Mitochondria, vital organelles within cells, govern energy metabolism. They play a pivotal role in maintaining redox homeostasis and are instrumental in the initiation and transmission of cell death signals, along with the synthesis of biological macromolecules. The role of mitochondria in tumor evolution and treatment has recently been the focus of extensive research. Studies indicate that the quality and biogenesis of mitochondria, along with their structure, functions, and macromolecule synthesis relevant to it, are intimately linked to tumorigenesis and the prognostic outcomes of clinical treatments. As such, therapies targeting mitochondria offer promising avenues to augment the efficacy of tumor treatment. We summarized the inherent links between mitochondrial structure, mitochondrial genes, metabolism of mitochondrial-related biological macromolecules, and mitochondria-regulated cell death in relation to tumorigenesis and progression. Furthermore, we reviewed the latest research progress in targeting mitochondria for tumor therapy. This study suggests that targeting mitochondria could open new avenues for developing tumor therapy.
{"title":"Mitochondria and tumorigenesis: Molecular basis and therapeutic implications","authors":"Chen Huang , Zichuan Xie , Jiajin Li , Chenliang Zhang","doi":"10.1016/j.gendis.2025.101806","DOIUrl":"10.1016/j.gendis.2025.101806","url":null,"abstract":"<div><div>Mitochondria, vital organelles within cells, govern energy metabolism. They play a pivotal role in maintaining redox homeostasis and are instrumental in the initiation and transmission of cell death signals, along with the synthesis of biological macromolecules. The role of mitochondria in tumor evolution and treatment has recently been the focus of extensive research. Studies indicate that the quality and biogenesis of mitochondria, along with their structure, functions, and macromolecule synthesis relevant to it, are intimately linked to tumorigenesis and the prognostic outcomes of clinical treatments. As such, therapies targeting mitochondria offer promising avenues to augment the efficacy of tumor treatment. We summarized the inherent links between mitochondrial structure, mitochondrial genes, metabolism of mitochondrial-related biological macromolecules, and mitochondria-regulated cell death in relation to tumorigenesis and progression. Furthermore, we reviewed the latest research progress in targeting mitochondria for tumor therapy. This study suggests that targeting mitochondria could open new avenues for developing tumor therapy.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 1","pages":"Article 101806"},"PeriodicalIF":9.4,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145155776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-11DOI: 10.1016/j.gendis.2025.101801
He Li , Jia-Jia Sheng , Sheng-An Zheng , Po-Wu Liu , Nayiyuan Wu , Wen-Jing Zeng , Ying-Hua Li , Jing Wang
Over the last few decades, platinum-based chemotherapy has served as the standard chemotherapy in treating ovarian cancer (OC). While most patients initially respond well to platinum-based chemotherapy, approximately 70% of patients eventually relapse and confer resistance to platinum. Recent preclinical evidence on platinum-resistant ovarian cancer (PROC) is encouraging. Various potential mechanisms, such as genomic and epigenetic alterations, pharmacological alterations, DNA damage repair, metabolic reprogramming, the tumor microenvironment (TME) and programmed cell death, have been implicated in platinum resistance. In addition, clinical trials regarding the treatment of PROC have shown considerable success, and a multitude of promising therapies are in progress. In this review, we comprehensively summarized the underlying mechanisms of platinum resistance in OC and proposed the most promising novel therapeutics and strategies employed in the treatment of PROC.
{"title":"Platinum-resistant ovarian cancer: From mechanisms to treatment strategies","authors":"He Li , Jia-Jia Sheng , Sheng-An Zheng , Po-Wu Liu , Nayiyuan Wu , Wen-Jing Zeng , Ying-Hua Li , Jing Wang","doi":"10.1016/j.gendis.2025.101801","DOIUrl":"10.1016/j.gendis.2025.101801","url":null,"abstract":"<div><div>Over the last few decades, platinum-based chemotherapy has served as the standard chemotherapy in treating ovarian cancer (OC). While most patients initially respond well to platinum-based chemotherapy, approximately 70% of patients eventually relapse and confer resistance to platinum. Recent preclinical evidence on platinum-resistant ovarian cancer (PROC) is encouraging. Various potential mechanisms, such as genomic and epigenetic alterations, pharmacological alterations, DNA damage repair, metabolic reprogramming, the tumor microenvironment (TME) and programmed cell death, have been implicated in platinum resistance. In addition, clinical trials regarding the treatment of PROC have shown considerable success, and a multitude of promising therapies are in progress. In this review, we comprehensively summarized the underlying mechanisms of platinum resistance in OC and proposed the most promising novel therapeutics and strategies employed in the treatment of PROC.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 2","pages":"Article 101801"},"PeriodicalIF":9.4,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-11DOI: 10.1016/j.gendis.2025.101803
Hongtao Zhu , Bo Yang , Hui Wang , Ping Nie , Xixi Wu , Ming Yong , Xingwei Jiang , Jianguo Hu
Intrauterine adhesion (IUA) leads to infertility or recurrent abortion; however, its etiology and pathological mechanism remain unclear. To explore the role and mechanism of the vitamin D receptor (VDR) in the pathogenesis of IUA. We found that VDR protein expression was lower in the endometria of patients with IUA than in those of the control group. Silencing VDR in endometrial epithelial cells inhibited autophagy, promoted the epithelial–mesenchymal transition (EMT) overexpression, and increased the phosphorylation of p-MTOR, p-AKT, and p-MAPK/ERK, while its overexpression suppressed the phosphorylation of p-MTOR, p-AKT, and p-MAPK/ERK. Also, the interaction between the VDR and p62 proteins was detected. Endometrial tissue in VDR knockout mice exhibited fibrosis, reduced VDR expression, decreased ATG7, LAMP1, and LC3-II levels, and increased p62 expression; the expression of the EMT marker CDH1 decreased while that of CDH2 increased. Treatment with rapamycin reversed this process. Our data indicate that the VDR receptor is a potential marker for diagnosing and treating IUA and that vitamin D may serve as a therapeutic agent for IUA.
{"title":"Vitamin D receptor loss promotes endometrial fibrosis via autophagy-mediated epithelial–mesenchymal transition","authors":"Hongtao Zhu , Bo Yang , Hui Wang , Ping Nie , Xixi Wu , Ming Yong , Xingwei Jiang , Jianguo Hu","doi":"10.1016/j.gendis.2025.101803","DOIUrl":"10.1016/j.gendis.2025.101803","url":null,"abstract":"<div><div>Intrauterine adhesion (IUA) leads to infertility or recurrent abortion; however, its etiology and pathological mechanism remain unclear. To explore the role and mechanism of the vitamin D receptor (VDR) in the pathogenesis of IUA. We found that VDR protein expression was lower in the endometria of patients with IUA than in those of the control group. Silencing VDR in endometrial epithelial cells inhibited autophagy, promoted the epithelial–mesenchymal transition (EMT) overexpression, and increased the phosphorylation of p-MTOR, p-AKT, and p-MAPK/ERK, while its overexpression suppressed the phosphorylation of p-MTOR, p-AKT, and p-MAPK/ERK. Also, the interaction between the VDR and p62 proteins was detected. Endometrial tissue in VDR knockout mice exhibited fibrosis, reduced VDR expression, decreased ATG7, LAMP1, and LC3-II levels, and increased p62 expression; the expression of the EMT marker CDH1 decreased while that of CDH2 increased. Treatment with rapamycin reversed this process. Our data indicate that the VDR receptor is a potential marker for diagnosing and treating IUA and that vitamin D may serve as a therapeutic agent for IUA.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 1","pages":"Article 101803"},"PeriodicalIF":9.4,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145321363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-09DOI: 10.1016/j.gendis.2025.101799
Zhaofu Tan , Hongbin Xin , Jian Chen , Ming Lei , Gang Tu , Lingfeng Tang
Previous studies have demonstrated a significant association between sialic acid binding Ig-like lectin 15 (SIGLEC15) and both the progression of malignant tumors and immune infiltration. This study comprehensively analyzed and elaborated the function and related mechanism of SIGLEC15 in breast cancer. We analyzed SIGLEC15 expression levels and predicted its functions using mRNA sequencing in a population-based dataset. Single-cell RNA sequencing was utilized to investigate the biological roles of SIGLEC15 within the tumor microenvironment (TME). Finally, we conducted both in vivo and in vitro experiments to validate the findings derived from the RNA sequencing analyses. Elevated SIGLEC15 expression was associated with favorable outcomes in breast cancer patients. Tumor cells exhibiting high SIGLEC15 expression demonstrated reduced epithelial–mesenchymal transition (EMT) tendencies compared to those with lower expression levels, potentially through the regulation of ZEB1 expression. However, anti-tumor immunity was significantly suppressed in the TME containing these tumor cells. Analysis of protein expression in patient samples revealed a negative correlation between SIGLEC15 expression and CD4, CD8 T-cell infiltration. In mouse models, tumor cells overexpressing SIGLEC15 exhibited diminished invasive and migratory capabilities. Furthermore, both in vitro and in vivo experiments confirmed that Nutlin-3a has a more pronounced inhibitory effect on breast cancer cells with elevated SIGLEC15 expression. The expression level of SIGLEC15 can serve as a biomarker to assess the malignancy of breast cancer and the degree of immune infiltration. Monitoring SIGLEC15 expression levels can facilitate more informed and personalized clinical decision-making for the treatment of breast cancer patients.
{"title":"SIGLEC15 modulates the immunosuppressive microenvironment and suppresses malignant phenotypes in triple-negative breast cancer","authors":"Zhaofu Tan , Hongbin Xin , Jian Chen , Ming Lei , Gang Tu , Lingfeng Tang","doi":"10.1016/j.gendis.2025.101799","DOIUrl":"10.1016/j.gendis.2025.101799","url":null,"abstract":"<div><div>Previous studies have demonstrated a significant association between sialic acid binding Ig-like lectin 15 (<em>SIGLEC15)</em> and both the progression of malignant tumors and immune infiltration. This study comprehensively analyzed and elaborated the function and related mechanism of <em>SIGLEC15</em> in breast cancer. We analyzed <em>SIGLEC15</em> expression levels and predicted its functions using mRNA sequencing in a population-based dataset. Single-cell RNA sequencing was utilized to investigate the biological roles of <em>SIGLEC15</em> within the tumor microenvironment (TME). Finally, we conducted both <em>in vivo</em> and <em>in vitro</em> experiments to validate the findings derived from the RNA sequencing analyses. Elevated <em>SIGLEC15</em> expression was associated with favorable outcomes in breast cancer patients. Tumor cells exhibiting high <em>SIGLEC15</em> expression demonstrated reduced epithelial–mesenchymal transition (EMT) tendencies compared to those with lower expression levels, potentially through the regulation of <em>ZEB1</em> expression. However, anti-tumor immunity was significantly suppressed in the TME containing these tumor cells. Analysis of protein expression in patient samples revealed a negative correlation between <em>SIGLEC15</em> expression and CD4, CD8 T-cell infiltration. In mouse models, tumor cells overexpressing <em>SIGLEC15</em> exhibited diminished invasive and migratory capabilities. Furthermore, both <em>in vitro</em> and <em>in vivo</em> experiments confirmed that Nutlin-3a has a more pronounced inhibitory effect on breast cancer cells with elevated <em>SIGLEC15</em> expression. The expression level of SIGLEC15 can serve as a biomarker to assess the malignancy of breast cancer and the degree of immune infiltration. Monitoring SIGLEC15 expression levels can facilitate more informed and personalized clinical decision-making for the treatment of breast cancer patients.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 1","pages":"Article 101799"},"PeriodicalIF":9.4,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145321364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-08DOI: 10.1016/j.gendis.2025.101797
Yufang Zou , Juan Tao , Yingzheng Gao , Jixuan Wang , Pengfei Wang , Jingyuan Yan , Zuqing Nie , Dewei Jiang , Xinwei Huang
Oncolytic viruses (OVs) represent a cutting-edge approach to cancer immunotherapy, characterized by their ability to selectively infect and eliminate tumor cells while sparing healthy tissues. Among the diverse OVs, type 1 herpes simplex virus (HSV-1) stands out due to its robust oncolytic activity, genetic malleability, broad cell tropism, and well-documented clinical safety. Advances in genetic engineering have further amplified the therapeutic efficacy of HSV-1 by enhancing tumor specificity, replication efficiency, and immunogenicity. Clinically significant HSV-1-based oncolytic viruses, such as T-VEC and G47Δ, have gained regulatory approvals for treating melanoma and malignant glioma, respectively, highlighting their transformative potential in cancer therapy. The attenuation strategies employed in most oncolytic HSV-1 (oHSV-1) strains, while ensuring safety, often reduce viral replication and cytotoxicity. To address this limitation, retargeting strategies focusing on HSV-1 glycoproteins (gD, gH/gL, and gB) have been developed. These modifications aim to abolish canonical receptor interactions and achieve tumor-specific targeting through ligand-receptor binding. Recent breakthroughs in understanding HSV entry mechanisms have enabled the creation of fully retargeted HSV vectors with enhanced specificity and efficacy. This review explores the molecular mechanisms underlying HSV glycoprotein-mediated cell entry, examines recent advances in receptor-retargeted oHSV-1 engineering, and discusses the challenges and future directions in the development of oncolytic HSV-based therapies.
{"title":"Engineering HSV-1 for oncolytic therapy: From molecular entry mechanisms to retargeting strategies","authors":"Yufang Zou , Juan Tao , Yingzheng Gao , Jixuan Wang , Pengfei Wang , Jingyuan Yan , Zuqing Nie , Dewei Jiang , Xinwei Huang","doi":"10.1016/j.gendis.2025.101797","DOIUrl":"10.1016/j.gendis.2025.101797","url":null,"abstract":"<div><div>Oncolytic viruses (OVs) represent a cutting-edge approach to cancer immunotherapy, characterized by their ability to selectively infect and eliminate tumor cells while sparing healthy tissues. Among the diverse OVs, type 1 herpes simplex virus (HSV-1) stands out due to its robust oncolytic activity, genetic malleability, broad cell tropism, and well-documented clinical safety. Advances in genetic engineering have further amplified the therapeutic efficacy of HSV-1 by enhancing tumor specificity, replication efficiency, and immunogenicity. Clinically significant HSV-1-based oncolytic viruses, such as T-VEC and G47Δ, have gained regulatory approvals for treating melanoma and malignant glioma, respectively, highlighting their transformative potential in cancer therapy. The attenuation strategies employed in most oncolytic HSV-1 (oHSV-1) strains, while ensuring safety, often reduce viral replication and cytotoxicity. To address this limitation, retargeting strategies focusing on HSV-1 glycoproteins (gD, gH/gL, and gB) have been developed. These modifications aim to abolish canonical receptor interactions and achieve tumor-specific targeting through ligand-receptor binding. Recent breakthroughs in understanding HSV entry mechanisms have enabled the creation of fully retargeted HSV vectors with enhanced specificity and efficacy. This review explores the molecular mechanisms underlying HSV glycoprotein-mediated cell entry, examines recent advances in receptor-retargeted oHSV-1 engineering, and discusses the challenges and future directions in the development of oncolytic HSV-based therapies.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 2","pages":"Article 101797"},"PeriodicalIF":9.4,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-06DOI: 10.1016/j.gendis.2025.101796
Ping Song , Fan Yang
Protein arginine methyltransferase 5 (PRMT5) is the primary type II methyltransferase that mainly catalyzes symmetric demethylation of arginine residues in both histone and nonhistone proteins. Increasing evidence has demonstrated that PRMT5 is indispensable in tumorigenesis and acquired therapeutic resistance in multiple malignancies. This review summarizes the clinical significance of PRMT5 in solid tumors such as lung cancer, breast cancer, and glioblastoma, its role in tumor immunology, and current clinical trials of PRMT5 inhibitors, and discusses the clinical status, current dilemma, and future perspectives of PRMT5 inhibition as a novel therapeutic strategy.
{"title":"Protein arginine methyltransferase 5 as a novel therapeutic target in solid tumors","authors":"Ping Song , Fan Yang","doi":"10.1016/j.gendis.2025.101796","DOIUrl":"10.1016/j.gendis.2025.101796","url":null,"abstract":"<div><div>Protein arginine methyltransferase 5 (PRMT5) is the primary type II methyltransferase that mainly catalyzes symmetric demethylation of arginine residues in both histone and nonhistone proteins. Increasing evidence has demonstrated that PRMT5 is indispensable in tumorigenesis and acquired therapeutic resistance in multiple malignancies. This review summarizes the clinical significance of PRMT5 in solid tumors such as lung cancer, breast cancer, and glioblastoma, its role in tumor immunology, and current clinical trials of PRMT5 inhibitors, and discusses the clinical status, current dilemma, and future perspectives of PRMT5 inhibition as a novel therapeutic strategy.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 1","pages":"Article 101796"},"PeriodicalIF":9.4,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145217178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1016/j.gendis.2025.101790
Fan Du , Bing Zhou
{"title":"Drosophila phenylketonuria modeling helps reveal the disease etiology and the modulation role of iron","authors":"Fan Du , Bing Zhou","doi":"10.1016/j.gendis.2025.101790","DOIUrl":"10.1016/j.gendis.2025.101790","url":null,"abstract":"","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 2","pages":"Article 101790"},"PeriodicalIF":9.4,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145577067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer stem cells (CSCs), progenitor tumor cells with stemness characteristics, play key roles in cancer's onset, progression, metastasis, relapse, and chemotherapy resistance. While the exact molecular mechanisms of CSC development are not fully understood, recent research has revealed regulatory pathways of their generation with the weighty involvement of non-coding RNAs. It has been found that some pseudogenes are transcribed to long non-coding RNAs (lncRNAs), which are functionally and structurally similar to typical lncRNAs with biological functions including sponge miRNAs, antisense RNA, and interactions with proteins. Outstandingly, various in vitro and in vivo evidence have demonstrated that dysregulation of pseudogene-derived lncRNAs is directly involved in the development of CSCs in different cancers, mainly through functioning as miRNA sponges for modulating CSC-related signaling pathways. Therefore, researchers have suggested that research in this field can reveal hidden aspects of CSC development and can also open a new window for developing novel cancer therapeutic and diagnostic targets. In this review, we comprehensively address the recent findings of previous studies on the dysregulated roles of pseudogene-derived lncRNAs in directing and generating CSCs in various cancers. Also, their clinical capacities in terms of biomarkers, diagnosis, and treatment for cancer will be discussed.
{"title":"Emerging roles of pseudogene-derived lncRNAs in cancer stem cells: Non-coding clues and therapeutic targets in cancer medicine","authors":"Seyed Taha Nourbakhsh , Fatemeh Mohamadhashem , Elahe Soltani Fard , Faezeh Mohamadhashem , Abdolreza Daraei","doi":"10.1016/j.gendis.2025.101793","DOIUrl":"10.1016/j.gendis.2025.101793","url":null,"abstract":"<div><div>Cancer stem cells (CSCs), progenitor tumor cells with stemness characteristics, play key roles in cancer's onset, progression, metastasis, relapse, and chemotherapy resistance. While the exact molecular mechanisms of CSC development are not fully understood, recent research has revealed regulatory pathways of their generation with the weighty involvement of non-coding RNAs. It has been found that some pseudogenes are transcribed to long non-coding RNAs (lncRNAs), which are functionally and structurally similar to typical lncRNAs with biological functions including sponge miRNAs, antisense RNA, and interactions with proteins. Outstandingly, various <em>in vitro</em> and <em>in vivo</em> evidence have demonstrated that dysregulation of pseudogene-derived lncRNAs is directly involved in the development of CSCs in different cancers, mainly through functioning as miRNA sponges for modulating CSC-related signaling pathways. Therefore, researchers have suggested that research in this field can reveal hidden aspects of CSC development and can also open a new window for developing novel cancer therapeutic and diagnostic targets. In this review, we comprehensively address the recent findings of previous studies on the dysregulated roles of pseudogene-derived lncRNAs in directing and generating CSCs in various cancers. Also, their clinical capacities in terms of biomarkers, diagnosis, and treatment for cancer will be discussed.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 2","pages":"Article 101793"},"PeriodicalIF":9.4,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Our research focused on the impact of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)–stimulator of interferon genes (STING) pathway on retinal inflammation and employed an endotoxin-induced uveitis (EIU) model. EIU was provoked in mice through the intravitreal administration of lipopolysaccharide. Transcriptome analysis was performed via bulk RNA sequencing. Cytosolic mitochondrial DNA levels in the retina were quantified via PCR. Western blotting was used to assess the activation of cGAS‒STING signaling at specified times after intravitreal lipopolysaccharide injection. To understand the influence of the cGAS‒STING pathway on inflammatory retinal disorders, Cgas knockout mice were developed. Fundus imaging and fluorescein angiography were conducted to observe vitreous inflammation. Microstructural analysis of the eyes was performed, and histopathological scoring was performed. Retinal leukocytosis assays were used to evaluate retinal inflammation. Analysis of these differentially expressed mRNAs revealed activation of the cGAS‒STING signaling pathway, which was confirmed by western blotting analysis of these proteins. Using Cgas knockout mice, we observed significant inhibition of endotoxin-induced intraocular inflammation, including reduced vitreous inflammation, reduced retinal vascular leakage, decreased leukocyte adhesion, inhibited infiltration and activation of macrophages in the retina, and inhibited microglial activation. These findings suggest that cGAS might be a potential novel therapeutic target for uveitis.
{"title":"cGAS knockout inhibited endotoxin-induced uveitis in mice","authors":"Yue Guo , Ruiping Gu , Jiaojiao Wei , Chunhui Jiang","doi":"10.1016/j.gendis.2025.101786","DOIUrl":"10.1016/j.gendis.2025.101786","url":null,"abstract":"<div><div>Our research focused on the impact of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)–stimulator of interferon genes (STING) pathway on retinal inflammation and employed an endotoxin-induced uveitis (EIU) model. EIU was provoked in mice through the intravitreal administration of lipopolysaccharide. Transcriptome analysis was performed via bulk RNA sequencing. Cytosolic mitochondrial DNA levels in the retina were quantified via PCR. Western blotting was used to assess the activation of cGAS‒STING signaling at specified times after intravitreal lipopolysaccharide injection. To understand the influence of the cGAS‒STING pathway on inflammatory retinal disorders, Cgas knockout mice were developed. Fundus imaging and fluorescein angiography were conducted to observe vitreous inflammation. Microstructural analysis of the eyes was performed, and histopathological scoring was performed. Retinal leukocytosis assays were used to evaluate retinal inflammation. Analysis of these differentially expressed mRNAs revealed activation of the cGAS‒STING signaling pathway, which was confirmed by western blotting analysis of these proteins. Using Cgas knockout mice, we observed significant inhibition of endotoxin-induced intraocular inflammation, including reduced vitreous inflammation, reduced retinal vascular leakage, decreased leukocyte adhesion, inhibited infiltration and activation of macrophages in the retina, and inhibited microglial activation. These findings suggest that cGAS might be a potential novel therapeutic target for uveitis.</div></div>","PeriodicalId":12689,"journal":{"name":"Genes & Diseases","volume":"13 2","pages":"Article 101786"},"PeriodicalIF":9.4,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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