Pharmacology & Therapeutics最新文献

{"title":"Current and future therapeutics targeting mast cells in disease","authors":"William P.M. Worrall,&nbsp;Laurent L. Reber","doi":"10.1016/j.pharmthera.2025.108892","DOIUrl":"10.1016/j.pharmthera.2025.108892","url":null,"abstract":"<div><div>Mast cells (MCs) are tissue resident immune cells which are best known for their detrimental role in allergy. Increasing evidence indicates that MCs are also central to the pathogenesis of chronic urticaria. Abnormal increase in MC burden, in most cases driven by gain-of-function mutations in the receptor KIT, can also lead to mastocytosis, a potentially severe malignant disease. Thus, MCs represent important therapeutic targets in all these diseases, and likely in a number of additional inflammatory conditions. In recent years, several monoclonal antibodies (mAbs) and small molecule inhibitors have been developed to directly target MCs or their mediators. Some of these therapeutics, including antagonists of the receptor MRGPRX2, tyrosine kinase inhibitors, anti-Siglec-6 and anti-KIT mAbs are now undergoing clinical evaluation. In this review, we describe the main mechanisms leading to MC activation, and their known functions in allergic diseases, chronic urticaria and mastocytosis. We then discuss recent preclinical and clinical data obtained with novel biologics aimed at targeting MCs in these diseases.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"273 ","pages":"Article 108892"},"PeriodicalIF":12.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144197931","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}

{"title":"Targeting myeloid cell immunometabolism to improve current non-small cell lung cancer therapies","authors":"Marah C. Runtsch ,&nbsp;Stefano Angiari ,&nbsp;Julia Kargl","doi":"10.1016/j.pharmthera.2025.108893","DOIUrl":"10.1016/j.pharmthera.2025.108893","url":null,"abstract":"<div><div>Although recent advancements in immunotherapy have improved clinical outcomes, non-small cell lung cancer (NSCLC) is still the deadliest cancer type, as current treatments fail in many patients. This highlights a need for continued studies on this complex and multifaceted malignancy. The lung tumor microenvironment (TME) is marked by an infiltration of innate immune cells of the myeloid lineage, including macrophages and neutrophils, which affect patient outcomes. These cells induce inflammation and functional responses that can both promote and inhibit tumor growth and progression, with these functions being directly linked to their intracellular metabolism. The lung TME provides a milieu of signals, including cytokines and metabolites, that induce metabolic reprogramming in tumor-associated myeloid cells. Here, we review the present understanding of tumor-associated myeloid cell metabolism specifically in the context of NSCLC. Recent studies demonstrated that some metabolic pathways have the potential to be manipulated pharmacologically to eliminate or reprogram pathogenic, pro-tumor, and/or immunosuppressive myeloid cells to anti-tumor states for NSCLC therapies. Therefore, we highlight and propose potential metabolic targets in these myeloid cells, focusing on macrophages and neutrophils. These cells have direct roles in affecting subsequent responses of adaptive cells and their cellular metabolism must be further investigated to identify potential pharmacologic therapeutic targets. Targeting myeloid cell metabolism in the TME may be used in combination with the current regimen of immune checkpoint inhibition (ICI) and chemotherapy to improve outcomes for lung cancer patients.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"273 ","pages":"Article 108893"},"PeriodicalIF":12.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245526","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}

{"title":"Recent advances in therapeutic targeting of the KRAS pathway in cancer","authors":"Nadia Hitchen ,&nbsp;Sarah Williams ,&nbsp;Jayesh Desai","doi":"10.1016/j.pharmthera.2025.108889","DOIUrl":"10.1016/j.pharmthera.2025.108889","url":null,"abstract":"<div><div>Recent advances in cancer therapy have significantly progressed through targeted inhibition of the rat sarcoma virus (RAS) signalling pathway, particularly focusing on Kirsten rat sarcoma virus (KRAS) mutations prevalent in cancers such as non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). Historically deemed “undruggable,” KRAS mutations, especially KRASG12C and KRASG12D, are now effectively targeted by specific inhibitors that have demonstrated promising clinical results. Agents such as Sotorasib, Adagrasib, and Divarasib exhibit notable efficacy against KRASG12C mutations, particularly in NSCLC, with combination strategies significantly improving outcomes, especially in CRC. With over 50 agents currently in development, targeting KRAS has become a rapidly expanding area of cancer therapeutics. However, substantial challenges remain, including optimizing clinical trial designs, particularly in early-phase trials, and integrating pharmacodynamic tools to refine dosing and treatment schedules, thus achieving an optimal balance between efficacy and patient tolerability. This review summarizes recent therapeutic advancements, highlighting the clinical development of KRAS-specific inhibitors, and emphasizes future strategies involving a combination of mutant-specific and broader mutant-independent approaches to overcome resistance, thereby offering promise for more durable cancer control and expanded patient eligibility.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"273 ","pages":"Article 108889"},"PeriodicalIF":12.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186160","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}

{"title":"Unveiling the silent threat: COVID-19 and myocardial injury","authors":"Ke Xu ,&nbsp;Wu He ,&nbsp;Bo Yu,&nbsp;James Jiqi Wang,&nbsp;Junfang Wu,&nbsp;Dao Wen Wang","doi":"10.1016/j.pharmthera.2025.108904","DOIUrl":"10.1016/j.pharmthera.2025.108904","url":null,"abstract":"<div><div>Since COVID-19 firstly appeared in 2019 December, it has been defined as an infectious disease mainly performing lung symptoms, which contracted more attention. However, more and more findings indicate myocardial injury appears in considerable proportion of COVID-19 patients (30 % – 50 %) not only but also major cause leading to the death in patients, many of whom may be even without severe respiratory symptoms. Meanwhile myocarditis after injecting vaccines has been paid more attention to globally which always performs uncontrollable inflammation and lead to death. Now myocardial injury has been a main complication in patients with long COVID-19, which is worthy of attention. Furthermore, myocardial injury or myocarditis is detectable and treatable. In order to abstract attention to myocardial injury associated with COVID-19 and provide more evidence and experience for patients who still suffer myocardial injury from COVID-19 vaccines or long COVID-19, the review comprehensively summarized previous researches from pathogenesis, clinical symptoms, diagnosis and treatment and emphasized the crucial role of RASS inhibitors especially ARBs.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"273 ","pages":"Article 108904"},"PeriodicalIF":12.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525844","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}

{"title":"N-methyl-D-aspartate receptors (NMDARs): a glutamate-activated cation channel with biased signaling and therapeutic potential in brain disorders","authors":"Xuan Zhang ,&nbsp;Wensheng Cai ,&nbsp;Chao Wang ,&nbsp;Jing Tian","doi":"10.1016/j.pharmthera.2025.108888","DOIUrl":"10.1016/j.pharmthera.2025.108888","url":null,"abstract":"<div><div>N-methyl-D-aspartate receptors (NMDARs) are a class of calcium-permeable ion channel that are extensively distributed throughout the body, composed of various subunits. The presence of diverse ligands and subcellular localizations of the receptors confers biased signaling and distinct functional roles. Activation of the NMDARs induces calcium influx, which plays a pivotal role in neurotransmitter release, synaptic plasticity, and intracellular signaling. Differential localization of NMDARs at synaptic and extrasynaptic sites results in divergent physiological effects; excessive or insufficient activation of NMDARs disrupts calcium homeostasis, leading to neuronal damage and subsequent neurological dysfunction as well as related diseases. Therefore, it is crucial to develop drugs targeting NMDARs with high efficacy and low toxicity for treating brain disorders associated with NMDARs abnormalities. In this review, we summarize both mechanism research and clinical studies on NMDARs while discussing potential therapeutic targets aimed at modulating ion channel activity through regulating mechanisms, subunit rearrangement, membrane expression, and the specific targeting of synaptic versus extrasynaptic NMDARs. Our aim is to provide new insights for innovative drug development.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"273 ","pages":"Article 108888"},"PeriodicalIF":12.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140959","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}

{"title":"Human intestinal enteroids: Nonclinical applications for predicting oral drug disposition, toxicity, and efficacy","authors":"Eimear T. O’Mahony ,&nbsp;Christopher M. Arian ,&nbsp;Kayenat S. Aryeh ,&nbsp;Kai Wang ,&nbsp;Kenneth E. Thummel ,&nbsp;Edward J. Kelly","doi":"10.1016/j.pharmthera.2025.108879","DOIUrl":"10.1016/j.pharmthera.2025.108879","url":null,"abstract":"<div><div>The application of human enteroid systems presents a significant opportunity within the drug development pipeline, highlighting considerable potential for advancements in the characterization and evaluation of new molecular entities. Derived from LGR5⁺ crypt-based columnar cells, enteroid systems more accurately recapitulate the microanatomy and physiological processes of the human intestinal mucosa compared to traditionally used systems. They contain the complement of major mucosal epithelial cell types, maintain the genetic identity of the donor and intestinal segment they were derived from, and exhibit biological functions and specific activities that are seen <em>in vivo</em>. In this review, we examine the applications of human enteroid systems in nonclinical drug development and compare findings to existing and emerging <em>in vitro</em> models of the small intestine. Specifically, we explore enteroid systems in the context of predicting oral drug disposition, focusing on apparent permeability, intestinal first-pass metabolism, and drug interactions, as well as their utility in assessing drug-induced gastrointestinal toxicity and screening therapeutic efficacy against enteric diseases. Additionally, we highlight aspects of enteroid systems that warrant further study.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"273 ","pages":"Article 108879"},"PeriodicalIF":12.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118466","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}

{"title":"Editorial: Pharmacological targets for the control of tissue remodelling and fibrosis","authors":"Peter Holzer","doi":"10.1016/j.pharmthera.2025.108880","DOIUrl":"10.1016/j.pharmthera.2025.108880","url":null,"abstract":"","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"272 ","pages":"Article 108880"},"PeriodicalIF":12.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126143","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}

{"title":"The many facets of biased signaling: Mechanisms and possible therapeutic implications","authors":"K. Helivier Solís,&nbsp;M. Teresa Romero-Ávila,&nbsp;Rocío Alcántara-Hernández,&nbsp;J. Adolfo García-Sáinz","doi":"10.1016/j.pharmthera.2025.108877","DOIUrl":"10.1016/j.pharmthera.2025.108877","url":null,"abstract":"<div><div>Receptor-mediated cell activation frequently results in a plethora of effects, and interestingly, not all agonists that act on a given receptor activate all of those actions to the same extent. Biased agonism refers to this fact, i.e., the possibility to activate only a part of the receptor's signaling capabilities. It is worth mentioning that Biased Signaling is an integral concept that includes the system (organisms, isolated tissues, or cells), the individual receptor studied, and the ligands. It should be remembered that the system's genetic expression profile defines the type, abundance, and cellular localization of proteins that participate in signaling. This short review will be focused on G protein receptors, but biased signaling occurs in many other receptor types.</div><div>Biased signaling can be related to the G proteins and β-arrestins available. Similarly, enzymes that catalyze receptor posttranslational modifications, such as phosphorylation, acylation, or ubiquitination, can play a role. G protein-coupled receptor signaling occurs at the plasma membrane, but it is well-established that endosomal signaling is a functional reality. Therefore, paying attention to cellular elements that participate in receptor endosomal traffic and destination (recycling to the plasma membrane/ degradation) is pertinent. There is still much to be known about these bias mechanisms, which are essential for basic knowledge of receptor drug action and for treating many pathological entities.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"272 ","pages":"Article 108877"},"PeriodicalIF":12.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092365","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}

{"title":"Post-COVID pulmonary sequelae: Mechanisms and potential targets to reduce persistent fibrosis","authors":"Emma C.A. Vreeman ,&nbsp;Janesh Pillay ,&nbsp;Janette K. Burgess","doi":"10.1016/j.pharmthera.2025.108891","DOIUrl":"10.1016/j.pharmthera.2025.108891","url":null,"abstract":"<div><div>After the severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) pandemic, the emergence of long-term sequelae post-infection poses a new healthcare challenge. Following initial infection with SARS-CoV-2, approximately 1 in 10 people experience post-acute sequelae of COVID-19 (PASC), also known as long COVID. PASC can affect the entire body, with the airways and lungs being a primary target of the initial viral infection. Many post-COVID symptoms have been associated with fibrotic lung lesions and diminished respiratory function. The reversibility, persistence, or progression of post-COVID-19 pulmonary fibrosis is still a topic of debate. We aimed to compare current findings and examined similar viral infections from the past, to increase understanding of prevalence, persistence and possible pharmacological targets of post-COVID-19 pulmonary fibrosis.</div><div>Recent studies have documented PASC symptoms persisting up to 3 years post-recovery, and lung impairments present after 15 years after infection with the similar SARS-CoV virus in 2003. These findings suggest the potential for long-term pulmonary fibrosis following SARS-CoV-2 infection, highlighting the need for new anti-fibrotic treatments capable of reversing pulmonary fibrosis. Besides the approved anti-fibrotics, pirfenidone and nintedanib, other promising treatments include histone deacetylase inhibitors, angiotensin receptor blockers and mesenchymal stem cells. The pathophysiological mechanisms underlying post-COVID-19 pulmonary fibrosis are still incompletely understood, necessitating future research to clarify the development of persistent post-COVID-19 pulmonary fibrosis following SARS-CoV-2 infection. Given the widespread transmission of SARS-CoV-2, even a low prevalence of persistent post-COVID-19 pulmonary fibrosis would represent a significant public health concern for which therapeutic strategies are essential to identify.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"272 ","pages":"Article 108891"},"PeriodicalIF":12.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186159","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}

{"title":"Unlocking the power of affibody conjugated radioactive metallopharmaceuticals for targeted cancer diagnosis and therapy","authors":"Dhanashree Murugan ,&nbsp;Harashkumar Vasanthakumari Thirumalaiswamy ,&nbsp;Vasanth Murugesan ,&nbsp;Janarthanan Venkatesan ,&nbsp;Unnikrishnan Balachandran ,&nbsp;Kalaiarasu Lakshminarayanan ,&nbsp;Drishty Satpati ,&nbsp;Stefan Nikolić ,&nbsp;Loganathan Rangasamy","doi":"10.1016/j.pharmthera.2025.108863","DOIUrl":"10.1016/j.pharmthera.2025.108863","url":null,"abstract":"<div><div>Cancer is the second-largest death-causing disease after cardiovascular diseases. Effective research on cancer diagnosis and subsequent elimination plays a vital role in reducing the cancer-related death toll. Radiotherapy is one of the best strategies that could kill masses of solid tumour tissues; however, the efficacy is limited due to the bystander effect. This issue could be solved by the emergence of targeted delivery of radiometallic complexes, enabling clinicians to monitor the tumour regions and effectively destroy the tumour. Affibody® molecules are a class of synthetic peptides known as antibody mimics having the binding sites of an antibody. The specificity of affibodies is found to be greater than that of antibodies due to their small size. This review intends to highlight the recent developments in the field of affibody-targeted radiometallopharmaceuticals. These approaches could be essential for early cancer detection, tumour staging, and monitoring the response to therapy and could produce better therapeutic outcomes. In an attempt to provide ideas and inspiration for the researchers to design affibody-conjugated radiopharmaceuticals that are clinically applicable, we have provided an in-depth exploration of the various types of affibody-conjugated radiopharmaceuticals that are currently in clinical trials and various other pre-clinically tested conjugates in this article. Only a few review reports on affibody-conjugated radiometallopharmaceuticals, typically focusing on a specific molecular target or radionuclides reported. In this review, we provide a comprehensive overview of most radiometals, such as ¹¹¹In, ⁶⁸Ga, ⁶⁴Cu, ⁵⁵Co, ⁵⁷Co, ⁴⁴Sc, ^99mTc, ⁸⁹Zr, ⁹⁰Y, ²¹¹At, ¹⁸⁸Re, and ¹⁷⁷Lu, choice of chelators, and potential cancer-associated molecular targets such HER2, EGFR or HER1, HER3, IGF-1R, PDGFRβ, VEGFR2, PD-L1, CAIX, PD-L1, neonatal Fc receptor (FcRn) and B7-H3. This approach highlights the advancements made over the past twenty years in affibody conjugates for radio imaging and therapy in oncology.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"272 ","pages":"Article 108863"},"PeriodicalIF":12.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954530","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}