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PKCθ: from T cell kinase to immunometabolic integrator. PKCθ：从T细胞激酶到免疫代谢整合子。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2026-06-01 Epub Date: 2026-05-07 DOI: 10.1016/j.tips.2026.04.003
Yongqi Li, Weiguang Sun, Yonghui Zhang
{"title":"PKCθ: from T cell kinase to immunometabolic integrator.","authors":"Yongqi Li, Weiguang Sun, Yonghui Zhang","doi":"10.1016/j.tips.2026.04.003","DOIUrl":"10.1016/j.tips.2026.04.003","url":null,"abstract":"<p><p>Protein kinase C theta (PKCθ) has long been viewed as a core T cell signaling molecule. Recent work, however, reveals functions far beyond this classic role. In this review, we integrate recent evidence to redefine PKCθ as a pan-immune and immunometabolic integrator that controls not only T cell activation but also macrophage phagocytosis, natural killer cell (NK) function, and systemic metabolism. We analyze its paradoxical roles in cancer-where it drives some tumors but is lost in others-and summarize the evolution of therapeutic strategies beyond ATP-competitive inhibition, including allosteric modulation, proteolysis-targeting chimera degradation, and disruption of protein-protein interactions (PPIs). This aims to move the PKCθ field from fragmented descriptions toward mechanistic understanding and precision intervention.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"694-705"},"PeriodicalIF":19.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857326","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}
引用次数: 0
Emerging opportunities for nicotinamide N-methyltransferase (NNMT) inhibitor clinical translation. 烟酰胺n -甲基转移酶（NNMT）抑制剂临床转化的新机遇。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2026-06-01 Epub Date: 2026-04-30 DOI: 10.1016/j.tips.2026.04.002
Noah Puleo, Maria Francesca Allega, Claus U Niemann, Ernst Lengyel
{"title":"Emerging opportunities for nicotinamide N-methyltransferase (NNMT) inhibitor clinical translation.","authors":"Noah Puleo, Maria Francesca Allega, Claus U Niemann, Ernst Lengyel","doi":"10.1016/j.tips.2026.04.002","DOIUrl":"10.1016/j.tips.2026.04.002","url":null,"abstract":"<p><p>Nicotinamide N-methyltransferase (NNMT) is an enzyme that helps regulate how cells balance energy and methylation potential; however, its abnormal activation can disrupt this balance, fueling diseases such as diabetes, obesity, fibrosis, and cancer. As a result, small-molecule inhibitors targeting NNMT have been developed to reduce this elevated activity, but insufficient target engagement, reduced bioavailability, and unknown safety profiles have led to limited preclinical success across diseases. Advances in NNMT small-molecule inhibitor development have yielded a number of compounds that address these concerns, resulting in drug-like compounds with high affinities for cellular NNMT and promising safety profiles. In this review, we assess the growing therapeutic potential of NNMT inhibitors by highlighting recent developments in NNMT pathophysiology and inhibitor medicinal chemistry.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"638-654"},"PeriodicalIF":19.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13138456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147821111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dupilumab (DUPIXENT) for bullous pemphigoid. Dupilumab （DUPIXENT）用于大疱性类天疱疮。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2026-05-29 DOI: 10.1016/j.tips.2026.05.003
Gowtham Subramanian, Wei Jun Lam, Elizabeth Huiwen Tham, Yik Weng Yew, Kenji Kabashima
{"title":"Dupilumab (DUPIXENT) for bullous pemphigoid.","authors":"Gowtham Subramanian, Wei Jun Lam, Elizabeth Huiwen Tham, Yik Weng Yew, Kenji Kabashima","doi":"10.1016/j.tips.2026.05.003","DOIUrl":"https://doi.org/10.1016/j.tips.2026.05.003","url":null,"abstract":"","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":19.9,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057161","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}
引用次数: 0
Small molecule modulation of organelle membrane contact sites. 细胞器膜接触位点的小分子调节。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-05-01 Epub Date: 2026-03-30 DOI: 10.1016/j.tips.2026.02.008
Minjeong Ko, Jiho You, Eunwoo Cho, Ho Jeong Kwon
{"title":"Small molecule modulation of organelle membrane contact sites.","authors":"Minjeong Ko, Jiho You, Eunwoo Cho, Ho Jeong Kwon","doi":"10.1016/j.tips.2026.02.008","DOIUrl":"10.1016/j.tips.2026.02.008","url":null,"abstract":"<p><p>Organelle membrane contact sites (MCSs) regulate calcium exchange, lipid transfer, metabolism, and cellular stress responses. Dysregulation of MCSs contributes to diverse diseases, yet pharmacological strategies that directly modulate contact architecture remain limited. Recent advances in chemoproteomics and live-cell imaging demonstrate that small molecules can remodel organelle contacts by modulating the conformational states of tethering proteins, coordinating associated effector and regulatory assemblies, and reshaping organelle networks. Here, we propose a pharmacological framework that classifies MCS modulators as stabilizers or destabilizers and review representative compounds, highlighting their molecular mechanisms and emerging therapeutic candidates. We further discuss advanced technologies for visualizing MCS dynamics and identifying small molecule-induced proteoforms. This review positions MCSs as actionable drug targets and outlines future directions for organelle-focused pharmacology.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"490-503"},"PeriodicalIF":24.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147594963","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}
引用次数: 0
Targeting the sensory-sympathetic axis for cancer immunotherapy. 以感觉交感轴为靶点的癌症免疫治疗。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-05-01 Epub Date: 2026-03-31 DOI: 10.1016/j.tips.2026.03.003
Wei-Lin Jin, Ming-Zhu Jin
{"title":"Targeting the sensory-sympathetic axis for cancer immunotherapy.","authors":"Wei-Lin Jin, Ming-Zhu Jin","doi":"10.1016/j.tips.2026.03.003","DOIUrl":"10.1016/j.tips.2026.03.003","url":null,"abstract":"<p><p>How tumors manipulate neural circuits to evade immunity is unclear. In a recent study, Wei et al. reveal, in lung adenocarcinoma, a vagal sensory-brain stem sympathetic circuit that suppresses macrophages and CD8<sup>+</sup> T cells via β<sub>2</sub>-adrenergic signaling. Disrupting this axis restores antitumor immunity, nominating β-blockers and neural modulation as promising therapies.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"467-469"},"PeriodicalIF":24.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147594970","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}
引用次数: 0
Macrophage heterogeneity and plasticity: mechanism and therapeutics. 巨噬细胞异质性和可塑性：机制和治疗。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-05-01 Epub Date: 2026-03-05 DOI: 10.1016/j.tips.2026.02.002
Shiming Li, Yurui Yang, Haibo Qiu, Lizhi Pang
{"title":"Macrophage heterogeneity and plasticity: mechanism and therapeutics.","authors":"Shiming Li, Yurui Yang, Haibo Qiu, Lizhi Pang","doi":"10.1016/j.tips.2026.02.002","DOIUrl":"10.1016/j.tips.2026.02.002","url":null,"abstract":"<p><p>Macrophages play pivotal roles in regulating immune responses during inflammation and cancer. Recent evidence indicates that macrophages are dynamic cells capable of switching between different functional states in response to stimuli from their local microenvironment. However, characterizing these functional states in the context of inflammation and cancer has been challenging due to a lack of powerful tools. To address this important issue, recent studies have employed single-cell technologies and emerging immunoinformatics methods to explore the relationship between macrophage phenotypic states and their cellular functions. Here, we synthesize insights from these studies and discuss the current understanding of macrophage diversity (heterogeneity) and adaptability (plasticity) in acute inflammation, chronic diseases, and cancer. We also highlight the molecular mechanisms that initiate macrophage state transitions during disease progression. By integrating knowledge gained from different disease models, we propose a conceptual framework for the future development of pharmacological approaches aimed at targeting macrophages effectively.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"537-554"},"PeriodicalIF":24.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147370412","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}
引用次数: 0
Pharmacological strategies targeting hepatocyte-mediated crosstalk in liver fibrosis. 针对肝纤维化中肝细胞介导的串扰的药理策略。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-05-01 Epub Date: 2026-03-23 DOI: 10.1016/j.tips.2026.01.010
Yue Zhang, Meng-Guang Wei, Xin-Yue Zhou, Lian-Wen Qi, Qun Liu
{"title":"Pharmacological strategies targeting hepatocyte-mediated crosstalk in liver fibrosis.","authors":"Yue Zhang, Meng-Guang Wei, Xin-Yue Zhou, Lian-Wen Qi, Qun Liu","doi":"10.1016/j.tips.2026.01.010","DOIUrl":"10.1016/j.tips.2026.01.010","url":null,"abstract":"<p><p>Liver fibrosis is a common pathological outcome of chronic liver injury. Many therapeutic agents show limited clinical efficacy or significant adverse effects due to the complex pathogenesis of liver fibrosis. This challenge underscores the urgent need to identify potential therapeutic targets and improve existing therapies. Hepatocytes serve as pivotal initiators of liver fibrosis that actively engage in signaling crosstalk with other hepatic cell types to promote fibrogenesis. Advances in understanding hepatocyte-centered signaling crosstalk have enabled the identification of potential therapeutic targets. Furthermore, combination therapies that regulate multiple pathways and drug modifications that improve pharmacological properties may help to minimize adverse effects and enhance the efficacy of existing treatments. This review highlights recent advances in hepatocyte-focused mechanisms underlying liver fibrosis and their translational potential. It provides a timely and comprehensive overview of current antifibrotic strategies.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"555-570"},"PeriodicalIF":24.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147515116","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}
引用次数: 0
Cancer pathogenesis and phase targeting through condensate fragility. 凝析物易碎性的肿瘤发病机制及期标。
IF 19.9 1区 医学
Trends in pharmacological sciences Pub Date : 2026-05-01 Epub Date: 2026-03-06 DOI: 10.1016/j.tips.2026.01.011
Menghua Wang, Takudzwa Chiwoneso, Zimeng Luo, Justice J Mallen, Yuanzheng Xia, Jianbo Sun
{"title":"Cancer pathogenesis and phase targeting through condensate fragility.","authors":"Menghua Wang, Takudzwa Chiwoneso, Zimeng Luo, Justice J Mallen, Yuanzheng Xia, Jianbo Sun","doi":"10.1016/j.tips.2026.01.011","DOIUrl":"10.1016/j.tips.2026.01.011","url":null,"abstract":"<p><p>Nuclear liquid-liquid phase separation (LLPS) is now recognized as a fundamental mechanism that organizes transcription and DNA repair machinery into dynamic, membraneless condensates essential for genome integrity and gene regulation. Dysregulated LLPS has emerged as a key driver of oncogenesis; yet, how pathological condensates simultaneously fuel transcriptional addiction and genomic instability remains incompletely understood. Recent biophysical and molecular advances, particularly in multivalency, concentration thresholds, and condensate material states, have revealed that cancer-associated mutations rewire phase behavior to generate hyperstable yet fragile condensates. This review explores the role of aberrant nuclear LLPS in cancer pathogenesis and therapy resistance and uniquely proposes phase targeting through condensate fragility as a precision oncology strategy, distinguishing itself by integrating oncogenic mechanisms with actionable biophysical vulnerabilities rather than focusing solely on molecular inhibition.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"522-536"},"PeriodicalIF":19.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373160","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}
引用次数: 0
Drugging cold-response networks for neuroprotection. 药物冷反应网络用于神经保护。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-05-01 Epub Date: 2026-03-19 DOI: 10.1016/j.tips.2026.02.003
Min Zhang, Chengli Liu, Aifang Cheng, Mingchang Li
{"title":"Drugging cold-response networks for neuroprotection.","authors":"Min Zhang, Chengli Liu, Aifang Cheng, Mingchang Li","doi":"10.1016/j.tips.2026.02.003","DOIUrl":"10.1016/j.tips.2026.02.003","url":null,"abstract":"<p><p>Therapeutic hypothermia is robustly neuroprotective in models but slow to initiate and hard to sustain clinically. This gap motivates pharmacological strategies that capture 'cold' protection at normothermia. Recent advances across the cold-response landscape have made RNA layer mechanisms operational. These include temperature-gated alternative splicing coupled to nonsense-mediated decay and temperature-sensitive RNA secondary structure elements such as RNA G-quadruplexes (rG4) thermometers, which are now quantifiable and tractable. In this review, we present a development-oriented framework that spans membrane thermosensors, intracellular temperature decoders, and downstream cold effectors. We focus on RNA layer mechanisms while treating upstream non-RNA elements as contextual adjuncts. We outline an RNA-binding motif protein 3 (RBM3)-first translational roadmap mainly built on two orthogonal modalities: splice-switching antisense oligonucleotides and rG4-oriented chemotypes. Lastly, we define pharmacodynamic anchors, realistic clinical windows, and safety gates for early-phase testing of normothermic hypothermia mimetics.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"474-489"},"PeriodicalIF":24.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147491671","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}
引用次数: 0
Induced proximity for dephosphorylation. 诱导邻近去磷酸化。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-05-01 Epub Date: 2026-03-25 DOI: 10.1016/j.tips.2026.02.010
Kwang-Su Park, Taeg Kyu Kwon
{"title":"Induced proximity for dephosphorylation.","authors":"Kwang-Su Park, Taeg Kyu Kwon","doi":"10.1016/j.tips.2026.02.010","DOIUrl":"10.1016/j.tips.2026.02.010","url":null,"abstract":"<p><p>Induced-proximity dephosphorylation is a strategy that recruits phosphatases to target proteins for selective and reversible phosphate removal. This strategy enables context-dependent reprogramming of pathological phosphorylation with improved mechanistic and pathway specificity. In this forum article, we outline its mechanistic basis, summarize recent advances, and discuss emerging therapeutic implications.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"470-473"},"PeriodicalIF":24.0,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147522206","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}
引用次数: 0
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