Free Radical Biology and Medicine最新文献

{"title":"U2AF1 mutation causes an oxidative stress and DNA repair defect in hematopoietic and leukemic cells.","authors":"Yishuang Li, Xuanjia Dong, Haiyan Xing, Wenbing Liu, Runxia Gu, Shaowei Qiu, Yingxi Xu, Hui Wei, Min Wang, Guoguang Zheng, Qing Rao, Jianxiang Wang","doi":"10.1016/j.freeradbiomed.2025.01.019","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.01.019","url":null,"abstract":"<p><p>U2AF1 is a core component of spliceosome and controls cell-fate specific alternative splicing. U2AF1 mutations have been frequently identified in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients, and mutations in U2AF1 are associated with poor prognosis in hematopoietic malignant diseases. Here, by forced expression of mutant U2AF1 (U2AF1 S34F) in hematopoietic and leukemic cell lines, we find that U2AF1 S34F causes increased reactive oxygen species (ROS) production. In hematopoietic cell line, a defect in mitochondrial function and DNA damage response deficiency are found in U2AF1 S34F expressing 32D cells. In leukemic cell line Molm13 cells, U2AF1 mutation leads to resistance to DNA damaging agents. Accumulation of DNA damage is also found in U2AF1 S34F expressing leukemic cells when treated with DNA damage agent. Finally, in our established hematopoietic-specific U2af1 S34F knock-in mice model, U2AF1 mutation leads to the development of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) and causes DNA damage accumulation in hematopoietic cells. Our study provides evidence that U2AF1 mutation causes DNA damage response deficiency and DNA damage accumulation in hematopoietic cells, and suggests that mutant U2AF1 induced higher ROS production, resistance to DNA damaging agents and increased genomic instability may contribute to poor prognosis of AML patients with U2AF1 mutations.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"228 ","pages":"379-391"},"PeriodicalIF":7.1,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TREM2 alleviates sepsis-induced acute lung injury by attenuating ferroptosis via the SHP1/STAT3 pathway.","authors":"Siyi Wu, Yuanjie He, Jiemei Li, Hanhong Zhuang, Peng Wang, Xiaojing He, Youyuan Guo, Zhiping Li, Honglei Shen, Liu Ye, Fei Lin","doi":"10.1016/j.freeradbiomed.2025.01.022","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.01.022","url":null,"abstract":"<p><p>Sepsis-induced acute lung injury (ALI) is a complex and life-threatening condition characterized by excessive inflammatory responses, ferroptosis, and oxidative stress. A comprehensive investigation and effective therapeutic strategies are crucial for managing this condition. In this study, we established in vivo sepsis models using lipopolysaccharide (LPS) in wild-type (WT) mice and triggering receptor expressed on myeloid cells 2 (TREM2) knockout (TREM2-KO) mice to assess lung morphology, oxidative stress, and ferroptosis. In vitro, RAW264.7 cells with TREM2 overexpression (TREM2-OE) or knockdown (TREM2-SiRNA) were utilized to assess oxidative stress and ferroptosis. RNA sequencing of LPS-stimulated cells transfected with either vector or TREM2-OE revealed significant differences in inflammation- and ferroptosis-related pathways. LPS-induced lung injury and ferroptosis were exacerbated in TREM2-KO mice and TREM2-SiRNA cells but alleviated by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Mechanistically, TREM2-KO led to SHP1 downregulation and STAT3-P upregulation, which were reversed by the SHP1 agonist SC-43. These findings highlight the role of TREM2 in the SHP1/STAT3 signaling pathway and its regulatory effects on ferroptosis. Our study demonstrates that TREM2, via the SHP1/STAT3 pathway, suppresses oxidative stress and ferroptosis, thereby significantly mitigating sepsis-induced ALI. These results underscore the pivotal role of TREM2 in modulating inflammatory responses and immunity, providing a theoretical foundation for developing therapeutic strategies.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143002881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"7,8-DHF inhibits BMSC oxidative stress via the TRKB/PI3K/AKT/NRF2 pathway to improve symptoms of postmenopausal osteoporosis\" [Free Radic. Biol. Med. 223 (2024) 413-429].","authors":"Dailuo Li, Zihang Zhao, Liyu Zhu, Haoran Feng, Junlong Song, Jiawei Fu, Jincheng Li, Zhanzhi Chen, Hailiang Fu","doi":"10.1016/j.freeradbiomed.2025.01.005","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.01.005","url":null,"abstract":"","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AdipoRon ameliorates chronic ethanol induced cardiac necroptosis by reducing ceramide mediated mtROS.","authors":"Yile Qian, Yanyu Qi, Junyi Lin, Tianyi Zhang, Lingjie Mo, Qiupeng Xue, Nianchang Zheng, Yaqin Niu, Xiaoru Dong, Yan Shi, Yan Jiang","doi":"10.1016/j.freeradbiomed.2025.01.018","DOIUrl":"10.1016/j.freeradbiomed.2025.01.018","url":null,"abstract":"<p><p>Chronic ethanol (EtOH) consumption has been widely recognized as a significant contributor to cardiotoxicity. However, no specific treatment is currently available to ameliorate chronic ethanol induced cardiotoxicity. Adiponectin receptor agonist AdipoRon exerts protective effects in multiple organs through alleviating lipotoxicity. Our previous study showed that chronic ethanol consumption increased de novo ceramide synthesis and necroptosis in myocardium. In this study, we investigated the role of AdipoRon on ceramide metabolism and necroptosis in chronic ethanol-treated myocardium. Eight-week-old C57/BL6J mice were fed with a Lieber-Decarli diet containing vehicle or AdipoRon for 12 weeks. Cardiac function, histology and oxidative stress were assessed. We found that chronic ethanol treatment decreased expression of AdipoR2 in myocardium and H9c2 cells, whereas AdipoRon improved cardiac function, reduced myocardium ceramide levels and suppressed necroptosis. By pharmacological interventions, RNA interference and point mutations in AdipoR2, we demonstrated that AdipoRon reduced ceramide levels through PPARα mediated lipid metabolism rather than AdipoR2's ceramidase activity. Using transmission electron microscope and reactive oxygen species (ROS) staining, we showed that chronic ethanol induced myocardium mitochondria damage and mitochondrial reactive oxygen species (mtROS) accumulation. Meanwhile, we found that AdipoRon ameliorated chronic ethanol induced cardiac necroptosis via the SIRT3-SOD2-mtROS pathway. Moreover, C6 ceramide treatment recapitulated chronic ethanol in inducing mtROS and necroptosis, whereas the ceramide synthesis inhibitors myriocin (MYR) and fumonisin B1 (FB1) attenuated chronic ethanol induced mtROS and necroptosis. Collectively, AdipoRon ameliorates chronic ethanol induced cardiac necroptosis by reducing ceramide de novo synthesis and mtROS, which highlights the therapeutic potential of targeting ceramide metabolism and oxidative stress pathways in treating ethanol induced cardiotoxicity.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"237-250"},"PeriodicalIF":7.1,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dectin-2 depletion alleviates osteoclast-induced bone loss in periodontitis via Syk/NOX2/ROS signaling.","authors":"Wengwanyue Ye, Yilin Liao, Xiaoyu Liu, Yuting Wang, Ting Li, Yaoyu Zhao, Zhenru He, Jingqiu Chen, Mengjie Yin, Yue Sheng, Yangge Du, Yaoting Ji, Hong He","doi":"10.1016/j.freeradbiomed.2025.01.011","DOIUrl":"10.1016/j.freeradbiomed.2025.01.011","url":null,"abstract":"<p><p>Periodontitis is the sixth most common disease worldwide and is closely associated with various systemic diseases, impacting overall health. It is characterized by the over-differentiation and activity of osteoclasts, leading to increased bone resorption and subsequent bone loss. Current treatments for bone loss are not ideal, highlighting the need for new targeted therapeutic strategies. Dectin-2, a member of the C-type lectin receptor (CLR) family, has recently been reported to play an important role in immune regulation, but its role in osteoclastogenesis has not been documented. This study identified a significant upregulation of Dectin-2 expression during osteoclast differentiation through single-cell sequencing and transcriptomic analysis. Knocking down Dectin-2 significantly inhibits the differentiation of RAW264.7 cells and bone marrow-derived macrophages (BMDMs) into osteoclasts, while overexpressing Dectin-2 enhances osteoclast differentiation and function. Mechanistically, transcriptomic analysis indicates that Dectin-2 deficiency disrupts redox homeostasis and affects the MAPK signaling pathway. Furthermore, the study demonstrates that Dectin-2 promotes osteoclastogenesis via the Syk/NOX2/ROS/MAPK signaling axis. In vivo, Dectin-2 knockout mice show reduced osteoclast numbers and decreased alveolar bone resorption in a periodontitis model. In conclusion, these findings suggest that Dectin-2 is a key regulatory factor in osteoclast-mediated bone resorption and may serve as a promising therapeutic target for bone diseases characterized by osteoclast overactivity, such as periodontitis.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"13-29"},"PeriodicalIF":7.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct Evaluation of Salivary Antioxidant Properties in Patients with Down Syndrome for assessment to Periodontal Disease and Premature Aging.","authors":"Ryohei Aoki, Kyo Kobayashi, Shiori Yokoyama, Chia-An Cheng, Hiroyuki Mishima, Tatsuro Kondoh, Tomoko Komatsu, Masaichi Chang-Il Lee","doi":"10.1016/j.freeradbiomed.2025.01.017","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.01.017","url":null,"abstract":"<p><p>To evaluate oxidative stress involved in Down syndrome periodontal disease and pathological premature aging, reactive oxygen species (ROS) such as superoxide (O₂^•-) and hydroxyl radical (HO^•) in human saliva were measured using electron spin resonance (ESR) spectroscopy. The groups consisted of 20 subjects in the Down syndrome (DS) child (D_SC) group (mean age 11.3 ± 4.2 years), 24 subjects in the normal(N) child (NC) group (mean age 8.5 ± 2.0 years), 31 subjects in the DS-adults (DsA) group (mean age 48.9 ± 6.5 years), and 24 subjects in the NA group (mean age 47.1 ± 4.9 years). Comparing DS and N groups, gingivitis index (GI), pocket depth (PD) were higher in group A than in group C depending on age. The salivary O₂^•- scavenging rate measured by ESR spectroscopy was lower in DS group, and the salivary antioxidant properties such as both O₂^•- and HO^• scavenging rate of DS and N groups, whose GI and PD increased with age, were higher in A group than in C group. These ROS antioxidant properties of saliva suggested the possibility of clinical evaluation for testing for periodontal disease and early aging, which are also characteristics of DS.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-COVID metabolic enzyme alterations in K18-hACE2 mice exacerbate alcohol-induced liver injury through transcriptional regulation.","authors":"SiYeong Park, Youn Woo Lee, Seunghoon Choi, Harin Jo, NaHyun Kim, Sumin Cho, Eunji Lee, Eun-Bin Choi, Inyoung Park, Young Jeon, Hyuna Noh, Sang-Hyuk Seok, Seung Hyun Oh, Yang-Kyu Choi, Ho-Keun Kwon, Jun-Young Seo, Ki Taek Nam, Jun Won Park, Kang-Seuk Choi, Ho-Young Lee, Jun-Won Yun, Je Kyung Seong","doi":"10.1016/j.freeradbiomed.2025.01.015","DOIUrl":"10.1016/j.freeradbiomed.2025.01.015","url":null,"abstract":"<p><p>Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a significant threat to global public health. Despite reports of liver injury during viral disease, the occurrence and detailed mechanisms underlying the development of secondary exogenous liver injury, particularly in relation to changes in metabolic enzymes, remain to be fully elucidated. Therefore, this study was aimed to investigate the mechanisms underlying SARS-CoV-2-induced molecular alterations in hepatic metabolism and the consequent secondary liver injury resulting from alcohol exposure. We investigated the potential effects of SARS-CoV-2 infection on alcohol-induced liver injury in Keratin 18 promoter-human angiotensin converting enzyme 2 (K18-hACE2) transgenic mice. Mice were intranasally infected with 1 × 10² PFU of SARS-CoV-2. Following a 14 d recovery period from infection, the recovered mice were orally administered alcohol at 6 g/kg. Prior SARS-CoV-2 infection aggravated alcohol-induced liver injury based on increased alanine aminotransferase levels and cytoplasmic vacuolation. Interestingly, infected mice exhibited lower blood alcohol levels and higher levels of acetaldehyde, a toxic alcohol metabolite, compared to uninfected mice after the same period of alcohol consumption. Along with alterations of several metabolic process-related terms identified through RNA sequencing, notably, upregulation of cytochrome P450 2E1 (CYP2E1) and CYP1A2 was observed in infected mice compared to control value prior to alcohol exposure, with no significant impact of SARS-CoV-2 on intestinal damage. Tumor necrosis factor-alpha persistently showed upregulated expression in the infected mice; it also enhanced aryl hydrocarbon receptor and Sp1 expressions and their binding activity to Cyp1a2 and Cyp2e1 promoters, respectively, in hepatocytes, promoting the upregulation of their transcription. Our findings suggest that SARS-CoV-2 infection exacerbates alcohol-induced liver injury through the transcriptional activation of Cyp1a2 and Cyp2e1, providing valuable insights for the development of clinical recommendations on long COVID.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"1-12"},"PeriodicalIF":7.1,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OAB-14 alleviates mitochondrial impairment through the SIRT3-dependent mechanism in APP/PS1 transgenic mice and N2a/APP cells.","authors":"Na Zheng, Ruo-Lin Cao, Dan-Yang Liu, Peng Liu, Xin-Yu Zhao, Shu-Xin Zhang, Min Huang, Zhong-Hui Zheng, Guo-Liang Chen, Li-Bo Zou","doi":"10.1016/j.freeradbiomed.2025.01.014","DOIUrl":"10.1016/j.freeradbiomed.2025.01.014","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive degenerative disease that affects a growing number of elderly individuals worldwide. OAB-14, a novel chemical compound developed by our research group, has been approved by the China Food and Drug Administration (FDA) for clinical trials in patients with AD (approval no. YD-OAB-220210). Previous studies have shown that OAB-14 enhances cognitive function in APP/PS1 transgenic mice and ameliorates abnormal mitochondrial morphology in the hippocampus. Mitochondrial dysfunction is a major risk factor for the development of AD, and maintaining healthy mitochondrial morphology and function is essential for improving the pathological changes and symptoms of AD. However, the protective effects of OAB-14 on mitochondria in AD and the underlying mechanisms remain unclear. This study aimed to investigate the protective effects of OAB-14 on the mitochondria of APP/PS1 transgenic mice and N2a/APP cells. Treatment with OAB-14 restored impaired mitochondrial function, mitochondrial dynamics, mitophagy, and mitochondrial DNA (mtDNA) in APP/PS1 transgenic mice and N2a/APP cells. In APP/PS1 transgenic mice and N2a/APP cells, OAB-14-treated elevated the expression and activity of SIRT3, decreased mitochondrial acetylation, and reduced mitochondrial reactive oxygen species (mtROS) levels. OAB-14 also attenuated mitochondrial acetylation, improved mitochondrial dynamics and mitophagy, and mitigated mtDNA damage in a SIRT3-dependent manner. In addition, OAB-14 suppressed mitochondrial Aβ accumulation in the hippocampus of APP/PS1 transgenic mice. This study provides further clarification on the potential therapeutic mechanisms of OAB-14 in the treatment of AD and lays the groundwork for future drug applications.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":"360-378"},"PeriodicalIF":7.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TREM1 interferes with macrophage mitophagy via the E2F1-mediated TOMM40 transcription axis in rheumatoid arthritis.","authors":"Zhen-Zhen Dai, Jing Xu, Qin Zhang, Han Zhou, Xiao-Man Liu, Hai Li","doi":"10.1016/j.freeradbiomed.2025.01.013","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.01.013","url":null,"abstract":"<p><p>Elevated synovial expression of the triggering receptor expressed on myeloid cells 1 (TREM1) has been identified as a significant biomarker for assessing disease activity in rheumatoid arthritis (RA). The upregulated expression of TREM1, induced by inflammatory mediators in infiltrating macrophages, plays a critical role in synovitis and joint destruction in RA. Our previous sequencing data linked TREM1 activation to aberrant mitophagy. Thus, we explored the efficacy of targeting TREM1 in treating experimental arthritis and its regulatory effect on mitophagy. TREM1 signalling activation was assessed via TREM1, DAP12, and p-SYK levels, and mitophagy was measured through PINK1, PARKIN, and LC3A/B levels. In vitro, TREM1-overexpressing RAW264.7 cells were generated, and the differences in expression and pathways were analyzed via RNA-seq. Changes in the number and morphology of mitochondria and mitophagy in TREM1-overexpressing RAW264.7 cells and normal control were observed via transmission electron microscopy, MitoTracker confocal microscopy and mitochondrial membrane potential analysis. The promotion of TOMM40 gene transcription by TREM1-activated E2F1 was determined via ChIP-PCR and E2F1 siRNA. We found that TREM1 was highly expressed and activated in the synovial tissues of CIA mice concomitant with abnormal mitophagy. The mitochondrial outer membrane transporter TOMM40 was upregulated in experimental arthritis, and the protein levels of PINK1 and LC3B were decreased. RNA-seq analysis indicated that mitophagy-related proteins were extensively downregulated and that the transcription factor E2F1 and the mitochondrial outer membrane transporter TOMM40 were significantly upregulated in TREM1-overexpressing cells. ChIP-PCR revealed that TREM1 overexpression significantly promoted the interaction between E2F1 and TOMM40 gene in RAW264.7 cells. E2F1 knockdown markedly reversed TOMM40 upregulation, mitophagy injury and ROS production in TREM1-overexpressing macrophages but not in control cells. Our study provides preliminary evidence that E2F1 regulates TOMM40 transcription and disrupts mitophagy flux in TREM1-activated macrophages. Inhibiting TREM1 effectively mitigated experimental arthritis by restoring macrophage mitophagy and reducing intracellular ROS levels.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":"228 ","pages":"267-280"},"PeriodicalIF":7.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peroxidasin is associated with a mesenchymal-like transcriptional phenotype and promotes invasion in metastatic melanoma.","authors":"Carlos C Smith-Díaz, Abhishek Kumar, Andrew Das, Paul Pace, Kenny Chitcholtan, Nicholas J Magon, Sultana Mehbuba Hossain, Michael R Eccles, Christine C Winterbourn, Martina Paumann-Page","doi":"10.1016/j.freeradbiomed.2025.01.007","DOIUrl":"https://doi.org/10.1016/j.freeradbiomed.2025.01.007","url":null,"abstract":"<p><p>Cutaneous melanoma is a highly invasive, heterogeneous and treatment resistant cancer. It's ability to dynamically shift between transcriptional states or phenotypes results in an adaptive cell plasticity that may drive cancer cell invasion or the development of therapy resistance. The expression of peroxidasin (PXDN), an extracellular matrix peroxidase, has been proposed to be associated with the invasive metastatic melanoma phenotype. We have confirmed this association by analysing the transcriptomes of 70 metastatic melanoma cell lines with variable levels of PXDN expression. This analysis highlighted a strong association between high PXDN expression and the undifferentiated invasive melanoma phenotype. To assess the functional role of PXDN in melanoma invasion, we performed a knockout of PXDN in a highly invasive cell line (NZM40). PXDN knockout decreased the invasive potential by ∼50% and decreased the expression of epithelial-mesenchymal transition and invasive marker genes as determined by RNAseq and substantiated by proteomics analysis. Bioinformatics analysis of differentially expressed genes following PXDN knockout highlighted decreases in genes linked to extracellular matrix formation, organisation and degradation as well as signalling pathways such as the WNT pathway. This study provides compelling evidence that PXDN plays a functional role in melanoma invasion by promoting an invasive, mesenchymal-like transcriptional phenotype.</p>","PeriodicalId":12407,"journal":{"name":"Free Radical Biology and Medicine","volume":" ","pages":""},"PeriodicalIF":7.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}