-RT, as recent research suggests promising advantages.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Here, we investigated how irradiation impacts TNBC cell behaviour and their microenvironment, building on our prior study of P- and X-RT effects on head and neck cancer.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Specifically, we investigated whether irradiation might inadvertently promote tumour growth by altering cells to release growth factors or cytokines that support tumour survival and progression.&lt;/p&gt;&lt;p&gt;To examine these effects, we developed TNBC cell populations (MDAMB231 and BT549) that are resilient to repeated X- or P-RT. The traits of aggressiveness, such as proliferation and migration were evaluated in these multi-irradiated cells. While proliferation rates in irradiated cells were like controls (Figure 1A,B), migration abilities were enhanced (Figure 1C,D), suggesting that these cells could have a greater potential for metastasis. This increase in migration mirrors findings in X-resistant medulloblastoma cells.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Since metastasis in TNBC frequently occurs via lymphatic vessels,&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; we investigated the impact of X- and P-RT on the expression of VEGFC, a key regulator of lymphangiogenesis, in our TNBC cell lines which exhibit higher basal levels of VEGFC compared to cell lines of other BC subtypes (Figure S1). Both irradiation types significantly upregulated VEGFC mRNA expression (Figure 1E) and increased secretion of VEGFC prot","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70330","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144108988","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":"Upregulated CEMIP promotes intervertebral disc degeneration via AP-1-mediated change in chromatin accessibility","authors":"Shibin Shu,&nbsp;Xin Zhang,&nbsp;Zhenhua Feng,&nbsp;Zhen Liu,&nbsp;Kaiyang Wang,&nbsp;Fengrui Li,&nbsp;Yating Wu,&nbsp;Bo Shi,&nbsp;Yong Qiu,&nbsp;Zezhang Zhu,&nbsp;Hongda Bao","doi":"10.1002/ctm2.70322","DOIUrl":"https://doi.org/10.1002/ctm2.70322","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;Intervertebral disc degeneration (IDD), a chronic and multifactorial skeletal disorder, is the primary cause of low back pain. It results in reduced disc height and nucleus pulposus hydration due to proteoglycan loss and nucleus pulposus cells (NPCs) dysfunction within a hypoxic microenvironment. Metabolic dysregulation initiates catabolic processes, leading to extracellular matrix (ECM) degradation and compromising disc biomechanical integrity. Emerging evidence highlights epigenetic modifications as pivotal in IDD, influencing NPC gene expression transcriptionally and post-transcriptionally.&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;In order to understand the epigenetic underpinnings of IDD, our study provided a comprehensive profile of chromatin accessibility changes in degenerated NPCs using Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq).\u0000&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;With motif enrichment analysis, we identified the activator protein-1 (AP-1) transcription factor critical in driving the chromatin accessibility changes during IDD. Integrative ATAC-seq and transcriptional profiling revealed cell migration-inducing protein (CEMIP) as a key biomarker and contributor to IDD, exhibiting marked upregulation in IDD. Furthermore, we demonstrated that the AP-1 family, especially, c-Fos, orchestrates the upregulation of CEMIP. Elevated CEMIP plasma levels correlated with clinical IDD severity, and CEMIP knockout mice demonstrated improved IDD.\u0000&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;Mechanistically, CEMIP disrupted ECM homeostasis through its regulation of high molecular weight hyaluronic acid (HMW-HA) degradation, and its contribution to fibrotic changes. Our findings highlight CEMIP's vital role in IDD and identify the AP-1 family as a critical regulator of IDD, providing new potential therapeutic targets for novel IDD interventions.&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;Integrative ATAC-seq and transcriptional profiling revealed CEMIPas a key biomarker and contributor to IDD, exhibiting marked upregulation in IDD.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Further, we demonstrated that the AP-1 family, especially, c-Fos, orchestrates the upregulation of CEMIP.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Elevated CEMIP plasma levels correlated ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70322","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144108989","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/ctm2.70332","DOIUrl":"https://doi.org/10.1002/ctm2.70332","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70332","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144085505","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":"Mitochondria-derived vesicles: A promising and potential target for tumour therapy","authors":"Xueqiang Peng,&nbsp;Yu Gao,&nbsp;Jiaxing Liu,&nbsp;Xinxin Shi,&nbsp;Wei Li,&nbsp;Yingbo Ma,&nbsp;Xuexin Li,&nbsp;Hangyu Li","doi":"10.1002/ctm2.70320","DOIUrl":"https://doi.org/10.1002/ctm2.70320","url":null,"abstract":"<p>Mitochondria-derived vesicles (MDVs) participate in early cellular defence mechanisms initiated in response to mitochondrial damage. They maintain mitochondrial quality control (MQC) by clearing damaged mitochondrial components, thereby ensuring the normal functioning of cellular processes. This process is crucial for cell survival and health, as mitochondria are the energy factories of cells, and their damage can cause cellular dysfunction and even death. Recent studies have shown that MDVs not only maintain mitochondrial health but also have a significant impact on tumour progression. MDVs selectively encapsulate and transport damaged mitochondrial proteins under oxidative stress and reduce the adverse effects of mitochondrial damage on cells, which may promote the survival and proliferation of tumour cells. Furthermore, it has been indicated that after cells experience mild stress, the number of MDVs significantly increases within 2–6 h, whereas mitophagy, a process of clearing damaged mitochondria, occurs 12–24 h later. This suggests that MDVs play a critical role in the early stress response of cells. Moreover, MDVs also have a significant role in intercellular communication, specifically in the tumour microenvironment. They can carry and transmit various bioactive molecules, such as proteins, nucleic acids, and lipids, which regulate tumour cell's growth, invasion, and metastasis. This intercellular communication may facilitate tumour spread and metastasis, making MDVs a potential therapeutic target. Advances in MDV research have identified novel biomarkers, clarified regulatory mechanisms, and provided evidence for clinical use. These breakthroughs pave the way for novel MDV-targeted therapies, offering improved treatment alternatives for cancer patients. Further research can identify MDVs' role in tumour development and elucidate future cancer treatment horizons.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70320","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143938858","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":"Lysine-specific demethylase 1 deletion reshapes tumour microenvironment to overcome acquired resistance to anti-programmed death 1 therapy in liver cancer","authors":"Chen Liang,&nbsp;Mu Ye,&nbsp;Lei Yu,&nbsp;Peng-Fei Zhang,&nbsp;Xiao-Jun Guo,&nbsp;Xian-Long Meng,&nbsp;Hai-Ying Zeng,&nbsp;Shu-Yang Hu,&nbsp;Dao-Han Zhang,&nbsp;Qi-Man Sun,&nbsp;Ying-Hao Shen,&nbsp;Jia-Bin Cai,&nbsp;Shuang-Qi Li,&nbsp;Zhen Chen,&nbsp;Ying-Hong Shi,&nbsp;Ai-Wu Ke,&nbsp;Yujiang G. Shi,&nbsp;Jian Zhou,&nbsp;Jia Fan,&nbsp;Fei-Zhen Wu,&nbsp;Xiao-Yong Huang,&nbsp;Guo-Ming Shi,&nbsp;Zheng Tang,&nbsp;Jia-Cheng Lu","doi":"10.1002/ctm2.70335","DOIUrl":"https://doi.org/10.1002/ctm2.70335","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;Immune checkpoint blockade, particularly targeting programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), shows promise in treating hepatocellular carcinoma (HCC). However, acquired resistance, especially in patients with ‘hot tumours’, limits sustained benefits. Lysine-specific demethylase 1 (LSD1) plays a role in converting ‘cold tumours’ to ‘hot tumours’, but its involvement in PD-1 inhibitor resistance in HCC is 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;LSD1 and PD-L1 expression, along with CD8&lt;sup&gt;+&lt;/sup&gt; T cell infiltration, were assessed using immunohistochemistry in HCC tissues, correlating these markers with patient prognosis. The impact of LSD1 deletion on tumour cell proliferation and CD8&lt;sup&gt;+&lt;/sup&gt; T cell interactions was examined in vitro. Mouse models were used to study the combined effects of LSD1 inhibition and anti-PD-1 therapy on tumour growth and the tumour microenvironment (TME). The clinical relevance of LSD1, CD74 and effector CD8&lt;sup&gt;+&lt;/sup&gt; T cells was validated in advanced HCC patients treated with PD-1 blockade.&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;LSD1 overexpression in HCC patients correlated with reduced PD-L1 expression, less CD8&lt;sup&gt;+&lt;/sup&gt; T cell infiltration and poorer prognosis. LSD1 deletion increased PD-L1 expression, boosted effector CD8&lt;sup&gt;+&lt;/sup&gt; T cells in vitro and inhibited tumour growth in vivo. While anti-PD-1 monotherapy initially suppressed tumour growth, it led to relapse upon antibody withdrawal. In contrast, combining LSD1 inhibition with anti-PD-1 therapy effectively halted tumour growth and prevented relapse, likely through TME remodelling, enhanced CD8&lt;sup&gt;+&lt;/sup&gt; T cell activity and improved CD74-mediated antigen presentation. Clinically, low LSD1 expression was associated with better response to anti-PD-1 therapy.&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;LSD1 deletion reshapes the TME, enhances CD8&lt;sup&gt;+&lt;/sup&gt; T cell function and prevents acquired resistance to anti-PD-1 therapy in HCC. The combination of LSD1 inhibitors and PD-1 blockade offers a promising strategy for overcoming resistance in advanced HCC.&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;Uncovering the synthetic lethality resulting from LSD1 deletion and PD1 inhibitor co-administration, evaluating their combined effects on tumour growth and TME remodelling.&lt;/li&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70335","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143938859","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":"IRF4 contributes to chemoresistance in IGH::BCL2-positive diffuse large B-cell lymphomas by mediating BCL2-induced SOX9 expression","authors":"Yirong Zhang,&nbsp;Zizhen Xu,&nbsp;Ruixin Sun,&nbsp;Yixuan Gao,&nbsp;Innocent Agida,&nbsp;Kasimujiang Aximujiang,&nbsp;Lin Yuan,&nbsp;Jiao Ma","doi":"10.1002/ctm2.70336","DOIUrl":"https://doi.org/10.1002/ctm2.70336","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;Diffuse large B-cell lymphoma (DLBCL), an aggressive type of non-Hodgkin's lymphoma, has a high relapse/refractory rate. We previously identified sex-determining region Y (SRY)-box transcription factor (SOX9) as a transcription factor that serves as a prognostic biomarker, particularly in BCL2-overexpressing DLBCL, and plays a vital role in lymphomagenesis. However, the molecular mechanisms that modulate the aberrant expression of SOX9 in this DLBCL subset remain unknown.&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;Cell viability, apoptosis and cell cycle assays were performed to determine whether SOX9 contributes to DLBCL chemoresistance and rescues silencing IRF4-induced phenotypes. Protein‒protein interactions and protein ubiquitination were elucidated using immunoprecipitation, immunohistochemistry, immunofluorescence and immunoblotting. Chromatin immunoprecipitation sequencing (ChIP-seq), ChIP and dual-luciferase reporter assays were used to investigate IRF4 binding to the SOX9 promoter. The therapeutic potential of IRF4 inhibition was evaluated in vitro and in a mouse model of DLBCL xenografts.&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;SOX9 enhanced the resistance of the BCL2-overexpressing DLBCL subset to chemotherapy or a BCL2 inhibitor. Moreover, BCL2 inhibition downregulated SOX9 in an immunoglobulin heavy chain/BCL2-positive DLBCL subset. We further identified IRF4 as a key regulator of BCL2-induced SOX9 expression, and ChIP-seq confirmed that IRF4 is a key transcription factor for SOX9 in DLBCL. In addition, BCL2 promotes IRF4 entry into the nucleus by enhancing protein stability and downregulating proteasomal ubiquitination, thereby enforcing SOX9-mediated phenotypes. Finally, in a DLBCL cell line and xenografted mouse model, in vivo inhibition of IRF4 with an hIRF4 antisense oligonucleotide repressed lymphomagenesis and DLBCL chemoresistance.&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 data support the conclusion that IRF4 plays an essential role in BCL2-induced upregulation of SOX9 expression, and targeting IRF4 may represent a promising therapeutic strategy to cure relapsed and refractory DLBCL.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Keypoints/Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;BCL2 activated IRF4 by enhancing its nuclear activity to induce sex-determining region Y (SRY)-box 9 protein (SOX9) aberrant expression, which is a critica","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70336","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143938942","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":"Downregulation of SENP1 impairs nuclear condensation of MEF2C and deteriorates ischemic cardiomyopathy","authors":"Ying Xie,&nbsp;Qiaoyuan Li,&nbsp;Xiyun Bian,&nbsp;Yan Yin,&nbsp;Zhuo Liang,&nbsp;Xu Liu,&nbsp;Tao Zhang,&nbsp;Xiaozhi Liu,&nbsp;Xin Quan,&nbsp;Yunlong Wang","doi":"10.1002/ctm2.70318","DOIUrl":"https://doi.org/10.1002/ctm2.70318","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Ischemic cardiomyopathy (ICM) is characterised by the insufficient capacity of the heart to effectively pump blood, which ultimately contributes to heart failure (HF). In this study, the down regulation of SENP1 is identified in the cardiomyocyte of ICM mouse models and in patients. The depletion of SENP1 exacerbates hypoxia-induced apoptosis of cardiomyocytes in vitro and deteriorated cardiomyocyte injury of ICM mice in vivo. Mechanistically, SENP1 deSUMOylates the SUMO2-mediated modification of MEF2C at lysine 401 for stabilising protein stability. Moreover, the interaction with SENP1 controls the nuclear condensation of MEF2C to promote the expression of genes critical for cardiomyocyte function. When rescuing SENP1 expression using adeno-associated virus serotype 9, the attenuation of cardiomyocyte injury is discerned in the mouse model of ICM. Therefore, these finding elicits a previously unrecognised role and mechanism of SENP1 in safeguarding cardiomyocyte in ICM progression while establishing a basis for the development of SENP1 as a potential marker for ICM diagnosis and treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>SNEP1 is downregulated in the cardiomyocyte of ICM mouse models and in patients.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>SENP1 deSUMOylates the SUMO2-mediated modification of MEF2C at lysine 401 for protein stability.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>The interaction with SENP1 controls the nuclear condensation of MEF2C to promote cardiomyocyte function.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Cardiac rescue of SENP1 alleviates ischemic heart injury in ICM mouse models by AAV9.</p>\u0000 </li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70318","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919375","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":"Unravelling tumour spatiotemporal heterogeneity using spatial multimodal data","authors":"Chunman Zuo,&nbsp;Junchao Zhu,&nbsp;Jiawei Zou,&nbsp;Luonan Chen","doi":"10.1002/ctm2.70331","DOIUrl":"https://doi.org/10.1002/ctm2.70331","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Analysing the genome, epigenome, transcriptome, proteome, and metabolome within the spatial context of cells has transformed our understanding of tumour spatiotemporal heterogeneity. Advances in spatial multi-omics technologies now reveal complex molecular interactions shaping cellular behaviour and tissue dynamics. This review highlights key technologies and computational methods that have advanced spatial domain identification and their pseudo-relations, as well as inference of intra- and inter-cellular molecular networks that drive disease progression. We also discuss strategies to address major challenges, including data sparsity, high-dimensionality, scalability, and heterogeneity. Furthermore, we outline how spatial multi-omics enables novel insights into disease mechanisms, advancing precision medicine and informing targeted therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>\u0000 <p>Advancements in spatial multi-omics facilitate our understanding of tumour spatiotemporal heterogeneity.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>AI-driven multimodal models uncover complex molecular interactions that underlie cellular behaviours and tissue dynamics.</p>\u0000 </li>\u0000 \u0000 <li>\u0000 <p>Combining multi-omics technologies and AI-enabled bioinformatics tools helps predict critical disease stages, such as pre-cancer, advancing precision medicine, and informing targeted therapeutic strategies.</p>\u0000 </li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70331","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919378","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":"USP22 promotes the proliferation and Sorafenib resistance of hepatocellular carcinoma cells via its deubiquitinase activity","authors":"Xiaochen Wang,&nbsp;Yijie Su,&nbsp;Bei Lan,&nbsp;Xuanyuan Li,&nbsp;Bodi Zhang,&nbsp;Liang Zhang,&nbsp;Yingmei Wang,&nbsp;Chunze Zhang,&nbsp;Chenghao Xuan","doi":"10.1002/ctm2.70324","DOIUrl":"https://doi.org/10.1002/ctm2.70324","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;Hepatocellular carcinoma remains one of the most lethal cancers, characterized by poor prognosis and low life expectancy. Unfortunately, there are very few molecular therapeutic options available for it. Sorafenib is a current standard first-line treatment for advanced hepatocellular carcinoma, however, drug resistance significantly limits its therapeutic efficacy.&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;Ubiquitin-specific protease 22 (USP22) expression level and its prognostic significance in hepatocellular carcinoma were analyzed using The Cancer Genome Atlas (TCGA) database. A series of cellular experiments related to cell proliferation and ferroptosis, and mouse tumor-bearing experiments were performed to investigate the role of USP22 in hepatocellular carcinoma cell growth and Sorafenib resistance. Flag affinity purification coupled with mass spectrometry, co-immunoprecipitation, and ubiquitination assays were conducted to identify direct substrates of USP22. Spike-in chromatin-immunoprecipitation (ChIP)-seq, RNA-seq, and ChIP assays were employed to explore the transcriptional substrates of USP22 as an H2BK120ub deubiquitinase.&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;Analysis of TCGA database reveals that USP22 is highly expressed in hepatocellular carcinoma tissues, which is closely associated with poor patient prognosis. Our data further indicates that USP22 promotes the proliferation of hepatocellular carcinoma cells via deubiquitinating and stabilizing cyclin-dependent kinase 11B (CDK11B). Additionally, USP22 acts as a novel inducer of Sorafenib resistance and suppresses Sorafenib-triggered ferroptosis in hepatocellular carcinoma cells. It reduces the transcription of transferrin receptor (TFRC) by decreasing H2BK120ub occupancy at &lt;i&gt;TFRC&lt;/i&gt; transcription start site (TSS) downstream region, thereby inhibiting ferroptosis upon Sorafenib treatment. Finally, animal experiments confirm the role of USP22 in promoting hepatocellular carcinoma cell growth and Sorafenib resistance in vivo. Taken together, this study demonstrates that USP22 promotes hepatocellular carcinoma growth and inhibits Sorafenib-induced ferroptosis by deubiquitinating non-histone substrate CDK11B and histone H2B, respectively.&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 findings suggest USP22 as a promising prognostic biomarker and therapeutic target for hepatocellular carcinoma patients, particularly those with Sorafenib resistance.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 5","pages":""},"PeriodicalIF":7.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70324","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919374","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}