Annual Review of Pathology-Mechanisms of Disease最新文献

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Zonation, Zonation, Zonation: The Real Estate of the Liver 分区，分区，分区：肝脏的房地产

IF 36.2 1区医学 Q1 PATHOLOGY

Annual Review of Pathology-Mechanisms of Disease

Pub Date : 2025-10-13 DOI: 10.1146/annurev-pathmechdis-042624-091820

Tyler M. Yasaka, Chang Kyung Kim, Vik Meadows, Satdarshan P. Monga

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.

肝脏是多种功能的中枢，包括代谢稳态、解毒和蛋白质合成。肝细胞是肝脏的主要主力，虽然看起来是同质的，但在小叶内表现出空间同一性，这反过来决定了基因和蛋白质的表达，并最终决定了功能。从门静脉三联体到中心静脉呈轴状，这种组织通常被称为代谢带。近年来，表达和功能的异质性现在被理解为远远超出肝细胞和代谢，包括非实质细胞和多种功能。虽然小叶通常被分为三个区域，但空间多组学技术揭示了一个更细致入微的画面，其中分区为折衷但功能强大的肝脏环境提供了一个坐标系统。我们总结了目前对肝脏分区的理解，因为它有助于劳动分工、损伤区室化和代谢途径的逐步安排，并讨论了这一框架对肝脏稳态、再生和疾病的影响。

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引用次数: 0

Gasdermins, Executors of Pyroptosis: A Decade in Perspective. Gasdermins，焦亡的执行者：十年的观点。

IF 36.2 1区医学 Q1 PATHOLOGY

Annual Review of Pathology-Mechanisms of Disease

Pub Date : 2025-10-09 DOI: 10.1146/annurev-pathmechdis-042624-121548

Bowen Zhou,Derek Abbott

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.

焦亡是一种分子定义的细胞死亡和裂解途径，依赖于由气凝胶蛋白家族形成的膜孔。自2015年原型gasdermin D的表征以来，尽管细胞死亡无关功能确实存在，但过去十年的大量研究已经揭示了这些细胞死亡因子在人类健康和疾病中的蛋白酶依赖性激活。许多调控机制，包括翻译后修饰、表达控制和激活系统中的重叠，已经被描述，但对gasdermins的药理学控制仍处于起步阶段。因此，除了少数选定的病例外，尚未实现疾病中气垫蛋白的特异性靶向。这篇综述从生物学机制的角度概括总结了这些发现，并强调了将这些知识从临床应用到临床的挑战。

引用次数: 0

Immunopathology of Glioblastoma 胶质母细胞瘤的免疫病理学

IF 36.2 1区医学 Q1 PATHOLOGY

Annual Review of Pathology-Mechanisms of Disease

Pub Date : 2025-10-08 DOI: 10.1146/annurev-pathmechdis-042524-025950

Jiabo Li, James L. Ross, Dolores Hambardzumyan, Daniel J. Brat

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.

胶质母细胞瘤（GBM）是最常见和恶性的原发性脑肿瘤，其特点是高度多样化和深度免疫抑制的肿瘤微环境（TME）为肿瘤进展提供了不受约束的环境，并显着复杂化了治疗干预。尽管嵌合抗原受体T细胞和免疫检查点抑制剂等免疫治疗方法取得了进展，但由于GBM TME的复杂性和强大的免疫逃避机制，其疗效仍然有限。在这篇综述中，我们阐明了TME中导致这种免疫抑制状态的细胞成分之间复杂的相互作用，包括肿瘤相关的巨噬细胞/小胶质细胞、髓源性抑制细胞、调节性T细胞和胶质瘤干细胞，以及其他导致TME复杂性的关键因素，如与中央坏死相关的严重缺氧、血脑屏障和细胞外基质。这篇综述还强调了免疫逃避的机制和最近的免疫治疗方法及其生物学原理，强调需要综合治疗策略，既针对免疫抑制因子，又增强免疫激活。

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引用次数: 0

Molecular Subtypes of Neuroendocrine Carcinoma: From Chaos to Consensus. 神经内分泌癌的分子亚型：从混乱到一致。

IF 36.2 1区医学 Q1 PATHOLOGY

Annual Review of Pathology-Mechanisms of Disease

Pub Date : 2025-10-08 DOI: 10.1146/annurev-pathmechdis-042524-023153

Zhanyu Wang,Nan Sun,Jie He,Esther Redin,Charles M Rudin

Neuroendocrine carcinomas (NECs) represent a notoriously aggressive family of lethal malignancies arising across diverse anatomical sites. Molecular subtyping based on 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.

神经内分泌癌（NECs）是一种非常具有侵略性的致命恶性肿瘤，发生在不同的解剖部位。基于关键转录因子ASCL1、NEUROD1、POU2F3和YAP1的分子分型可以显著提高对小细胞肺癌（SCLC）肿瘤异质性的认识。除SCLC外，肺外NECs也表现出类似的异质性，同样受这些转录决定因素的支配。最近的研究进一步确定了由谱系指定因子HNF4A驱动的第五种亚型。本综述旨在提出一个统一的泛nec分类框架，以便在肺、胃肠胰腺（GEP）和泌尿生殖系统中进行一致的分子分型。我们描述了ANHPY亚型（神经内分泌型、神经元型、gep样型、簇样型和上皮-间质转化表型）的独特谱系特征，并探讨了它们与定义机制、遗传改变、临床病理特征和治疗脆弱性的联系。这个统一的框架作为精确的NEC研究和管理的分子路线图。

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引用次数: 0

Role of Chromatin Looping Factors in Leukemia. 染色质环化因子在白血病中的作用。

IF 36.2 1区医学 Q1 PATHOLOGY

Annual Review of Pathology-Mechanisms of Disease

Pub Date : 2025-09-15 DOI: 10.1146/annurev-pathmechdis-051222-014420

Shira G Glushakow-Smith,Zuzana Tothova

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.

基因组组织需要在遗传物质的紧凑存储和精细调节基因调控的能力之间取得复杂的平衡。染色质环通过组织协调调节的基因群和它们的调节元件形成环来实现这种平衡，同时也压缩DNA以适应细胞核的小体积。许多dna结合和相关蛋白，包括CTCF和内聚蛋白，作为染色质环因子介导这一过程。鉴于染色质环和基因表达之间的紧密联系，无序的基因组组织与包括癌症在内的疾病发展有关。染色质环因子的复发性突变在癌症中很常见，特别是血癌，如白血病和骨髓增生异常综合征。在这篇综述中，我们描述了我们对健康和恶性造血中染色质环化过程的理解的演变，并讨论了靶向染色质环化因子在白血病中的治疗潜力。

引用次数: 0

Exploring the Complex Pathophysiology of Necrotizing Enterocolitis in Preterm Neonates. 探讨早产儿坏死性小肠结肠炎的复杂病理生理学。

IF 36.2 1区医学 Q1 PATHOLOGY

Annual Review of Pathology-Mechanisms of Disease

Pub Date : 2025-09-15 DOI: 10.1146/annurev-pathmechdis-070224-014223

Bo Li,Mina Yeganeh,Dorothy Lee,Sinobol Chusilp,Felicia Balsamo,Niloofar Ganji,Chen-Yi Wang,Andrea Zito,George Biouss,Agostino Pierro

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.

坏死性小肠结肠炎（NEC）是早产儿最常见的胃肠道急症，晚期死亡率为30-50%。尽管经过数十年的研究，其多因素病理生理机制仍未完全了解。本文综述了NEC研究的最新进展，并提出了其发病机制的综合理论框架。我们研究了关键的影响因素，包括肠血管发育、粘膜免疫、肠道再生、肠神经系统和肠道微生物群，强调了早产如何破坏这些过程并使新生儿易患NEC。此外，我们提出了一个NEC发病机制的序列模型，假设早产儿肠道微循环受损会影响血液流动，从而导致局部缺血。这会引发上皮屏障功能障碍，加剧炎症反应，损害肠道再生，破坏肠神经系统功能，共同推动NEC的进展。通过整合实验和临床研究结果，我们提供了早产儿NEC发病的全面视角，并确定了未来研究和治疗干预的潜在途径。

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引用次数: 0

Clonal Hematopoiesis in Nonmalignant Disease: Functional Consequences of Mutated Immune Cells by Clonal Hematopoiesis in the Diseased Tissue. 非恶性疾病中的克隆造血：病变组织中克隆造血导致免疫细胞突变的功能后果。

IF 36.2 1区医学 Q1 PATHOLOGY

Annual Review of Pathology-Mechanisms of Disease

Pub Date : 2025-09-10 DOI: 10.1146/annurev-pathmechdis-111523-023442

Youngil Koh,Isak W Tengesdal,Siddhartha Jaiswal

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.

克隆造血，最初被确定为血液系统恶性肿瘤的前兆，已成为各种非恶性疾病的重要因素。最近的研究强调了造血干细胞的体细胞突变如何导致循环突变免疫细胞的扩增，从而对器官功能和疾病进展产生深远影响。这些突变克隆显示出改变的炎症谱和组织特异性功能后果，导致各种疾病，包括动脉粥样硬化性心血管疾病、骨质疏松症、心力衰竭和神经退行性疾病。关键突变，特别是在调节表观遗传学（TET2, DNMT3A, ASXL1），剪接（SF3B1, U2AF1）和DNA损伤修复（TP53, PPM1D）的基因中，改变免疫反应并促进慢性炎症。有趣的是，虽然克隆造血加剧了许多炎症状况，但它与阿尔茨海默病的保护作用有关，可能是由于小胶质细胞功能增强。了解非恶性疾病中克隆造血的机制基础可以为有针对性的治疗策略提供信息，特别是那些旨在调节炎症的治疗策略。这篇综述探讨了克隆造血的基因和器官特异性作用，强调了其在疾病发病机制和潜在干预措施中的意义。

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引用次数: 0

Fibroblast Modulation of Stem Cell Lineage Infidelity and Metaplasia in Tissue Fibrosis 成纤维细胞对组织纤维化中干细胞谱系不忠和化生的调节

IF 36.2 1区医学 Q1 PATHOLOGY

Annual Review of Pathology-Mechanisms of Disease

Pub Date : 2025-08-21 DOI: 10.1146/annurev-pathmechdis-042624-111827

Tsukasa Kadota, Tien Peng

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.

上皮干细胞在体内平衡过程中根据区域特异性身份进行分离。然而，组织扰动可以诱导干细胞在其解剖室外采用谱系身份的显著可塑性。根据组织的不同，这种现象被称为谱系不忠或化生，干细胞轨迹可以决定与许多疾病相关的再生结果，包括纤维化。虽然许多研究已经阐明了控制干细胞身份转换能力的内在机制，但对提醒干细胞并改变其谱系决定的微环境因素知之甚少。成纤维细胞是一种结构细胞，为干细胞提供必要的支架，但成纤维细胞也能感知组织环境的外部变化，从而驱动组织反应。在这篇综述中，我们探讨了成纤维细胞作为谱系可塑性的关键协调者的作用，这种可塑性模糊了区室的身份，从而启动适当的修复或疾病。

引用次数: 0

Unraveling Mechanisms of Genetic Risks in Metabolic Dysfunction-Associated Steatotic Liver Diseases: A Pathway to Precision Medicine. 代谢功能障碍相关脂肪变性肝病遗传风险机制的揭示：通往精准医学的途径。

IF 34.5 1区医学 Q1 PATHOLOGY

Annual Review of Pathology-Mechanisms of Disease

Pub Date : 2025-01-01 DOI: 10.1146/annurev-pathmechdis-111523-023430

Xiang Zhang, Kyong-Mi Chang, Jun Yu, Rohit Loomba

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health problem, affecting ∼1 billion people. This condition is well established to have a heritable component with strong familial clustering. With the extraordinary breakthroughs in genetic research techniques coupled with their application to large-scale biobanks, the field of genetics in MASLD has expanded rapidly. In this review, we summarize evidence regarding genetic predisposition to MASLD drawn from family and twin studies. Significantly, we delve into detailed genetic variations associated with diverse pathogenic mechanisms driving MASLD. We highlight the interplay between these genetic variants and their connections with metabolic factors, the gut microbiome, and metabolites, which collectively influence MASLD progression. These discoveries are paving the way for precise medicine, including noninvasive diagnostics and therapies. The promising landscape of novel genetically informed drug targets such as RNA interference is explored. Many of these therapies are currently under clinical validation, raising hopes for more effective MASLD treatment.

代谢功能障碍相关的脂肪变性肝病（MASLD）是一个日益严重的全球健康问题，影响约10亿人。这种情况很好地建立了具有强家族聚集性的遗传成分。随着遗传研究技术的非凡突破及其在大规模生物库中的应用，MASLD的遗传学领域迅速扩大。在这篇综述中，我们总结了来自家庭和双胞胎研究的关于MASLD遗传易感性的证据。值得注意的是，我们深入研究了与驱动MASLD的各种致病机制相关的详细遗传变异。我们强调这些遗传变异之间的相互作用及其与代谢因子、肠道微生物组和代谢物的联系，这些因素共同影响MASLD的进展。这些发现为包括非侵入性诊断和治疗在内的精准医学铺平了道路。探索了RNA干扰等新型遗传信息药物靶点的前景。许多这些疗法目前正在临床验证中，增加了更有效治疗MASLD的希望。

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引用次数: 0

Roles of Cellular Neighborhoods in Hepatocellular Carcinoma Pathogenesis. 细胞邻域在肝癌发病机制中的作用。

IF 34.5 1区医学 Q1 PATHOLOGY

Annual Review of Pathology-Mechanisms of Disease

Pub Date : 2025-01-01 DOI: 10.1146/annurev-pathmechdis-111523-023520

Lichun Ma, Cherry Caiyi Li, Xin Wei Wang

The development of hepatocellular carcinoma (HCC) involves an intricate interplay among various cell types within the liver. Unraveling the orchestration of these cells, particularly in the context of various etiologies, may hold the key to deciphering the underlying mechanisms of this complex disease. The advancement of single-cell and spatial technologies has revolutionized our ability to determine cellular neighborhoods and understand their crucial roles in disease pathogenesis. In this review, we highlight the current research landscape on cellular neighborhoods in chronic liver disease and HCC, as well as the emerging computational approaches applicable to delineate disease-associated cellular neighborhoods, which may offer insights into the molecular mechanisms underlying HCC pathogenesis and pave the way for effective disease interventions.

肝细胞癌（HCC）的发展涉及肝脏内各种细胞类型之间复杂的相互作用。解开这些细胞的协调，特别是在各种病因的背景下，可能是破译这种复杂疾病的潜在机制的关键。单细胞和空间技术的进步彻底改变了我们确定细胞邻域的能力，并了解它们在疾病发病机制中的关键作用。在这篇综述中，我们重点介绍了目前慢性肝病和HCC中细胞邻域的研究现状，以及适用于描述疾病相关细胞邻域的新兴计算方法，这可能为HCC发病机制的分子机制提供见解，并为有效的疾病干预铺平道路。

引用次数: 0

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