The degradation and recycling of damaged proteins and organelles through autophagy is a vital process to maintain terminally differentiated cells under energy-demanding physiological conditions and mechanical stress. Clinical and molecular studies of numerous congenital disorders of striated muscle and inherited neuropathies have reported severe autophagy defects as an underlying pathological mechanism. In this review, we investigate the genetic mutations underlying lower motor neuron diseases, skeletal muscle dystrophies, and (cardio)myopathies and how these mutations disrupt autophagy pathways. Through an in-depth analysis of the defective step of the autophagy pathway, we propose pharmacological targets that are able to correct the autophagy defects, thereby improving disease pathology. Finally, we discuss the current limitations in the development of autophagy-modulating drugs and propose novel technologies to support this growing field. By outlining key mechanisms and targets, this review supports the development of more effective autophagy modulators for rare diseases.
Microglia-the parenchymal tissue-resident macrophages of the brain and spinal cord-are essential to support brain health by integrating environmental cues and performing immune functions and reparative processes. Yet across neurodegenerative diseases, these long-lived cells become increasingly unable to meet the demands of their homeostatic roles. In this review, we trace the arc of microglial function from competence to dysfunction, examining how their roles, for example, in synaptic pruning, phagocytosis, and interferon signaling, can shift from protective to pathogenic. Using Alzheimer's disease, inherited microgliopathies, and Aicardi-Goutières syndrome as case studies, we highlight the ways in which microglia fail-through metabolic exhaustion, lysosomal overload, inflammatory gain of function, or failure to respond. We consider how genetic and environmental factors converge to drive this "microglial incompetence," and discuss emerging strategies to reset or replace dysfunctional microglia. Understanding when and how microglia go awry may unlock new paths for treating a wide spectrum of neurodegenerative diseases.
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.
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.
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.
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.
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.
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, is essential to overcome current limitations to the development of broadly protective norovirus vaccines.
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.
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 built around normal B-cell development and the different modes by which lymphomas achieve key hallmarks of cancer-hallmarks that can inform on patient management.
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.
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.
The liver serves as a central hub for a diverse set of functions including metabolic homeostasis, detoxification, and protein synthesis. While appearing homogeneous, hepatocytes, the major workhorse in the liver, demonstrate spatial identity within the lobule, which in turn dictates gene and protein expression and, eventually, function. Presenting as an axis from the portal triad to the central vein, this organization has been conventionally referred to as metabolic zonation. In recent years, the heterogeneity in expression and function is now understood to extend well beyond hepatocytes and metabolism to include nonparenchymal cells and diverse functions. Although the lobule is conventionally divided into three zones, spatial multi-omics technologies reveal a more nuanced picture, where zonation provides a coordinate system for an eclectic but highly functional hepatic milieu. We summarize the current understanding of liver zonation as it contributes to division of labor, injury compartmentalization, and stepwise arrangement of metabolic pathways and discuss the implications of this framework for liver homeostasis, regeneration, and disease.
Pyroptosis is a molecularly defined pathway of cell death and lysis relying on formation of membrane pores by the family of gasdermin proteins. Since the characterization of prototypical gasdermin D in 2015, intense effort in the past decade has shed light on protease-dependent activation of these agents of cellular demise in human health and disease, although cell death-independent functions do exist. Numerous regulatory mechanisms ranging from posttranslational modification, control of expression, and overlap in activation systems have been described, but pharmacologic control of gasdermins is still in its infancy. Thus, gasdermin-specific targeting in disease has not yet been achieved outside of a few select cases. This review summarizes these findings broadly from a perspective of biological mechanisms and highlights the forthcoming challenges hindering bench-to-bedside adoption of this knowledge.
Glioblastoma (GBM), the most frequent and malignant primary brain tumor, is characterized by a highly diverse and profoundly immunosuppressive tumor microenvironment (TME) that provides an unconstrained environment for tumor progression and significantly complicates therapeutic interventions. Despite advances in immunotherapeutic approaches, such as chimeric antigen receptor T cell and immune checkpoint inhibitors, efficacy remains limited due to the complexity of the GBM TME and robust immune evasion mechanisms. In this review, we elucidate the intricate interplay among cellular components within the TME that lead to this immunosuppressive state, including tumor-associated macrophages/microglia, myeloid-derived suppressor cells, regulatory T cells, and glioma stem cells, as well as other critical elements that contribute to TME complexity, such as the severe hypoxia associated with central necrosis, the blood-brain barrier, and the extracellular matrix. This review also highlights mechanisms of immune evasion and recent immunotherapeutic approaches along with their biologic rationale, underscoring the need for integrated therapeutic strategies that both target immunosuppressive elements and enhance immune activation.
Neuroendocrine carcinomas (NECs) represent a notoriously aggressive family of lethal malignancies arising across diverse anatomical sites. Molecular subtyping based on the key transcription factors ASCL1, NEUROD1, POU2F3, and YAP1 has significantly advanced understanding of tumor heterogeneity in small cell lung cancer (SCLC). Beyond SCLC, extrapulmonary NECs demonstrate analogous heterogeneity, similarly governed by these transcriptional determinants. Recent studies have further identified a fifth subtype driven by the lineage-specifying factor HNF4A. This review aims to propose a unified pan-NEC classification framework for consistent molecular subtyping across pulmonary, gastro-entero-pancreatic (GEP), and genitourinary systems. We delineate the distinct lineage hallmarks of the ANHPY subtypes (neuroendocrine, neuronal, GEP-like, tuft-like, and epithelial-mesenchymal transition phenotypes) and explore their connections to defining mechanisms, genetic alterations, clinicopathological features, and therapeutic vulnerabilities. This unified framework serves as a molecular roadmap for precise NEC research and management.
Genomic organization requires an intricate balance between the compact storage of genetic material and the ability to finely tune gene regulation. Chromatin looping achieves this balance by organizing concordantly regulated groups of genes and their regulatory elements into loops while also condensing DNA to fit into the small volume of a nucleus. A number of DNA-binding and associated proteins, including CTCF and cohesin, act as chromatin looping factors that mediate this process. Given the tight association between chromatin looping and gene expression, disordered genomic organization has been linked to disease development, including cancer. Recurrent mutations in chromatin looping factors are common in cancer, in particular blood cancers such as leukemia and myelodysplastic syndromes. In this review, we describe the evolution of our understanding of the chromatin looping process in healthy and malignant hematopoiesis and discuss the therapeutic potential of targeting chromatin looping factors in leukemia.
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in preterm neonates, with a mortality rate of 30-50% in advanced cases. Despite decades of research, its multifactorial pathophysiology remains incompletely understood. This review summarizes recent advances in NEC research and proposes an integrative theoretical framework for its pathogenesis. We examine key contributing factors, including intestinal vascular development, mucosal immunity, intestinal regeneration, the enteric nervous system, and the gut microbiome, highlighting how prematurity disrupts these processes and predisposes neonates to NEC. Furthermore, we propose a sequential model of NEC pathogenesis, hypothesizing that impaired intestinal microcirculation in preterm neonates compromises blood flow in response to enteral feeding, leading to localized ischemia. This initiates epithelial barrier dysfunction, exacerbates inflammatory responses, impairs intestinal regeneration, and disrupts enteric nervous system function, collectively driving NEC progression. By integrating experimental and clinical findings, we provide a comprehensive perspective on NEC initiation in preterm neonates and identify potential avenues for future research and therapeutic interventions.
Clonal hematopoiesis, originally identified as a precursor to hematologic malignancies, has emerged as a significant factor in various nonmalignant diseases. Recent research highlights how somatic mutations in hematopoietic stem cells lead to the expansion of circulating mutated immune cells that exert profound effects on organ function and disease progression. These mutated clones display altered inflammatory profiles and tissue-specific functional consequences, contributing to various diseases including atherosclerotic cardiovascular disease, osteoporosis, heart failure, and neurodegenerative conditions. Key mutations, particularly in genes regulating epigenetics ( TET2 , DNMT3A , ASXL1 ), splicing ( SF3B1 , U2AF1 ), and DNA damage repair ( TP53 , PPM1D ), modify immune responses and promote chronic inflammation. Intriguingly, while clonal hematopoiesis exacerbates many inflammatory conditions, it has been linked to a protective effect in Alzheimer's disease, potentially due to enhanced microglial function. Understanding the mechanistic underpinnings of clonal hematopoiesis in nonmalignant disease may inform targeted therapeutic strategies, particularly those aimed at modulating inflammation. This review explores the gene- and organ-specific roles of clonal hematopoiesis, highlighting its implications for disease pathogenesis and potential interventions.
Epithelial stem cells are segregated on the basis of region-specific identities during homeostasis. However, tissue perturbations can induce remarkable plasticity in stem cells to adopt lineage identities outside their anatomical compartments. This phenomenon has been termed lineage infidelity or metaplasia depending on the tissue, and the stem cell trajectory can determine regenerative outcomes relevant to many diseases, including fibrosis. While many studies have shed light on stem-cell intrinsic mechanisms that govern their ability to switch identities, much less is known about microenvironmental factors that alert stem cells and modify their lineage decisions. Fibroblasts are structural cells that provide the necessary scaffolding for stem cells in their native niche, but fibroblasts also sense external changes to the tissue environment to drive the tissue response. In this review, we explore the role of fibroblasts as a critical orchestrator of lineage plasticity that blurs compartmental identities to initiate proper repair or disease.
