The interplay between metabolomics and epigenetics is a key glioma driver. Both tumor-intrinsic and microenvironmental metabolic cues can shape chromatin. Epigenetic methylation and demethylation are metabolically regulated by S-adenosyl methionine (SAM) (via methionine metabolism) and the TCA-cycle-related metabolite α-ketoglutarate (α-KG), respectively. Additionally, glycolysis and the TCA cycle modulate histone acetylation and lactylation. Gliomas in both adults and children hijack these pathways. Adult isocitrate dehydrogenase (IDH)-wild-type tumors enhance glycolysis via epidermal growth factor receptor to alter chromatin. IDH-mutant gliomas generate D-2-hydroxyglutarate (D-2HG), which inhibits α-KG demethylases to create epigenetic hypermethylation. Pediatric gliomas, including gliomas with lysine-to-methionine mutations at residue 27 of histone H3 and posterior fossa group A ependymomas, can also rewire metabolism to regulate chromatin. These pathways can be targeted for therapeutic development. Inhibiting IDH mutations with vorasidenib lowers D-2HG and is beneficial to patients. Other drugs like ONC201 and metformin can metabolically suppress oncogenic chromatin states in pediatric gliomas. This dynamic cross talk between metabolism and epigenetics not only underpins tumor biology but also presents opportunities for innovative therapeutic strategies.
{"title":"Integration and Intersection of Cancer Metabolism with Epigenetic Pathways in Gliomas.","authors":"Siva Kumar Natarajan,Matthew Pun,James Haggerty-Skeans,Sriram Venneti","doi":"10.1146/annurev-pathmechdis-111523-023424","DOIUrl":"https://doi.org/10.1146/annurev-pathmechdis-111523-023424","url":null,"abstract":"The interplay between metabolomics and epigenetics is a key glioma driver. Both tumor-intrinsic and microenvironmental metabolic cues can shape chromatin. Epigenetic methylation and demethylation are metabolically regulated by S-adenosyl methionine (SAM) (via methionine metabolism) and the TCA-cycle-related metabolite α-ketoglutarate (α-KG), respectively. Additionally, glycolysis and the TCA cycle modulate histone acetylation and lactylation. Gliomas in both adults and children hijack these pathways. Adult isocitrate dehydrogenase (IDH)-wild-type tumors enhance glycolysis via epidermal growth factor receptor to alter chromatin. IDH-mutant gliomas generate D-2-hydroxyglutarate (D-2HG), which inhibits α-KG demethylases to create epigenetic hypermethylation. Pediatric gliomas, including gliomas with lysine-to-methionine mutations at residue 27 of histone H3 and posterior fossa group A ependymomas, can also rewire metabolism to regulate chromatin. These pathways can be targeted for therapeutic development. Inhibiting IDH mutations with vorasidenib lowers D-2HG and is beneficial to patients. Other drugs like ONC201 and metformin can metabolically suppress oncogenic chromatin states in pediatric gliomas. This dynamic cross talk between metabolism and epigenetics not only underpins tumor biology but also presents opportunities for innovative therapeutic strategies.","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":"154 1","pages":""},"PeriodicalIF":36.2,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145545228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-29DOI: 10.1146/annurev-pathmechdis-080624-105114
Max J.B. Cowan, Sarah Davidson, Mark Coles, Christopher D. Buckley
Fibroblasts have been canonically considered as extracellular matrix organizing cells but are now recognized as active participants in immune regulation and tissue homeostasis. In the context of fibrosis, fibroblasts are a well-understood contributor to global morbidity and mortality across cardiac, pulmonary, renal, and hepatic tissue. Beyond this, the fibroblast is a key contributor to barrier immunity and stem cell niche formation and a determinant of vascular permeability, yet it is also capable of lymphocyte homeostasis in the context of lymphoid tissue regulation. Here, we explore the role of fibroblasts across acute and chronic inflammation and their relationship to innate and adaptive immune elements, through the lens of immune-mediated inflammatory diseases. Together, the diversity of fibroblast functions presents a therapeutic challenge, but one with the potential to restore inflamed tissue to health. We discuss novel approaches driven by technological developments that now make immunotherapeutic interventions targeting fibroblasts increasingly possible.
{"title":"The Role of Fibroblasts Across Inflammation and Immunity","authors":"Max J.B. Cowan, Sarah Davidson, Mark Coles, Christopher D. Buckley","doi":"10.1146/annurev-pathmechdis-080624-105114","DOIUrl":"https://doi.org/10.1146/annurev-pathmechdis-080624-105114","url":null,"abstract":"Fibroblasts have been canonically considered as extracellular matrix organizing cells but are now recognized as active participants in immune regulation and tissue homeostasis. In the context of fibrosis, fibroblasts are a well-understood contributor to global morbidity and mortality across cardiac, pulmonary, renal, and hepatic tissue. Beyond this, the fibroblast is a key contributor to barrier immunity and stem cell niche formation and a determinant of vascular permeability, yet it is also capable of lymphocyte homeostasis in the context of lymphoid tissue regulation. Here, we explore the role of fibroblasts across acute and chronic inflammation and their relationship to innate and adaptive immune elements, through the lens of immune-mediated inflammatory diseases. Together, the diversity of fibroblast functions presents a therapeutic challenge, but one with the potential to restore inflamed tissue to health. We discuss novel approaches driven by technological developments that now make immunotherapeutic interventions targeting fibroblasts increasingly possible.","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":"85 1","pages":""},"PeriodicalIF":36.2,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145397490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-28DOI: 10.1146/annurev-pathmechdis-111523-023453
Chisato Shimizu,José María Pérez Pomares,Conor J Loy,Iwijn De Vlaminck,Adriana H Tremoulet,Adrián Ruiz-Villalba,Jane C Burns
Kawasaki disease (KD) has replaced rheumatic fever as the most common cause of pediatric acquired heart disease across the globe. The acute illness, characterized by fever and associated mucocutaneous features, is associated with a coronary artery arteritis and myocarditis. The destruction of the arterial wall leads to aneurysm formation in 25% of untreated children. Myocardial inflammation accompanies the vasculitis, and the long-term consequences of this acute inflammation are still being defined. Our incomplete understanding of the pathology stems in part from the unknown etiology of this vasculitis. We review here the current understanding of the pathology of KD and the animal models used to elucidate KD pathogenesis and define new therapeutic targets. Improved imaging techniques and cell-free RNA studies are critically contributing to our understanding of KD pathology, but much remains to be learned before we gain more complete knowledge of this complex and important condition.
{"title":"Pathology of the Coronary Arteries and Myocardium in Kawasaki Disease.","authors":"Chisato Shimizu,José María Pérez Pomares,Conor J Loy,Iwijn De Vlaminck,Adriana H Tremoulet,Adrián Ruiz-Villalba,Jane C Burns","doi":"10.1146/annurev-pathmechdis-111523-023453","DOIUrl":"https://doi.org/10.1146/annurev-pathmechdis-111523-023453","url":null,"abstract":"Kawasaki disease (KD) has replaced rheumatic fever as the most common cause of pediatric acquired heart disease across the globe. The acute illness, characterized by fever and associated mucocutaneous features, is associated with a coronary artery arteritis and myocarditis. The destruction of the arterial wall leads to aneurysm formation in 25% of untreated children. Myocardial inflammation accompanies the vasculitis, and the long-term consequences of this acute inflammation are still being defined. Our incomplete understanding of the pathology stems in part from the unknown etiology of this vasculitis. We review here the current understanding of the pathology of KD and the animal models used to elucidate KD pathogenesis and define new therapeutic targets. Improved imaging techniques and cell-free RNA studies are critically contributing to our understanding of KD pathology, but much remains to be learned before we gain more complete knowledge of this complex and important condition.","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":"51 1","pages":""},"PeriodicalIF":36.2,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145380828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-28DOI: 10.1146/annurev-pathmechdis-042524-030646
Jonah Lin,Adam J Gehring
Hepatitis B virus (HBV) chronically infects 250 million people worldwide, making it a primary risk factor for progressive liver disease. The virus itself is not responsible for liver damage. HBV can replicate at very high levels and produces large amounts of viral antigen, but this does not lead to hepatocyte death or liver inflammation. Instead, pathogenesis of chronic hepatitis B (CHB) is driven by the interaction between the host immune system and the virus. In chronically infected individuals, the HBV-specific immune response is dysfunctional and not able to clear the infection. This inability to clear the virus leads to aberrant immune activation in the liver, causing hepatocellular damage that, over time, leads to fibrosis, cirrhosis, and liver cancer. This review covers two aspects of sequalae associated with CHB: (a) mechanisms of tissue damage leading to fibrosis and (b) dysfunctional features of HBV-specific immunity.
{"title":"Role of Immune Cells in Hepatitis B Virus and Associated Sequelae.","authors":"Jonah Lin,Adam J Gehring","doi":"10.1146/annurev-pathmechdis-042524-030646","DOIUrl":"https://doi.org/10.1146/annurev-pathmechdis-042524-030646","url":null,"abstract":"Hepatitis B virus (HBV) chronically infects 250 million people worldwide, making it a primary risk factor for progressive liver disease. The virus itself is not responsible for liver damage. HBV can replicate at very high levels and produces large amounts of viral antigen, but this does not lead to hepatocyte death or liver inflammation. Instead, pathogenesis of chronic hepatitis B (CHB) is driven by the interaction between the host immune system and the virus. In chronically infected individuals, the HBV-specific immune response is dysfunctional and not able to clear the infection. This inability to clear the virus leads to aberrant immune activation in the liver, causing hepatocellular damage that, over time, leads to fibrosis, cirrhosis, and liver cancer. This review covers two aspects of sequalae associated with CHB: (a) mechanisms of tissue damage leading to fibrosis and (b) dysfunctional features of HBV-specific immunity.","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":"57 1","pages":""},"PeriodicalIF":36.2,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145380826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-28DOI: 10.1146/annurev-pathmechdis-042424-114814
Laura Groeger,Eckart Meese,Andreas Keller
In 2024, the Nobel Prize committee recognized the groundbreaking discovery of microRNAs (miRNAs), highlighting their fundamental role in gene regulation. Since their identification, extensive research has established that miRNAs are critical for maintaining cellular homeostasis, with their dysregulation contributing to various diseases, including cancer, neurological disorders, and cardiovascular diseases. While much of the focus has been on miRNAs in cancer, growing evidence suggests that they also play a pivotal role in viral and bacterial infections. In this review, we examine both the host miRNA response to infection and pathogen-derived small regulatory RNAs, highlighting key players such as miR-21, miR-146a, and miR-155. Finally, we discuss future research directions, emphasizing the need for functional studies, deeper exploration of bacterial and viral small RNAs, and the investigation of cross-kingdom RNA exchange.
{"title":"The Role of MicroRNAs in Viral and Bacterial Infections.","authors":"Laura Groeger,Eckart Meese,Andreas Keller","doi":"10.1146/annurev-pathmechdis-042424-114814","DOIUrl":"https://doi.org/10.1146/annurev-pathmechdis-042424-114814","url":null,"abstract":"In 2024, the Nobel Prize committee recognized the groundbreaking discovery of microRNAs (miRNAs), highlighting their fundamental role in gene regulation. Since their identification, extensive research has established that miRNAs are critical for maintaining cellular homeostasis, with their dysregulation contributing to various diseases, including cancer, neurological disorders, and cardiovascular diseases. While much of the focus has been on miRNAs in cancer, growing evidence suggests that they also play a pivotal role in viral and bacterial infections. In this review, we examine both the host miRNA response to infection and pathogen-derived small regulatory RNAs, highlighting key players such as miR-21, miR-146a, and miR-155. Finally, we discuss future research directions, emphasizing the need for functional studies, deeper exploration of bacterial and viral small RNAs, and the investigation of cross-kingdom RNA exchange.","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":"103 1","pages":""},"PeriodicalIF":36.2,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145380829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-16DOI: 10.1146/annurev-pathmechdis-042524-021922
Arya B Ökten,Joseph E Craft,Craig B Wilen
Human noroviruses are the predominant cause of acute gastroenteritis globally, causing significant morbidity and mortality especially in low- and middle-income countries. Despite this immense public health burden, there are no commercially available vaccines or antiviral drugs, highlighting a critical unmet medical need. Norovirus vaccine development faces several challenges including extensive viral diversity and limited mechanistic understanding of protective immunity. While several vaccine candidates-including virus-like particle, adenovirus-vector, and mRNA-lipid nanoparticle vaccines-are in clinical trials, none have achieved complete protection in adults or demonstrated efficacy in young children. Understanding the mechanisms underlying norovirus immunity and the relative importance of mucosal responses remains crucial for vaccine optimization. Continued research addressing these basic questions, along with strategic antigen selection and platform optimization, are essential to overcome current limitations to the development of broadly protective norovirus vaccines.
{"title":"Mechanisms of Norovirus Immunity: Implications for Vaccine Design.","authors":"Arya B Ökten,Joseph E Craft,Craig B Wilen","doi":"10.1146/annurev-pathmechdis-042524-021922","DOIUrl":"https://doi.org/10.1146/annurev-pathmechdis-042524-021922","url":null,"abstract":"Human noroviruses are the predominant cause of acute gastroenteritis globally, causing significant morbidity and mortality especially in low- and middle-income countries. Despite this immense public health burden, there are no commercially available vaccines or antiviral drugs, highlighting a critical unmet medical need. Norovirus vaccine development faces several challenges including extensive viral diversity and limited mechanistic understanding of protective immunity. While several vaccine candidates-including virus-like particle, adenovirus-vector, and mRNA-lipid nanoparticle vaccines-are in clinical trials, none have achieved complete protection in adults or demonstrated efficacy in young children. Understanding the mechanisms underlying norovirus immunity and the relative importance of mucosal responses remains crucial for vaccine optimization. Continued research addressing these basic questions, along with strategic antigen selection and platform optimization, are essential to overcome current limitations to the development of broadly protective norovirus vaccines.","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":"356 1","pages":""},"PeriodicalIF":36.2,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-16DOI: 10.1146/annurev-pathmechdis-111523-023413
Laura K Hilton,Brett Collinge,David W Scott
Aggressive B-cell lymphomas are a heterogeneous group of neoplasms, organized in the current classifications into more than 20 categories on the basis of morphology, immunophenotype, clinical presentation, and limited molecular features. Over the past 25 years, there has been an exponential accumulation of detailed genomic characterizations of these lymphomas. Many defined categories have been confirmed as relatively homogeneous, fulfilling the classification ideal of sharing core biological hallmarks. However, the largest group, diffuse large B-cell lymphoma, not otherwise specified, which makes up 70-74% of the patients, has been revealed to be remarkably heterogeneous at a genomic and biological level. In this review, we summarize the current state of knowledge and then propose an evolution of the classification of aggressive B-cell lymphomas to a genomics-informed taxonomy based around normal B-cell development and the different modes by which lymphomas achieve key hallmarks of cancer-hallmarks that can inform on patient management.
{"title":"Genomic Taxonomy of Aggressive B-Cell Lymphoid Neoplasms.","authors":"Laura K Hilton,Brett Collinge,David W Scott","doi":"10.1146/annurev-pathmechdis-111523-023413","DOIUrl":"https://doi.org/10.1146/annurev-pathmechdis-111523-023413","url":null,"abstract":"Aggressive B-cell lymphomas are a heterogeneous group of neoplasms, organized in the current classifications into more than 20 categories on the basis of morphology, immunophenotype, clinical presentation, and limited molecular features. Over the past 25 years, there has been an exponential accumulation of detailed genomic characterizations of these lymphomas. Many defined categories have been confirmed as relatively homogeneous, fulfilling the classification ideal of sharing core biological hallmarks. However, the largest group, diffuse large B-cell lymphoma, not otherwise specified, which makes up 70-74% of the patients, has been revealed to be remarkably heterogeneous at a genomic and biological level. In this review, we summarize the current state of knowledge and then propose an evolution of the classification of aggressive B-cell lymphomas to a genomics-informed taxonomy based around normal B-cell development and the different modes by which lymphomas achieve key hallmarks of cancer-hallmarks that can inform on patient management.","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":"104 1","pages":""},"PeriodicalIF":36.2,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-16DOI: 10.1146/annurev-pathmechdis-042424-114052
Madison J Granoski,Aleksandra Stojic,Stephen Z Lee,David J Marchant
Respiratory syncytial virus (RSV) is one of the leading causes of infant hospitalization and mortality worldwide. RSV pathogenesis is a result of various virus-host interactions. While significant work has been done to elucidate mechanisms of RSV pathogenesis at a systemic level from the host perspective, here we examine how RSV pathogenesis occurs on a molecular level. While each RSV protein plays an essential role in establishing and advancing disease, each one also executes multifaceted strategies for evasion of host detection. In this review, we outline how each component of the RSV replication cycle works to co-opt host cell proteins and modulate host immune responses during entry, transcription, replication, translation, assembly, and egress. We examine the latest literature regarding RSV protein function and discuss outstanding questions in the field.
{"title":"Molecular Mechanisms of Respiratory Syncytial Virus Pathogenesis.","authors":"Madison J Granoski,Aleksandra Stojic,Stephen Z Lee,David J Marchant","doi":"10.1146/annurev-pathmechdis-042424-114052","DOIUrl":"https://doi.org/10.1146/annurev-pathmechdis-042424-114052","url":null,"abstract":"Respiratory syncytial virus (RSV) is one of the leading causes of infant hospitalization and mortality worldwide. RSV pathogenesis is a result of various virus-host interactions. While significant work has been done to elucidate mechanisms of RSV pathogenesis at a systemic level from the host perspective, here we examine how RSV pathogenesis occurs on a molecular level. While each RSV protein plays an essential role in establishing and advancing disease, each one also executes multifaceted strategies for evasion of host detection. In this review, we outline how each component of the RSV replication cycle works to co-opt host cell proteins and modulate host immune responses during entry, transcription, replication, translation, assembly, and egress. We examine the latest literature regarding RSV protein function and discuss outstanding questions in the field.","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":"33 1","pages":""},"PeriodicalIF":36.2,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145305334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14DOI: 10.1146/annurev-pathmechdis-042624-105942
Debra Toiber,Björn Schumacher
The maintenance of a stable genome requires constant repair. Congenital DNA repair defects lead to cancer susceptibility and progeroid (premature aging-like) syndromes. Even with intact repair, DNA lesions accumulate in aging organisms, leading to replication and transcription stress and age-dependent somatic mutations. These, in turn, can compromise cellular function and elevate cancer risk. DNA damage response (DDR) mechanisms can lead to cellular death and senescence, and targeting the DDR has emerged as therapeutic strategy not only in cancer but also to protect from age-associated phenotypes. Inhibiting DNA repair can promote cancer cell death. Eliminating senescent cells may alleviate proinflammatory consequences on their tissue environment. Moreover, strategies to limit DNA damage and augment repair in normal cells are in active development. Here, we review emerging concepts for targeting genome maintenance mechanisms to lower cancer risk and lengthen healthy lifespan by extending the integrity and functionality of somatic genomes.
{"title":"Targeting Genome Stability to Mitigate Human Aging and Disease.","authors":"Debra Toiber,Björn Schumacher","doi":"10.1146/annurev-pathmechdis-042624-105942","DOIUrl":"https://doi.org/10.1146/annurev-pathmechdis-042624-105942","url":null,"abstract":"The maintenance of a stable genome requires constant repair. Congenital DNA repair defects lead to cancer susceptibility and progeroid (premature aging-like) syndromes. Even with intact repair, DNA lesions accumulate in aging organisms, leading to replication and transcription stress and age-dependent somatic mutations. These, in turn, can compromise cellular function and elevate cancer risk. DNA damage response (DDR) mechanisms can lead to cellular death and senescence, and targeting the DDR has emerged as therapeutic strategy not only in cancer but also to protect from age-associated phenotypes. Inhibiting DNA repair can promote cancer cell death. Eliminating senescent cells may alleviate proinflammatory consequences on their tissue environment. Moreover, strategies to limit DNA damage and augment repair in normal cells are in active development. Here, we review emerging concepts for targeting genome maintenance mechanisms to lower cancer risk and lengthen healthy lifespan by extending the integrity and functionality of somatic genomes.","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":"8 1","pages":""},"PeriodicalIF":36.2,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14DOI: 10.1146/annurev-pathmechdis-111523-023434
Sarah Chiang
Uterine sarcomas are rare cancers with diverse clinical, histologic, and genomic profiles. At the genetic level, they can be classified into simple and complex genomic sarcomas, exemplified by endometrial stromal sarcoma (ESS) and uterine leiomyosarcoma (uLMS), respectively. Sequencing technologies in research and clinical settings have significantly advanced the molecular understanding of these tumors. New entities characterized by distinctive morphologies and genomic alterations have expanded the category of uterine sarcomas with simple genomes beyond ESS to include variant uLMS and fibrosarcoma-like uterine sarcoma (FUS). Molecular profiling of uLMS has also uncovered possible therapeutic targets in the most common type of uterine sarcoma, where prognostication and clinical management remain challenging. This review discusses the current histologic and molecular classification of low- and high-grade ESS, FUS, and conventional and variant uLMS and explores the potential impact of the genetic alterations observed in these uterine sarcomas on treatment.
{"title":"Molecular Pathogenesis of Uterine Sarcomas: Mechanisms and Implications for Treatment.","authors":"Sarah Chiang","doi":"10.1146/annurev-pathmechdis-111523-023434","DOIUrl":"https://doi.org/10.1146/annurev-pathmechdis-111523-023434","url":null,"abstract":"Uterine sarcomas are rare cancers with diverse clinical, histologic, and genomic profiles. At the genetic level, they can be classified into simple and complex genomic sarcomas, exemplified by endometrial stromal sarcoma (ESS) and uterine leiomyosarcoma (uLMS), respectively. Sequencing technologies in research and clinical settings have significantly advanced the molecular understanding of these tumors. New entities characterized by distinctive morphologies and genomic alterations have expanded the category of uterine sarcomas with simple genomes beyond ESS to include variant uLMS and fibrosarcoma-like uterine sarcoma (FUS). Molecular profiling of uLMS has also uncovered possible therapeutic targets in the most common type of uterine sarcoma, where prognostication and clinical management remain challenging. This review discusses the current histologic and molecular classification of low- and high-grade ESS, FUS, and conventional and variant uLMS and explores the potential impact of the genetic alterations observed in these uterine sarcomas on treatment.","PeriodicalId":50753,"journal":{"name":"Annual Review of Pathology-Mechanisms of Disease","volume":"13 1","pages":""},"PeriodicalIF":36.2,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145288204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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