Molecular Medicine最新文献

{"title":"miR-27a-5p, miR-21-5p, miR-1246 and miR-4508: a candidate microRNA signature in the protection and regulation of viral infection in mild COVID-19.","authors":"Malena Gajate-Arenas, Candela Sirvent-Blanco, Omar García-Pérez, Angélica Domínguez-de-Barros, José E Piñero, Jacob Lorenzo-Morales, Elizabeth Córdoba-Lanús","doi":"10.1186/s10020-025-01154-0","DOIUrl":"10.1186/s10020-025-01154-0","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) are gene regulators essential for cell homeostasis, their alteration is related to a pathological state, including infectious diseases like COVID-19. Identifying an altered profile of circulating miRNAs in mild COVID-19 may enhance our knowledge of the pathogenesis of SARS-CoV-2 and the range of clinical phenotypes. In the present study, a miRNA screening was performed by Next Generation Sequencing (NGS), and the expression levels of 13 resulting miRNAs were validated through RT-qPCR in the serum of 40 mild cases compared to 29 non-infected individuals. An in-silico analysis was performed to detect target genes and their related pathways. From the validated miRNAs, miR-1246 (p < 0.001), miR-423-5p (p < 0.001), miR-21-5p (p = 0.005), miR-146a-5p (p < 0.001), miR-4508 (p = 0.001), miR-629-5p (p < 0.001), and miR-210-3p (p = 0.002) were found downregulated in infected individuals. Only miR-27a-5p was overexpressed in subjects with COVID-19 (p = 0.013) and associated with SARS-CoV-2 infection (p = 0.010). The KEGG pathways and GO analysis revealed that the differentially expressed miRNAs were related to viral processes or immunological pathways: miR-27a-5p acts on the TGF-beta pathway; miR-21-5p targets SMAD7, which is associated with the inflammatory response in the lung; miR-1246 acts on p53 pathway; and miR-4508 acts on ICAM2. In conclusion, the most relevant miRNAs, miR-27a-5p and miR-21-5p, were differently expressed in mild forms of COVID-19. The higher expression of miR-27a-5p observed in mild COVID-19 cases may suggest a protective effect against severe forms of the disease. Reduced expression of miR-21-5p may prevent pulmonary inflammation and the progression of fibrosis. The downregulation of miR-1246 and miR-4508 in mild COVID-19 cases may conduct the correct control of the infection. Moreover, miR-423-5p might be a suitable biomarker in the early stages of SARS-CoV-2 infection.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"102"},"PeriodicalIF":6.0,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epimedium brevicornum Maxim alleviates diabetes osteoporosis by regulating AGE-RAGE signaling pathway.","authors":"Shan Shan Lei, Yu Yan Wang, Xiao Wen Huang, Xu Ping Wang, Ming Gao, Bo Li","doi":"10.1186/s10020-025-01152-2","DOIUrl":"10.1186/s10020-025-01152-2","url":null,"abstract":"<p><strong>Objectives: </strong>Epimedium brevicornum Maxim (EP) has a history of utilization in Chinese traditional medicine for the treatment of bone diseases. However, the precise mechanism by which EP extract (EPE) operates in Diabetes osteoporosis (DOP) remains ambiguous. The study was aimed to explore the effects and underlying mechanisms of EPE on DOP, with particular emphasis on the AGE-RAGE pathway.</p><p><strong>Methods: </strong>The DOP model was induced through a combination of a high-sugar and high-fat diet along with streptozotocin injection. Following treatment with EPE, blood glucose levels, body weight, and serum biomarkers were measured. The trabecular microstructure of the femur was analyzed using micro-CT tomography and H&E staining. Bioinformatics techniques, including network pharmacology and molecular docking, were utilized to identify key targets of EP for DOP. The predicted targets and pathways were further validated through RT-PCR, TSA analysis ELISA, and western blotting (WB), respectively.</p><p><strong>Results: </strong>The findings from animal experiments indicate that EPE has a positive impact on weight and blood glucose levels, particularly in reversing the decrease and disordered arrangement of bone trabeculae. Bioinformatics analysis reveals the involvement of the AGE-RAGE pathways in the treatment of DOP with EPE. Subsequent animal validation experiments demonstrate that EPE can regulate key proteins AGE-RAGE pathway, resulting in reducing the inflammatory factors and apoptosis, including advanced Glycation End-products (RGEs), receptor for Advanced Glycation End-products (RAGE), Interleukin-6 (IL-6), Interleukin-1β (IL-1β), Nuclear Factor Kappa B (NF-κB), BCL2-Associated X protein (Bax), B-cell lymphoma 2(Bcl2), and etc. CONCLUSION: This study provides clear evidence that EPE mitigates DOP through enhancement of the AGE-RAGE pathways, offering innovative insights and approaches for clinical utilization.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"101"},"PeriodicalIF":6.0,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LXRα agonists ameliorates acute rejection after liver transplantation via ABCA1/MAPK and PI3K/AKT/mTOR signaling axis in macrophages.","authors":"Xiaoyan Qin, Dingheng Hu, Qi Li, Shiyi Zhang, Zheng Qin, Liangxu Wang, Rui Liao, Zhongjun Wu, Yanyao Liu","doi":"10.1186/s10020-025-01153-1","DOIUrl":"10.1186/s10020-025-01153-1","url":null,"abstract":"<p><strong>Introduction: </strong>Liver X receptor α (LXRα) plays an important role in inflammatory immune response induced by hepatic ischemia-reperfusion injury (IRI) and acute rejection (AR). Macrophage M1-polarization play an important role in the occurrence and development of AR. Although the activation of LXR has anti-inflammatory effects, the role of LXRα in AR after liver transplantation (LT) has not been elucidated.</p><p><strong>Objective: </strong>We aimed to investigate LXRα anti-inflammatory and macrophage polarization regulation effects and mechanisms in acute rejection rat models.</p><p><strong>Methods: </strong>LXRα anti-inflammatory and liver function protective effects was initially measured in primary Kupffer cells and LT rat models. Subsequently, a flow cytometry assay was used to detect the regulation effect of LXRα in macrophage polarization. HE staining, TUNEL and ELISA were used to evaluate the co-treatment effects of TO901317 and tacrolimus on hepatic apoptosis and liver acute rejection after LT.</p><p><strong>Results: </strong>In this study, we found that LPS can inhibit the expression of LXRα and activate MAPK pathway and PI3K/AKT/mTOR. We also found that LXRα agonist (TO901317) could improve liver function and rat survival after LT by activating the level of ABCA1 and inhibiting MAPK. TO901317 could inhibit macrophage M1-polarization by activating PI3K/AKT/mTOR signal pathway to improve the liver lesion of AR rats after liver transplantation. Additionally, co-treatment with TO901317 and tacrolimus more effectively alleviated the damaging effects of AR following LT than either drug alone.</p><p><strong>Conclusion: </strong>Our results suggest that the activation of LXRα can improve liver function and rat survival after LT by regulate ABCA1/MAPK and PI3K/AKT/mTOR signaling axis in macrophages.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"99"},"PeriodicalIF":6.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sirtuin1 mitigates hypoxia-induced cardiomyocyte apoptosis in myocardial infarction via PHD3/HIF-1α.","authors":"Yafen Chen, Shuyao Shan, Qiqi Xue, Yan Ren, Qihong Wu, Jiawei Chen, Ke Yang, Jiumei Cao","doi":"10.1186/s10020-025-01155-z","DOIUrl":"10.1186/s10020-025-01155-z","url":null,"abstract":"<p><strong>Background: </strong>Acute myocardial infarction (AMI) is a leading cause of mortality, characterized by myocardial ischemia that induces cardiomyocyte apoptosis and subsequent cardiac dysfunction. Sirtuin 1 (Sirt1) has emerged as a key regulator of cell survival and apoptosis, particularly under hypoxic conditions.</p><p><strong>Methods: </strong>An AMI animal model was established via ligation of the left anterior descending (LAD) coronary artery. Gene expression in the infarcted region was evaluated at various time points. Sirt1 overexpression and control lentivirus were administered to the peri-infarct region of mice heart. After LAD ligation, assessment on myocardial infarct size, cardiac function, and cardiomyocyte apoptosis were performed. In vitro, primary mouse cardiomyocytes subjected to hypoxia were analyzed for gene expression, while interactions among Sirt1, Phd3, and Hif-1α were explored using diverse treatment approaches.</p><p><strong>Results: </strong>A significant reduction in Sirt1 and Phd3 expression, along with an increase in Hif-1α and cleaved caspase-3, was observed in a time-dependent manner post-myocardial infarction (MI). In vitro findings revealed that hypoxia decreased nuclear Sirt1 and cytoplasmic Phd3 levels while promoting a time-dependent increase in Hif-1α and cleaved caspase-3. Furthermore, Sirt1 overexpression enhanced Phd3 expression in cardiomyocytes, suppressed Hif-1α and cleaved caspase-3 levels, and alleviated hypoxia-induced cardiomyocyte apoptosis. Notably, knockdown of Phd3 negated Sirt1's inhibitory effect on Hif-1α, whereas Hif-1α knockdown promoted Sirt1 expression. Sirt1 overexpression reduced infarct size, decreased cardiomyocyte apoptosis, and improved cardiac function.</p><p><strong>Conclusions: </strong>Sirt1 effectively reduces cardiomyocyte apoptosis and myocardial infarction size while enhancing cardiac function post-MI, primarily through the Phd3/Hif-1α signaling pathway.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"100"},"PeriodicalIF":6.0,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11909899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metrnl ameliorates myocardial ischemia-reperfusion injury by activating AMPK-mediated M2 macrophage polarization.","authors":"De-Xin Chen, Yang-Yi Feng, Hai-Yan Wang, Chuang-Hong Lu, De-Zhao Liu, Chen Gong, Yan Xue, Na Na, Feng Huang","doi":"10.1186/s10020-025-01150-4","DOIUrl":"10.1186/s10020-025-01150-4","url":null,"abstract":"<p><strong>Background: </strong>Meteorin-like hormone (Metrnl) is prominently expressed in activated M2 macrophages and has demonstrated potential therapeutic effects in a range of cardiovascular diseases by modulating inflammatory responses. Nevertheless, its precise role and the underlying mechanisms in myocardial ischemia/reperfusion injury (MI/RI) are not fully understood. This study examined whether Metrnl can mitigate MI/RI through the AMPK-mediated polarization of M2 macrophages.</p><p><strong>Methods: </strong>In vivo, adeno-associated virus 9 containing the F4/80 promoter (AAV9-F4/80) was utilized to overexpress Metrnl in mouse cardiac macrophages before MI/RI surgery. In vitro, mouse bone marrow-derived macrophages (BMDMs) were treated with recombinant protein Metrnl, and the human cardiomyocyte cell line AC16 was subjected to hypoxia/reoxygenation (H/R) after co-culture with the supernatant of these macrophages. Cardiac function was assessed via echocardiography, H&E staining, and Evans blue-TTC staining. Inflammatory infiltration was evaluated by RT-qPCR and ELISA, apoptosis by Western blotting and TUNEL staining, and macrophage polarization by immunofluorescence staining and flow cytometry.</p><p><strong>Results: </strong>In vivo, Metrnl overexpression in cardiac macrophages significantly attenuated MI/RI, as evidenced by reduced myocardial infarct size, enhancement of cardiac function, diminished inflammatory cell infiltration, and decreased cardiomyocyte apoptosis. Furthermore, Metrnl overexpression promoted M1 to M2 macrophage polarization. In vitro, BMDMs treated with Metrnl shifted towards M2 polarization, characterized by decreased expression of inflammatory cytokines (IL-1β, MCP-1, TNF-α) and increased expression of the anti-inflammatory cytokine IL-10. Additionally, supernatant from Metrnl-treated macrophages protected AC16 cells from apoptosis under H/R conditions, as evidenced by decreased BAX expression and increased BCL-2 expression. However, these effects of Metrnl were inhibited by the AMPK inhibitor Compound C.</p><p><strong>Conclusions: </strong>Metrnl alleviates MI/RI by activating AMPK-mediated M2 macrophage polarization to attenuate inflammatory response and cardiomyocyte apoptosis. This study highlights the therapeutic potential of Metrnl in MI/RI, and identifies it as a promising target for the treatment of ischemic heart disease.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"98"},"PeriodicalIF":6.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide screening in human embryonic stem cells identifies genes and pathways involved in the p53 pathway.","authors":"Amir Haddad, Tamar Golan-Lev, Nissim Benvenisty, Michal Goldberg","doi":"10.1186/s10020-025-01141-5","DOIUrl":"10.1186/s10020-025-01141-5","url":null,"abstract":"<p><strong>Background: </strong>The tumor suppressor protein, p53, which is mutated in half of human tumors, plays a critical role in cellular responses to DNA damage and maintenance of genome stability. Therefore, increasing our understanding of the p53 pathway is essential for improving cancer treatment and diagnosis.</p><p><strong>Methods: </strong>This study, which aimed to identify genes and pathways that mediate resistance to p53 upregulation, used genome-wide CRISPR-Cas9 loss-of-function screening done with Nutlin-3a, which inhibits p53-MDM2 interaction, resulting in p53 accumulation and apoptotic cell death. We used bioinformatics analysis for the identification of genes and pathways that are involved in the p53 pathway and cell survival assays to validate specific genes. In addition, we used RNA-seq to identify differentially expressed p53 target genes in gene knockout (KO) cell lines.</p><p><strong>Results: </strong>Our screen revealed three significantly enriched pathways: The heparan sulfate glycosaminoglycan biosynthesis, diphthamide biosynthesis and Hippo pathway. Notably, TRIP12 was significantly enriched in our screen. We found that TRIP12 is required for the p53-dependent transcription of several pro-apoptotic genes.</p><p><strong>Conclusion: </strong>Our study has identified two novel pathways that play a role in p53-mediated growth restriction. Moreover, we have highlighted the interaction between the Hippo and the p53 pathways. Interestingly, we have shown that TRIP12 plays an important function in the p53 pathway by selectively affecting its role as a transcription factor.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"97"},"PeriodicalIF":6.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11907909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of two biological subgroups of complex regional pain syndrome type 1 by transcriptomic profiling of skin and blood in women.","authors":"Melina Pérez Vertti Valdés, Astrid Jüngel, Pamela Bitterli, Jan Devan, Hubert Rehrauer, Lennart Opitz, Laura Sirucek, Petra Schweinhardt, Sabrina Catanzaro, Oliver Distler, Florian Brunner, Stefan Dudli","doi":"10.1186/s10020-025-01148-y","DOIUrl":"10.1186/s10020-025-01148-y","url":null,"abstract":"<p><strong>Background: </strong>Patients with Complex Regional Pain Syndrome (CRPS) present prolonged, debilitating pain and functional impairment. Treatments are not disease-modifying due to the poorly understood underlying pathomechanisms. This study aimed to identify the molecular signatures of potential CRPS type 1 subgroups.</p><p><strong>Methods: </strong>Twelve women with CRPS type 1 were included. Demographics and pain questionnaires were recorded. Skin biopsies of the affected and non-affected limbs (n = 6 + 6) and peripheral blood (n = 11) were collected. RNA sequencing was performed on skin and peripheral blood mononuclear cells (PBMCs). Twenty cytokines were quantified in blood plasma (n = 12).</p><p><strong>Results: </strong>Cluster analysis of the affected skin identified two CRPS subgroups (SG). SG1 exhibited increased gene expression related to epidermal development, metabolic processes, and a greater abundance of keratinocytes. SG2 showed enhanced transcriptomic changes in inflammatory, immune, and fibrotic processes, along with higher abundance of fibroblasts, macrophages, and endothelial cells. PBMCs transcriptomics revealed the same SG1/SG2 clusters and highlighted a stronger inflammatory response in the blood of SG1, suggesting distinct tissue-specific immune responses for the subgroups. Interleukin-1 receptor antagonist (IL-1RA) levels were higher in the blood plasma of SG1 (FDR = 0.01), consistent with its encoding gene IL1RN expression in PBMCs (log2 FC = 1.10, P < 0.001) and affected skin (log2 FC = 0.88, P = 0.006). Subgroups did not differ in demographic or clinical parameters but correlations among clinical factors varied between them.</p><p><strong>Conclusions: </strong>This study identified two potential biological subgroups of CRPS type 1 in women through skin and blood transcriptomic profiling, advancing the understanding of this condition. This could facilitate the development of targeted treatments for CRPS type 1.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"94"},"PeriodicalIF":6.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143616107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased HA/CD44/TGFβ signaling implicates in renal fibrosis of a Col4a5 mutant Alport mice.","authors":"Yantao Bao, Weiqing Wu, Jiyun Lin, Yuankai Yang, Sheng Lin, Jindi Su, Yueyuan Qin, Baojiang Wang, Shan Duan","doi":"10.1186/s10020-025-01146-0","DOIUrl":"10.1186/s10020-025-01146-0","url":null,"abstract":"<p><p>X-linked Alport syndrome (XLAS) caused by X-linked COL4A5 gene mutation is a hereditary disease that affects mainly the kidney. XLAS patients, especially males whose single copy of the COL4A5 gene is disrupted, suffer from a life-threatening renal disease, the mechanism of which remains unclear. Renal fibrosis is a characteristic pathology observed in XLAS kidney tissue. However, the molecular path from COL4A5 loss-of-function to fibrotic pathology is largely unknown. On the basis of a previously established XLAS mouse model, our study revealed an activated CD44-TGFβ signaling known to strongly promote fibrosis, along with an increased level of low molecular weight hyaluronan (LMW-HA) instead of high molecular weight hyaluronan (HMW-HA), to activate CD44-dependent TGFβ signaling in XLAS renal tissues. Additionally, hyaluronan synthase 2 (HAS2), an enzyme primarily responsible for HA production, was found to be upregulated in XLAS. In particular, in vitro studies revealed that COL4A5 knockdown in human kidney-derived HEK-293 cells can upregulate HAS2 at both the RNA and protein levels. The novel contribution of our study is finding that COL4A5 deficiency may lead to HAS2 overexpression and HA accumulation to activate CD44-TGFβ signaling, thereby promoting fibrosis, possibly suggesting that HAS2 and CD44 are potential therapeutic targets for impeding renal fibrosis in XLAS.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"96"},"PeriodicalIF":6.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143616186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WBP1 regulates mitochondrial function and ferroptosis to modulate chemoresistance in colorectal cancer.","authors":"Yang Wang, Dachuan Qi, Guijie Ge, Ning Cao, Xiangdong Liu, Na Zhu, Feng Li, Xiang Huang, Kui Yu, Jinzhou Zheng, Daoheng Wang, Wenyan Yao, Lili Chen, Ziyang Dong","doi":"10.1186/s10020-025-01151-3","DOIUrl":"10.1186/s10020-025-01151-3","url":null,"abstract":"<p><p>Chemoresistance continues to pose a significant challenge in managing colorectal cancer (CRC), resulting in unfavorable outcomes for patients. Recent findings indicate that ferroptosis, an innovative type of regulated cell death, might influence chemoresistance. In this research, we explored how WW domain-binding protein 1 (WBP1) affects mitochondrial function, cell growth, ferroptosis, and chemoresistance in CRC cells. By employing both genetic and pharmacological methods, we found that WBP1 is essential for maintaining mitochondrial respiration in CRC cells. WBP1 depletion impaired mitochondrial function, leading to reduced cell proliferation and increased ferroptosis. Exogenous mitochondria from wild-type cells restored mitochondrial function, cell proliferation, and suppressed ferroptosis in WBP1-deficient cells, indicating that mitochondrial function acts downstream of WBP1. Importantly, we demonstrated that targeting WBP1 or its mediated mitochondrial function sensitized chemoresistant CRC cells to 5-fluorouracil and oxaliplatin by inducing ferroptosis. Furthermore, we analyzed transcriptome data from CRC patients, which indicated that increased WBP1 expression correlated with poor outcomes for patients receiving chemotherapy, thus highlighting the clinical significance of our observations. Collectively, our results pinpoint WBP1 as a significant modulator of mitochondrial function and ferroptosis in CRC cells and imply that targeting WBP1 may represent a viable approach to tackling chemoresistance. These insights offer a deeper understanding of the molecular pathways underlying CRC chemoresistance and may guide the development of new treatment options.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"93"},"PeriodicalIF":6.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11900258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143616175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transposition element MERVL regulates DNA demethylation through TET3 in oxidative-damaged mouse preimplantation embryos.","authors":"Lihong Liu, Siyao Ha, Dan Cao, MingQing Li, Zhiling Li","doi":"10.1186/s10020-025-01143-3","DOIUrl":"10.1186/s10020-025-01143-3","url":null,"abstract":"<p><p>Transposable elements (TEs) comprise approximately half of eukaryotic genomes and significantly contribute to genome plasticity. In this study, we focused on a specific TE, MERVL, which exhibits particular expression during the 2-cell stage and commonly serves as an indicator of embryonic totipotency. However, its precise role in embryo development remains mysterious. We utilized DRUG-seq to investigate the effects of oxidative damage on genes and TEs expression. Our findings revealed that exposure to hydrogen peroxide (H₂O₂) could induce DNA damage, apoptosis, and incomplete DNA demethylation in embryos, which were potentially associated with MERVL expression. To further explore its function, antisense nucleotides (ASO) targeting MERVL were constructed to knockdown the expression in early embryos. Notably, this knockdown led to the occurrence of DNA damage and apoptosis as early as the 2-cell stage, consequently reducing the number of embryos that could progress to the blastocyst stage. Moreover, we discovered that MERVL exerted an influence on the reprogramming of embryonic DNA methylation. In MERVL-deficient embryos, the activity of the DNA demethylase ten-eleven translocation 3 (TET3) was suppressed, resulting in impaired demethylation when compared to normal development. This impairment might underpin the mechanism that impacts embryonic development. Collectively, our study not only verified the crucial role of MERVL in embryonic development but also probed its regulatory function in DNA methylation reprogramming, thereby laying a solid foundation for further investigations into MERVL's role.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"95"},"PeriodicalIF":6.0,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143616174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}