Pharmacology & Therapeutics最新文献

Oxidative stress and antioxidant therapeutic mechanisms 氧化应激和抗氧化治疗机制

IF 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-11-30 DOI: 10.1016/j.pharmthera.2025.108962

Hengrui Liu , Yaqi Jiao , Peng-Chao Wang , Yingjie Chen , Maokai Xu , Xiaojuan Zhang , Xiaochun Zheng , Zhenshan Yang

Oxidative stress is now understood as a disturbance in the cellular redox balance, involving the accumulation of reactive oxygen, nitrogen, and other reactive species beyond the capacity of antioxidant defenses, with effects that range from essential redox signaling to harmful oxidative damage. Reactive oxygen and nitrogen species are generated from both endogenous metabolic processes and exogenous environmental factors. While controlled levels of oxidative stress contribute to cellular signaling and homeostasis, excessive oxidative damage can lead to pathological conditions, including cardiovascular diseases, diabetes, neurodegenerative disorders, inflammatory conditions, and cancer. To counteract oxidative damage, the body employs a complex antioxidant defense system, comprising endogenous enzymatic and non-enzymatic mechanisms, as well as exogenous dietary antioxidants. Therefore, understanding the regulatory pathways and mechanisms of antioxidants is essential for exploring their role in disease prevention, aging, and immune function. This review provides a comprehensive analysis of oxidative stress, its impact on cellular function, and its involvement in disease pathogenesis. Furthermore, it discusses current therapeutic intervention mechanisms, including dietary strategies, pharmacological antioxidants, and clinical trials evaluating antioxidant efficacy. Finally, emerging research directions, such as novel antioxidant compounds, gene therapy, and personalized antioxidant treatments, are highlighted as potential avenues for future exploration.

氧化应激现在被理解为细胞氧化还原平衡的紊乱，涉及活性氧、氮和其他活性物质的积累，超过抗氧化防御能力，其影响范围从必需的氧化还原信号到有害的氧化损伤。活性氧和活性氮是由内源性代谢过程和外源性环境因素共同产生的。虽然受控制的氧化应激水平有助于细胞信号传导和体内平衡，但过度的氧化损伤可能导致病理状况，包括心血管疾病、糖尿病、神经退行性疾病、炎症和癌症。为了对抗氧化损伤，身体采用了一个复杂的抗氧化防御系统，包括内源性酶和非酶机制，以及外源性膳食抗氧化剂。因此，了解抗氧化剂的调控途径和机制对于探索其在疾病预防、衰老和免疫功能中的作用至关重要。本文综述了氧化应激对细胞功能的影响及其在疾病发病机制中的作用。此外，它还讨论了目前的治疗干预机制，包括饮食策略，药理抗氧化剂和临床试验评估抗氧化效果。最后，强调了新型抗氧化化合物、基因治疗和个性化抗氧化治疗等新兴研究方向是未来探索的潜在途径。

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引用次数: 0

Corrigendum to “Drug discovery through biophysical techniques: Methods and applications” [pharmacology and therapeutics volume 277 (2026) 108947] “通过生物物理技术发现药物：方法和应用”的勘误表[药理学和治疗学卷277 (2026)108947]

IF 13.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-11-28 DOI: 10.1016/j.pharmthera.2025.108961

Yinhao Zhou, Haiyun Hu, Qiuyan Huang, Yuwei Tang, Yanli Liu

引用次数: 0

RNA-based drugs: current, imminent and possible therapeutic applications 基于rna的药物：当前、即将和可能的治疗应用

IF 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-11-19 DOI: 10.1016/j.pharmthera.2025.108958

Sebastiano A. Torrisi , Federica Geraci , Lidia Diolosà , Angelina De Luca , Luca Falzone , Filippo Drago , Massimo Libra , Gian Marco Leggio

In a relatively brief period, the mRNA COVID-19 vaccines have saved millions of lives and have considerably contributed to return to normality after the pandemic. More broadly, the development of RNA-based drugs represents a real paradigm shift with promising therapeutic applications. Besides their safety and efficacy, RNA-based drugs are essentially easy to design and manufactured and may therefore be cost effective. At the pharmacological level, the development of RNA-based drugs marks a breakthrough because these drugs can reach previously “undruggable” pharmacological targets. This clearly represents a step toward the possible establishment of personalized treatments for several difficult-to-treat diseases. This review provides an updated, critical, and comprehensive pharmacological analysis of the current RNA therapeutics landscape, including both approved RNA-based drugs and key investigational candidates. We summarize the state of clinical progress, highlighting pharmacological mechanisms, challenges in drug delivery, tolerability, and clinical outcomes. Our comprehensive overview emphasizes the versatility of RNA-based drugs, illustrating their therapeutic application across various diseases such as cancer, neurodegenerative, cardiovascular, metabolic, rare genetic, and infectious diseases. Also, we uniquely explore the concept of RNA-based drugs repurposing, which may leverage shared pathophysiological mechanisms across diseases to accelerate clinical impact.

在相对较短的时间内，mRNA COVID-19疫苗挽救了数百万人的生命，并为大流行后的恢复正常做出了重大贡献。更广泛地说，基于rna的药物的开发代表了一种真正的范式转变，具有良好的治疗应用前景。除了安全性和有效性之外，基于rna的药物基本上易于设计和制造，因此可能具有成本效益。在药理学层面，基于rna的药物的开发标志着一个突破，因为这些药物可以达到以前“不可药物”的药理学靶点。这显然是朝着可能建立针对几种难治性疾病的个性化治疗迈出的一步。这篇综述提供了当前RNA治疗领域的最新、关键和全面的药理学分析，包括已批准的RNA药物和关键的研究候选药物。我们总结了临床进展的状态，强调药理学机制，在给药，耐受性和临床结果的挑战。我们的综合概述强调了基于rna的药物的多功能性，说明了它们在各种疾病中的治疗应用，如癌症、神经退行性疾病、心血管疾病、代谢疾病、罕见遗传疾病和传染病。此外，我们独特地探索了基于rna的药物再利用的概念，这可能会利用疾病之间共享的病理生理机制来加速临床影响。

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引用次数: 0

Next-generation nanocarriers for therapeutic oligonucleotides: Precision targeting and stimuli-responsive cancer therapy 用于治疗寡核苷酸的下一代纳米载体：精确靶向和刺激反应性癌症治疗

IF 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-11-19 DOI: 10.1016/j.pharmthera.2025.108960

Yantong Li , Mei Zhang , Junjie Gu , Yao He , Mi Zhou , Yunfeng Lin

Therapeutic oligonucleotides (TOs) have emerged as a promising gene therapy approach for tumor treatment, offering high specificity and therapeutic efficacy by directly modulating target gene expression and subsequent protein synthesis. However, the clinical translation of TOs remains hindered by critical challenges, including suboptimal targeting efficiency, insufficient responsiveness, lysosomal entrapment, poor stability, and potential off-target effects. To address these limitations, advanced delivery systems with precise targeting and stimuli-responsive capabilities are essential. Nanocarrier systems, characterized by their high targeting precision and controlled drug release, have gained widespread application in tumor gene therapy. Integrating TOs with intelligent nanocarrier systems enables safe, stable, efficient, and targeted delivery to tumor tissues, presenting a highly promising strategy for precise cancer gene therapy. This review provides a comprehensive overview of current advancements in the design of intelligent nanoparticles for TOs delivery. It discusses the classification of TOs and their therapeutic mechanisms, the categorization of nanocarriers, the binding modes between TOs and nanomaterials, and strategies to achieve tumor-specific targeting and responsiveness. By addressing these critical design considerations, this review aims to inform the development of next-generation nanomaterials for improved TOs-based tumor therapy.

治疗性寡核苷酸（TOs）已成为一种很有前景的肿瘤基因治疗方法，通过直接调节靶基因表达和随后的蛋白质合成，具有高特异性和治疗效果。然而，TOs的临床翻译仍然受到一些关键挑战的阻碍，包括靶向效率不理想、反应性不足、溶酶体包裹、稳定性差和潜在的脱靶效应。为了解决这些限制，具有精确瞄准和刺激响应能力的先进交付系统是必不可少的。纳米载体系统具有靶向精度高、药物释放可控等特点，在肿瘤基因治疗中得到了广泛的应用。将TOs与智能纳米载体系统相结合，可以安全、稳定、高效、靶向地递送到肿瘤组织，为精确的癌症基因治疗提供了一种非常有前途的策略。本文综述了目前用于TOs递送的智能纳米颗粒的设计进展。本文讨论了肿瘤受体的分类及其治疗机制、纳米载体的分类、肿瘤受体与纳米材料的结合模式以及实现肿瘤特异性靶向和反应性的策略。通过解决这些关键的设计考虑，本综述旨在为下一代纳米材料的开发提供信息，以改善基于tos的肿瘤治疗。

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引用次数: 0

Cell phenotypic conversion and fate change during the host defense response, tissue injury and repair 在宿主防御反应、组织损伤和修复过程中，细胞表型转换和命运改变

IF 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-11-18 DOI: 10.1016/j.pharmthera.2025.108959

Xin Shi , Gabriel Mekis , Kevin J. Simms , Bin Gao , Ping Zhang

In the process of host response to insults of serious injury/intense stressor, many types of somatic cells can undergo phenotypic conversion and fate change. The typical feature of cell conversion in this circumstance is to acquire the status of upstream precursors, which commonly accompanies transcriptional alteration to enhance cell proliferation and increase the plasticity of differentiation toward the lineage(s) needed in urgency for defending host against injury as well as maintaining/restoring the integrity of organ tissue function. The extent of cell conversion varies dependent on cell types and insult properties. Pattern ligands derived from pathogens and damaged tissues as well as the dynamic changes in systemic neurohumoral environment and local niche cue mediate cell conversion. Distinctive signaling interplays are involved in regulating various types of cell conversion. Better understanding the phenomena of cell conversion and their underlying regulatory mechanisms is critical for advancing regenerative medicine and developing novel therapeutic strategies to promote host defense as well as optimal repair of organ tissue injury. This article reviews recent progress in investigation on cell conversion and state change in different organ tissue environments with focus on bone marrow, vascular endothelium, lung, liver, and intestine. Discussion on delineating the signaling mechanisms is extended. Efforts in exploring the correlated therapeutic approaches are addressed to highlight the substantial potential in clinical application for this field of regenerative medicine.

在宿主对严重损伤/强应激源的反应过程中，多种类型的体细胞可发生表型转换和命运改变。在这种情况下，细胞转化的典型特征是获得上游前体的地位，这通常伴随着转录改变，以增强细胞增殖并增加向谱系分化的可塑性，这是保护宿主免受损伤以及维持/恢复器官组织功能完整性所迫切需要的。细胞转化的程度取决于细胞类型和侮辱性质。来自病原体和受损组织的模式配体以及系统神经体液环境和局部生态位的动态变化介导细胞转化。不同的信号相互作用参与调节各种类型的细胞转化。更好地理解细胞转化现象及其潜在的调节机制对于推进再生医学和开发新的治疗策略来促进宿主防御和器官组织损伤的最佳修复至关重要。本文综述了近年来在骨髓、血管内皮、肺、肝和肠等不同器官组织环境中细胞转化和状态变化的研究进展。进一步讨论了信号机制的描述。努力探索相关的治疗方法，以突出这一再生医学领域临床应用的巨大潜力。

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引用次数: 0

Treatment approaches for alcohol use disorder with metabolic dysfunction 酒精使用障碍伴代谢功能障碍的治疗方法

IF 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-11-12 DOI: 10.1016/j.pharmthera.2025.108957

Alexandra C. Wagner , Jeesun Jung , Pal Pacher , Falk.W. Lohoff

Alcohol use disorder (AUD) and alcohol excess contribute significantly to morbidity and mortality through their multisystem effects, particularly on liver health. When combined with metabolic dysfunction––defined as obesity, hypertension, type 2 diabetes, and dyslipidemia––alcohol consumption has additive and synergistic effects that are associated with liver disease progression and increased risk of cardiovascular, cancer-related, hepatic, and all-cause mortality. Despite growing recognition of these overlapping risk factors, there remains no universally accepted threshold for “safe” alcohol consumption, as individual vulnerability varies widely depending on genetic, metabolic, and environmental factors.

Individuals with co-occurring AUD and metabolic dysfunction face unique clinical challenges, yet current treatment frameworks rarely address this intersection. Existing pharmacologic and behavioral therapies for AUD are limited in efficacy and uptake, and they are often not tailored to the metabolic risks that accompany heavy drinking. This comorbid population represents an underrecognized group with clinical complexity and unmet therapeutic needs.

In this review, we synthesize current knowledge across hepatology, psychiatry, and addiction medicine to characterize the shared pathophysiology and comorbidities of co-occurring AUD and metabolic dysfunction. We examine mortality trends, highlight gaps in current treatment paradigms, and evaluate how emerging research and treatments for MASLD, MetALD, and ALD can inform more effective clinical care strategies. Our aim is to establish a more unified framework for understanding and treating individuals with co-occurring AUD and metabolic dysfunction.

酒精使用障碍（AUD）和酒精过量通过其多系统效应，特别是对肝脏健康的影响，对发病率和死亡率有显著影响。当与代谢功能障碍（定义为肥胖、高血压、2型糖尿病和血脂异常）合并时，饮酒具有累加性和协同效应，与肝脏疾病进展和心血管疾病、癌症相关疾病、肝脏疾病和全因死亡风险增加有关。尽管越来越多的人认识到这些重叠的风险因素，但仍然没有普遍接受的“安全”饮酒阈值，因为个体的脆弱性取决于遗传、代谢和环境因素。同时发生AUD和代谢功能障碍的个体面临着独特的临床挑战，但目前的治疗框架很少解决这一交叉点。现有的AUD的药理学和行为疗法在疗效和吸收方面是有限的，而且它们往往不能针对伴随大量饮酒的代谢风险。这一合并症人群代表了一个未被充分认识的群体，具有临床复杂性和未满足的治疗需求。在这篇综述中，我们综合了目前在肝病学、精神病学和成瘾医学方面的知识，以表征共同发生的AUD和代谢功能障碍的共同病理生理和合并症。我们研究了死亡率趋势，强调了当前治疗范例中的差距，并评估了MASLD、MetALD和ALD的新兴研究和治疗方法如何为更有效的临床护理策略提供信息。我们的目标是建立一个更统一的框架来理解和治疗同时发生AUD和代谢功能障碍的个体。

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引用次数: 0

RNA renaissance: Harnessing non-coding RNA therapeutics for hepatocellular carcinoma RNA复兴：利用非编码RNA治疗肝癌

IF 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-11-12 DOI: 10.1016/j.pharmthera.2025.108956

Subhas Das , Soumyabrata Chatterjee , Tushar Patel , Soma Banerjee

Non-coding RNAs (ncRNAs) represent a diverse group of RNAs that exhibit an important role in various cellular mechanisms by regulating gene expression at both transcription and translation levels without being translated into proteins. Despite their canonical cellular functions, dysregulation of ncRNAs especially microRNAs (miRNAs), circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) have been widely documented in various diseases including cancer. Owing to their potential to regulate multiple genes and signaling pathways simultaneously, targeting individual ncRNA provides a multi-faceted therapeutic approach. Moreover, the liver's inherent ability for rapid uptake of systemically administered such ncRNAs-based therapy renders it as a suitable target for developing effective therapeutics for liver cancer. Here, we have conducted a meta-analysis of the published literature on miRNAs deregulated in HCC to uncover multifunctional miRNAs driving various oncogenic pathways corroborated by experimental validations as well. However, for therapeutic purposes, lncRNAs that sequester several such miRNAs have been also identified in HCC, highlighting them as promising targets for ncRNA-based therapy in HCC. Regardless of promising preclinical studies, very few ncRNA-based therapeutics have entered clinical trials. Therefore, recognizing these limitations, we have discussed the challenges impeding the development of ncRNA-based treatments along with some probable solutions.

非编码rna （Non-coding RNAs, ncRNAs）是一组不同的rna，它们通过在转录和翻译水平上调节基因表达而不被翻译成蛋白质，在各种细胞机制中发挥重要作用。尽管它们具有典型的细胞功能，但ncRNAs尤其是microRNAs （miRNAs）、环状rna （circRNAs）和长链非编码rna （lncRNAs）的失调在包括癌症在内的各种疾病中已被广泛记录。由于它们同时调节多个基因和信号通路的潜力，靶向单个ncRNA提供了一种多方面的治疗方法。此外，肝脏具有快速吸收系统给予的基于ncrnas的治疗的固有能力，使其成为开发有效肝癌治疗方法的合适靶点。在此，我们对已发表的关于HCC中mirna失调的文献进行了荟萃分析，以揭示驱动各种致癌途径的多功能mirna，并得到实验验证。然而，出于治疗目的，在HCC中也发现了分离几种此类mirna的lncrna，这表明它们是HCC中基于ncrna治疗的有希望的靶点。尽管有前景的临床前研究，但很少有基于ncrna的治疗方法进入临床试验。因此，认识到这些局限性，我们讨论了阻碍基于ncrna的治疗发展的挑战以及一些可能的解决方案。

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引用次数: 0

Drug discovery through biophysical techniques: Methods and applications 通过生物物理技术发现药物：方法和应用

IF 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-11-06 DOI: 10.1016/j.pharmthera.2025.108947

Yinhao Zhou, Haiyun Hu, Qiuyan Huang, Yuwei Tang, Yanli Liu

The rapid advancements in drug discovery have underscored the critical demand for sophisticated analytical methodologies capable of delivering comprehensive insights into molecular interactions, thereby accelerating the development of innovative therapeutic agents. As modern drug discovery increasingly depends on precise characterization of molecular dynamics and protein behavior, biophysical techniques have emerged as indispensable tools in pharmaceutical development. These techniques provide robust platforms for investigating protein–ligand interactions, elucidating structural basis, and deciphering cellular mechanisms—all essential components of rational drug design. In this review, we systematically summarize pivotal biophysical technologies shaping contemporary drug discovery, including Förster resonance energy transfer (FRET), fluorescence polarization (FP), thermal shift assays (TSA/CETSA), surface plasmon resonance (SPR), bio-layer interferometry (BLI), microscale thermophoresis (MST), isothermal titration calorimetry (ITC), nuclear magnetic resonance (NMR), X-ray crystallography, and advanced mass spectrometry (MS)-based approaches such as hydrogen–deuterium exchange mass spectrometry (HDX-MS) and crosslinking mass spectrometry (XL-MS). For each technique, we trace its historical development, outline fundamental principles, and highlight key innovations that have cemented its role in drug research. We also objectively evaluate the strengths and limitations of each method and discuss emerging trends, including improvements in sensitivity, automation, and high-throughput implementation. These developments promise to maintain their pivotal role in advancing biomedical research and therapeutic innovation, particularly in addressing the growing complexity of drug targets and the urgent need for precision medicine solutions.

药物发现的快速发展强调了对复杂的分析方法的关键需求，这些分析方法能够提供对分子相互作用的全面见解，从而加速创新治疗剂的开发。由于现代药物发现越来越依赖于分子动力学和蛋白质行为的精确表征，生物物理技术已成为药物开发中不可或缺的工具。这些技术为研究蛋白质-配体相互作用、阐明结构基础和破译细胞机制提供了强大的平台，这些都是合理药物设计的重要组成部分。在这篇综述中，我们系统地总结了影响当代药物发现的关键生物物理技术，包括Förster共振能量转移（FRET）、荧光极化（FP）、热移测定（TSA/CETSA）、表面等离子体共振（SPR）、生物层干涉（BLI）、微尺度热电泳（MST）、等温滴定量热法（ITC）、核磁共振（NMR）、x射线晶体学、以及基于先进质谱（MS）的方法，如氢-氘交换质谱（HDX-MS）和交联质谱（XL-MS）。对于每一种技术，我们追溯其历史发展，概述基本原理，并强调了巩固其在药物研究中的作用的关键创新。我们还客观地评估了每种方法的优势和局限性，并讨论了新兴趋势，包括灵敏度、自动化和高通量实现的改进。这些发展有望在推进生物医学研究和治疗创新方面保持其关键作用，特别是在解决药物靶点日益复杂和对精准医疗解决方案的迫切需求方面。

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引用次数: 0

A map of molecular drug targets and therapeutics for the US FDA-approved drugs: The impact of expedited regulatory pathways and first-in-class drug approvals on drug innovation 美国fda批准药物的分子药物靶点和治疗方法图：加速监管途径和首类药物批准对药物创新的影响

IF 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-11-02 DOI: 10.1016/j.pharmthera.2025.108945

Pitchai Balakumar , N.V.L. Sirisha Mulukuri , Gowraganahalli Jagadeesh

Despite advances in pharmaceutical innovation, there is a lack of insights into recent FDA drug approval trends, particularly concerning molecular targets, therapeutic areas, and diseases. Here, we map the molecular targets of 465 drugs approved by the US FDA from 2015 to 2024: 29% were biologics, 71% were NMEs, 50% targeted orphan diseases, and 41% were first-in-class drugs with novel mechanisms. Five major protein classes predominate as drug targets: enzymes (17%), kinases (16%), GPCRs (12%), transporter proteins (4%), and nuclear receptors (3.7%), highlighting a focus on chronic and life-threatening diseases, especially orphan disease indications. We compare regular and expedited review pathways across different therapeutic areas and observe that FDA expedited review programs have significantly increased access (67%) to new therapeutics, notably in oncology, where 80% to 100% of drugs utilize at least one expedited pathway. More than 70% of expedited approvals involved multiple pathways. Priority review emerged as the most common approval type, while accelerated approval was the least frequent. These findings illustrate ongoing trends in first-in-class drugs, the factors that drive drug innovation, and expedited approval processes. They also emphasize the importance of regulatory mechanisms in expediting the delivery of new treatments to patients. In our study, we examine the trends in drug approvals for non-communicable diseases, including cardiovascular diseases (8.6%), cancer (29%), respiratory illnesses (4.3%), and diabetes (3%), along with their pharmacological properties.

尽管制药创新取得了进步，但缺乏对FDA药物批准趋势的了解，特别是在分子靶点、治疗领域和疾病方面。在这里，我们绘制了2015年至2024年美国FDA批准的465种药物的分子靶点图：29%为生物制剂，71%为NMEs， 50%为靶向孤儿病，41%为具有新机制的同类首药。五大蛋白类主要作为药物靶点：酶（17%）、激酶（16%）、gpcr（12%）、转运蛋白（4%）和核受体（3.7%），重点关注慢性和危及生命的疾病，特别是孤儿病适应症。我们比较了不同治疗领域的常规和加速审查途径，观察到FDA加速审查计划显著增加了新疗法的可及性（67%），特别是在肿瘤学领域，其中80%至100%的药物使用至少一种加速途径。超过70%的快速审批涉及多种途径。优先审查是最常见的批准类型，而加速批准是最不常见的。这些发现说明了首类药物的持续趋势、推动药物创新的因素以及加快审批程序。他们还强调了监管机制在加快向患者提供新疗法方面的重要性。在我们的研究中，我们研究了非传染性疾病的药物批准趋势，包括心血管疾病（8.6%）、癌症（29%）、呼吸系统疾病（4.3%）和糖尿病（3%），以及它们的药理学特性。

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引用次数: 0

Molecular, metabolic, and histological subtypes of pancreatic ductal adenocarcinoma and its tumor microenvironment: Insights into tumor heterogeneity and clinical implications 胰腺导管腺癌的分子、代谢和组织学亚型及其肿瘤微环境：对肿瘤异质性和临床意义的见解

IF 12.5 1区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacology & Therapeutics

Pub Date : 2025-11-01 DOI: 10.1016/j.pharmthera.2025.108946

Yuuki Ohara , Huaitian Liu , Paloma Moreno , Seiya Suzuki , S. Perwez Hussain

Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous cancer with poor prognosis and limited therapeutic options. Bulk transcriptomic profiling has identified two major gene expression–based molecular subtypes: classical/progenitor and basal-like/squamous/quasimesenchymal. These subtypes differ in biological characteristics, differentiation status, drug sensitivity, and clinical outcomes. Advances in single-cell and spatial transcriptomics have further revealed intermediate/hybrid states, as well as distinct subtypes within the tumor microenvironment. These technologies have also uncovered intratumoral heterogeneity, tumor–stroma interactions, and spatially organized transcriptional programs that further shape subtype identity and plasticity, which can shift over time or under therapeutic pressure. In parallel, metabolomic analyses have revealed distinct metabolic subtypes that align with molecular subtypes and highlight subtype-specific metabolic rewiring and vulnerabilities. Furthermore, recent deep learning approaches applied to histopathology allow for high-resolution, morphology-based subtype prediction using Hematoxylin & Eosin-stained slides, providing practical and potentially scalable diagnostic tools. These multi-layered insights are reshaping PDAC taxonomy and enhancing our understanding of how transcriptional, metabolic, and spatial features together define tumor behavior and therapeutic response. This review discusses molecular (transcriptomic), metabolic, and histological subtyping approaches for PDAC, with the aim of enabling practical, cost-effective diagnosis and personalized medicine. By integrating data from recent experimental and clinical studies, we aim to provide a comprehensive and accessible overview of PDAC subtype heterogeneity, which may help guide future subtype-informed therapeutic strategies.

胰腺导管腺癌（PDAC）是一种高度异质性的癌症，预后差，治疗选择有限。大量转录组学分析已经确定了两种主要的基于基因表达的分子亚型：经典/祖细胞亚型和基底样/鳞状/准间质亚型。这些亚型在生物学特征、分化状态、药物敏感性和临床结果方面存在差异。单细胞和空间转录组学的进展进一步揭示了肿瘤微环境中的中间/杂交状态以及不同的亚型。这些技术还揭示了肿瘤内异质性、肿瘤-基质相互作用和空间组织的转录程序，这些程序进一步塑造了亚型的身份和可塑性，这些身份和可塑性可以随着时间或治疗压力而改变。与此同时，代谢组学分析揭示了与分子亚型一致的不同代谢亚型，并突出了亚型特异性代谢重连接和脆弱性。此外，最近应用于组织病理学的深度学习方法允许使用苏木精和伊红染色的载玻片进行高分辨率，基于形态的亚型预测，提供实用且具有潜在可扩展性的诊断工具。这些多层次的见解正在重塑PDAC分类，并增强我们对转录、代谢和空间特征如何共同定义肿瘤行为和治疗反应的理解。这篇综述讨论了PDAC的分子（转录组学）、代谢和组织学亚型方法，目的是实现实用、成本效益高的诊断和个性化医疗。通过整合最近的实验和临床研究数据，我们的目标是提供PDAC亚型异质性的全面和可访问的概述，这可能有助于指导未来的亚型知情治疗策略。

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引用次数: 0