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Perianal fistulizing Crohn's disease: emerging biology, therapeutics, and roadmap for precision treatment. 肛周瘘管性克罗恩病：新兴生物学、治疗方法和精确治疗路线图。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-10-20 DOI: 10.1016/j.tips.2026.09.010
Virginia Solitano, Lorenzo Bertani, Clelia Di Salvo, Davide Giuseppe Ribaldone, Luca Antonioli
{"title":"Perianal fistulizing Crohn's disease: emerging biology, therapeutics, and roadmap for precision treatment.","authors":"Virginia Solitano, Lorenzo Bertani, Clelia Di Salvo, Davide Giuseppe Ribaldone, Luca Antonioli","doi":"10.1016/j.tips.2026.09.010","DOIUrl":"https://doi.org/10.1016/j.tips.2026.09.010","url":null,"abstract":"<p><p>Perianal fistulizing Crohn's disease (PFCD) remains difficult to treat despite integrated medical and surgical management, and no validated biomarkers are currently available to guide pharmacological treatment selection. Recent single-cell, spatial, and multiomic studies have identified immune, stromal, epithelial, and microbial features across fistula tissue and rectal mucosa, expanding the biological characterization of PFCD. In this review, we examine how these molecular advances refine the biological understanding of PFCD and inform the evaluation of current and emerging pharmacological strategies. We critically assess the efficacy, safety, and strength of clinical evidence across distinct therapeutic approaches. We also discuss how molecular insights could support biomarker development for patient stratification and treatment selection, alongside anatomical phenotype, surgical context, and standardized multidimensional assessment of fistula healing.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":24.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149228703","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
Engineering monocytes and macrophages for therapeutic control. 工程单核细胞和巨噬细胞用于治疗控制。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-10-16 DOI: 10.1016/j.tips.2026.09.009
Yunzhu Chen, Christine E Brown, Yanhong Shi, Mingye Feng
{"title":"Engineering monocytes and macrophages for therapeutic control.","authors":"Yunzhu Chen, Christine E Brown, Yanhong Shi, Mingye Feng","doi":"10.1016/j.tips.2026.09.009","DOIUrl":"https://doi.org/10.1016/j.tips.2026.09.009","url":null,"abstract":"<p><p>Engineered monocytes and macrophages are emerging as therapeutic platforms for eliminating pathological targets, remodeling diseased tissues, and coordinating local immune responses. Early clinical studies support their feasibility, but target recognition alone does not ensure sustained function after tissue entry. Recent advances in myeloid-adapted receptors, context-responsive circuits, checkpoint and metabolic engineering, in vivo mRNA delivery, and stem-cell-derived platforms have expanded the strategies available to improve tissue tracking, control cellular plasticity, and sustain effector capacity. Previous reviews have commonly organized the field by disease, target, or platform. Here, we examine engineered monocyte and macrophage therapies as integrated pharmacological systems structured across four coupled layers-sensing, signal integration, actuation, and delivery-and discuss how their coordination determines tissue exposure, functional durability, and pharmacodynamic readouts across therapeutic settings.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":24.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207940","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
Precision toxicity control in checkpoint immunotherapy. 检查点免疫治疗的精确毒性控制。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-10-08 DOI: 10.1016/j.tips.2026.09.005
Zhen Sun, Xiaoyi Yang, Weiming Shen, Zhe Li, Ming Guan, Xuan Deng, Haojie Jin
{"title":"Precision toxicity control in checkpoint immunotherapy.","authors":"Zhen Sun, Xiaoyi Yang, Weiming Shen, Zhe Li, Ming Guan, Xuan Deng, Haojie Jin","doi":"10.1016/j.tips.2026.09.005","DOIUrl":"https://doi.org/10.1016/j.tips.2026.09.005","url":null,"abstract":"<p><p>Immune checkpoint inhibitors have changed cancer management. However, immune-related adverse events (irAEs) can disrupt treatment and limit effective combination strategies. The standard of care tends to involve broad immunosuppression, which may compromise antitumor immunity and fail to address the dominant biology of distinct irAEs. Some evidence suggests that irAEs can be mitigated through mechanism-based interventions, including cytokine blockade, tissue-restricted immunomodulation, and strategies targeting pathogenic lymphocytes or humoral pathways. Emerging irAE biomarkers help support personalized risk assessment, diagnosis, and intervention selection. In this review, we examine key advances in targeted interventions and biomarkers and outline a translational and clinical path forward, ranging from clinically useful irAE taxonomies to biomarker-guided trials, to advance precision toxicity control toward clinical practice.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":24.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149138468","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 tumor resistance mechanisms to antimetabolite treatment. 新出现的肿瘤抗代谢物治疗的耐药机制。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-10-07 DOI: 10.1016/j.tips.2026.09.008
Juan L Coelho-Silva, Diego A Pereira-Martins, João A Machado-Neto
{"title":"Emerging tumor resistance mechanisms to antimetabolite treatment.","authors":"Juan L Coelho-Silva, Diego A Pereira-Martins, João A Machado-Neto","doi":"10.1016/j.tips.2026.09.008","DOIUrl":"https://doi.org/10.1016/j.tips.2026.09.008","url":null,"abstract":"<p><p>Antimetabolites have been used to treat cancer since the 1950s, yet how tumors survive remains unclear. Two studies by Moss and colleagues and Witus and colleagues show that surviving cells recycle nucleotides and reshape mitochondria, revealing a shared resistance program. Because this program is measurable, it could identify, before treatment, which patients would benefit from drugs that block it.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":24.0,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149128611","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
Epigenetic programming via lysine-specific demethylase 1 regulates responses to immune checkpoint blockade. 通过赖氨酸特异性去甲基酶1的表观遗传编程调节对免疫检查点封锁的反应。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-10-01 DOI: 10.1016/j.tips.2026.09.006
Xiaoshuang Niu, Bin Yu
{"title":"Epigenetic programming via lysine-specific demethylase 1 regulates responses to immune checkpoint blockade.","authors":"Xiaoshuang Niu, Bin Yu","doi":"10.1016/j.tips.2026.09.006","DOIUrl":"https://doi.org/10.1016/j.tips.2026.09.006","url":null,"abstract":"<p><p>Immune checkpoint blockade has revolutionized cancer therapy, but durable benefit remains limited by immune-cold tumor states, poor antigen presentation, T cell exhaustion, and adaptive resistance. Recent studies position lysine-specific demethylase 1 (LSD1) as a druggable epigenetic regulator that links these barriers across tumor and immune cells. Emerging evidence shows that targeting LSD1 can restore major histocompatibility complex class I antigen presentation, activate viral mimicry and interferon programs, modulate programmed death-ligand 1 in a context-dependent manner, influence CD8<sup>+</sup> T cell state transitions, and restrain tumor plasticity. In this review, we feature these mechanistic advances, compare evolving drug classes, and outline biomarker-guided strategies that may support the rational development of next-generation combination immunotherapy.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":""},"PeriodicalIF":24.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149115338","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
The expanding role of Cav3 channels in glioblastoma. Cav3通道在胶质母细胞瘤中的扩展作用。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-10-01 Epub Date: 2026-09-04 DOI: 10.1016/j.tips.2026.08.012
Maria Casals, Judit Herreros, Carles Cantí
{"title":"The expanding role of Cav3 channels in glioblastoma.","authors":"Maria Casals, Judit Herreros, Carles Cantí","doi":"10.1016/j.tips.2026.08.012","DOIUrl":"10.1016/j.tips.2026.08.012","url":null,"abstract":"<p><p>Tumor-intrinsic voltage-gated Cav3 calcium channels, comprising the Cav3.1, Cav3.2 and Cav3.3 isoforms, have been implicated in cancer cell proliferation and survival. Recent work by Dube et al. reveals a role for microenvironmental Cav3.2 channels in glioblastoma, promoting neuron-cancer cell crosstalk and identifying changes in immune-related programs associated with Cav3.2 deficiency.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"1064-1066"},"PeriodicalIF":24.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148892389","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
Lipophagy and lipid droplets in neurodegeneration. 神经退行性变中的脂噬和脂滴。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-10-01 Epub Date: 2026-09-22 DOI: 10.1016/j.tips.2026.08.004
Nicholas W McKee, Yue Jing, Rashid Serdah, Senthilkumar Thulasingam, Xenia S Lopez, Ee Phie Tan
{"title":"Lipophagy and lipid droplets in neurodegeneration.","authors":"Nicholas W McKee, Yue Jing, Rashid Serdah, Senthilkumar Thulasingam, Xenia S Lopez, Ee Phie Tan","doi":"10.1016/j.tips.2026.08.004","DOIUrl":"10.1016/j.tips.2026.08.004","url":null,"abstract":"<p><p>Lipid droplet (LD) accumulation in neurons and glia is a feature of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) and is associated with oxidative stress and neuroinflammation. Although protein-targeted monotherapies have achieved partial clinical success, continued disease progression in many patients suggests that additional cellular mechanisms contribute to pathogenesis. Lipophagy, the selective autophagic degradation of LDs, provides a potential clearance route but has been studied primarily in hepatocytes under nutrient deprivation. Recent studies have begun to map noncanonical regulatory mechanisms of lipophagy, identify disease-associated points of failure in AD, PD, and ALS, and report compounds that enhance LD clearance through mechanisms distinct from canonical nutrient sensing. In this article, we review these advances and discuss the emerging rationale for exploring neuron- and context-specific approaches to modulate lipophagy as a complementary strategy in neurodegeneration.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"1116-1135"},"PeriodicalIF":24.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13632763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149026168","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
AI virtual cells for drug discovery and pharmacology. 用于药物发现和药理学的人工智能虚拟细胞。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-10-01 Epub Date: 2026-09-09 DOI: 10.1016/j.tips.2026.08.006
Shihang Wang, Yang Zhang, Dong Wang, Huanxiang Liu, Xiaojun Yao
{"title":"AI virtual cells for drug discovery and pharmacology.","authors":"Shihang Wang, Yang Zhang, Dong Wang, Huanxiang Liu, Xiaojun Yao","doi":"10.1016/j.tips.2026.08.006","DOIUrl":"10.1016/j.tips.2026.08.006","url":null,"abstract":"<p><p>Drug discovery relies on cellular assays to determine whether a candidate produces a desired response, reveals its mechanism, or causes toxicity, but only a small fraction of compound-dose-time-context combinations can be measured experimentally. Recent perturbation atlases, single-cell and imaging technologies, and intervention-conditioned AI models now make prediction of unmeasured cellular responses a testable objective. AI virtual cells could therefore complement conventional discovery by prioritizing compounds, contexts, and follow-up experiments rather than replacing laboratory assays. Here, we review the resources and modeling advances supporting this capability, assess their value for mechanism-of-action analysis, efficacy, safety, resistance, and combination studies, and define evidence requirements for pharmacological use. Data coverage makes oncology, including immuno-oncology, plausible early proving grounds, with safety assessment as a crosscutting use case; broader deployment requires perturbation-specific, mechanistic, and decision-level validation.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"1085-1098"},"PeriodicalIF":24.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148921102","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
Midnolin-directed protein degradation beyond ubiquitin. midnolin导向的蛋白质降解超越泛素。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-10-01 Epub Date: 2026-09-14 DOI: 10.1016/j.tips.2026.08.005
Yuwei Tang, Yinhao Zhou, Xin Zhang, Zhengjie Peng, Yanli Liu
{"title":"Midnolin-directed protein degradation beyond ubiquitin.","authors":"Yuwei Tang, Yinhao Zhou, Xin Zhang, Zhengjie Peng, Yanli Liu","doi":"10.1016/j.tips.2026.08.005","DOIUrl":"10.1016/j.tips.2026.08.005","url":null,"abstract":"<p><p>Targeted protein degradation has emerged as a powerful way to eliminate disease-driving proteins rather than merely inhibit them. However, most current approaches depend on ubiquitin ligases, whereas midnolin bypasses E3 recruitment and substrate ubiquitination while converging on the same 26S proteasome used for canonical ubiquitin-dependent degradation. Recent structural, biochemical, and disease studies have defined how midnolin recognizes β-strand-forming degrons, positions substrates at the 26S proteasome, and contributes to interferon regulatory factor 4 regulation, while engineered midnolin-targeting chimeras and midnolin-based targeting chimeras have redirected this pathway toward β-catenin and c-Myc. By linking endogenous pathway biology with engineered degrader pharmacology, this review compares midnolin-directed degradation with proteolysis-targeting chimeras and molecular glue degraders and identifies the design, delivery, and safety principles that will determine whether it becomes a useful ubiquitin-independent complement to existing degraders.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"1171-1185"},"PeriodicalIF":24.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148971504","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
De-Nterm-ining GLP1R signaling bias. 消除GLP1R信号偏倚。
IF 24 1区 医学
Trends in pharmacological sciences Pub Date : 2026-10-01 Epub Date: 2026-08-27 DOI: 10.1016/j.tips.2026.08.002
Johannes Broichhagen, David J Hodson
{"title":"De-Nterm-ining GLP1R signaling bias.","authors":"Johannes Broichhagen, David J Hodson","doi":"10.1016/j.tips.2026.08.002","DOIUrl":"10.1016/j.tips.2026.08.002","url":null,"abstract":"<p><p>Biased agonism has emerged as a promising strategy for improving incretin therapeutics, yet the structural determinants of signaling bias remain incompletely understood. Building on their recent parathyroid hormone 1 receptor-β-arrestin structure, Zhao and colleagues identify extracellular loop 3 as a conformational switch controlling glucagon-like peptide-1 receptor transducer selectivity, enabling rational design of biased agonists.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":" ","pages":"1069-1071"},"PeriodicalIF":24.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148841156","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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