Pharmacological research最新文献

{"title":"Targeting Acod1/itaconate in cancer therapy: Mechanisms and opportunities","authors":"Tianlin Deng ,&nbsp;Xiuyan Li ,&nbsp;Shuodong Wu ,&nbsp;Jing Kong ,&nbsp;Xiaodong Wu","doi":"10.1016/j.phrs.2026.108139","DOIUrl":"10.1016/j.phrs.2026.108139","url":null,"abstract":"<div><div>Globally, cancer claims nearly 10 million lives annually, where tumor heterogeneity, the immunosuppressive microenvironment, and therapeutic resistance constitute fundamental clinical challenges. In recent years, immunometabolic reprogramming has emerged as a cutting-edge research frontier, revealing novel mechanisms by which metabolites orchestrate immune responses. Itaconate—an immunometabolite primarily synthesized by macrophages—serves as a pivotal molecular hub bridging metabolic stress and anti-tumor immunity. This review systematically traces the evolution of itaconate from an industrial chemical to a key immunometabolite; comprehensively elucidates its dual roles (pro-tumorigenic vs. anti-tumorigenic) within the tumor microenvironment; synthesizes preclinical evidence of itaconate and its derivatives across diverse tumor systems; and consolidates emerging adjuvant therapeutic strategies targeting the Acod1/itaconate pathway. Collectively, this work aims to provide innovative immunometabolic perspectives for overcoming current barriers in cancer therapy.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108139"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic caffeine consumption prevents obesity-induced cognitive and memory impairments by reducing neuroinflammation and enhancing neuronal activity in the hippocampus","authors":"Adriana M. Capucho ,&nbsp;José Ponce de Leão ,&nbsp;Karine Correa Flor ,&nbsp;Gonçalo M. Melo ,&nbsp;Marcos Vinicius Fernandes ,&nbsp;Joana F. Sacramento ,&nbsp;Sílvia V. Conde","doi":"10.1016/j.phrs.2026.108140","DOIUrl":"10.1016/j.phrs.2026.108140","url":null,"abstract":"<div><div>Obesity and its associated metabolic disturbances increase the risk of cognitive decline, dementia, and anxiety-related disorders. Chronic caffeine consumption was suggested to prevent synaptic and cognitive deficits, but the underlying mechanisms remain unclear. Here, we investigated whether caffeine protects against cognitive and memory deficits and anxiety induced by a hypercaloric diet, and explored the molecular mechanisms involved. Ten-week-old male Wistar rats were assigned to three groups: normal chow (control), high-fat high-sucrose (HFHSu, 25 weeks), and HFHSu plus caffeine (HFHSuCaff, 1 g/L last 11 weeks). Insulin sensitivity and glucose tolerance were assessed at weeks 14 and 25. Behavioral tests (open field, novel object recognition (NOR), Y-maze, block test, elevated plus maze (EPM)) evaluated memory, cognition, and anxiety. Hippocampal tissues were analyzed by Western blot and immunohistochemistry for insulin signaling, neuronal activity and microglia activation. HFHSu feeding promoted obesity, insulin resistance, and glucose intolerance, accompanied by impaired memory and cognition (reductions in Y-maze, NOR, and block test), increased anxiety (54.5 % time in EPM open arms), reduced hippocampal glutamatergic (41.1 % VGlut) and adenosinergic signaling (22.4 %, 11.1 %, 22.6 % in A1, A2A, A2B receptors), and elevated neuroinflammation (elevated GFAP, IBA-1, IL-6 receptor levels; altered microglial morphology) compared with control. Caffeine intake ameliorated metabolic, cognitive, and neuroinflammatory alterations, except for anxiety. Notably, caffeine increased hippocampal neuronal activity by 25.22, 94.84 and 61.51 % in CA1, CA2 and CA3 areas. In conclusion, chronic caffeine consumption mitigates obesity-induced cognitive and memory deficits via modulation of hippocampal glutamatergic and adenosinergic signaling and reduced neuroinflammation, highlighting its potential as a neuroprotective intervention.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108140"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-specific targeting of a mitochondrial Kv1.3 channel inhibitor through conjugation to gastrin/cholecystokinin B receptor ligand strongly reduces pancreatic ductal adenocarcinoma in orthotopic models","authors":"Sofia Parrasia ,&nbsp;Carlotta Paoli ,&nbsp;Tatiana Varanita ,&nbsp;Valentina Brillo ,&nbsp;Mostafa A.L. Abdel-Salam ,&nbsp;Alberto Ongaro ,&nbsp;Claudia Honisch ,&nbsp;Beatrice Angi ,&nbsp;Magdalena Bachmann ,&nbsp;Filippo Bergamin ,&nbsp;Vincenzo Corbo ,&nbsp;Elena Fiorini ,&nbsp;Andrea Rossa ,&nbsp;Giovanna Bossio ,&nbsp;Erich Gulbins ,&nbsp;Alessandro Carrer ,&nbsp;Mario Zoratti ,&nbsp;Andrea Mattarei ,&nbsp;Paolo Ruzza ,&nbsp;Lucia Biasutto ,&nbsp;Ildiko Szabo","doi":"10.1016/j.phrs.2026.108150","DOIUrl":"10.1016/j.phrs.2026.108150","url":null,"abstract":"<div><div>Pancreatic ductal adenocarcinoma (PDAC) is a highly chemoresistant and immunoresistant tumor with an overall five-year survival rate of less than 10 %. Current treatments for PDAC are rather limited, highlighting the importance of finding novel strategies. In this study, we investigated a strategy for the tumor-specific targeting of PAPTP, a small molecule that reduces PDAC growth by inhibiting the mitochondrial potassium channel mtKv1.3, thereby inducing mitochondrial dysfunction and killing cancer cells. PAPTP was reversibly conjugated to three tumor-penetrating peptides: iRGD, VH434, and a short version of minigastrin (CCK2p). These recognize neuropilin-1 and integrin (iRGD), the low-density lipoprotein receptor (VH434), and the gastrin/cholecystokinin B receptor (CCK2p). <em>In vivo</em> pharmacokinetic studies revealed that the PAPTP-bound iRGD peptide underwent rapid metabolic cleavage, which prevented optimal uptake of the construct into PDAC. The VH434 conjugate was highly hemolytic. However, CCK2p-PAPTP exhibited preferential distribution to the pancreas in animals bearing orthotopic PDAC. Efficacy studies revealed a reduction in mean tumor volume of up to 65 % in two independent orthotopic mouse models, with no tumor evident in some of the animals treated with the CCK2p-bound PAPTP construct. Our data suggest that tumor-specific targeting of small molecules may be a promising strategy for precision medicine against PDAC.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108150"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathophysiological significance of the TRPM2 ion channel as a potential target in cancer, neurological disorders, and ischemia/reperfusion injury","authors":"Sara Sultana,&nbsp;Yang Xie,&nbsp;Mir Shahriar Kamal,&nbsp;Wei Li","doi":"10.1016/j.phrs.2026.108132","DOIUrl":"10.1016/j.phrs.2026.108132","url":null,"abstract":"<div><div>The transient receptor potential melastatin 2 (TRPM2) ion channel is a redox-sensitive, non-specific cation channel that plays a vital role in the regulation of Ca²⁺ homeostasis and cellular functions in response to oxidative stress. However, aberrant expression of TRPM2 is associated with various pathological conditions. Overexpression of TRPM2 promotes cell survival in multiple malignancies, including neuroblastoma, lung, prostate, stomach, and pancreatic cancers. TRPM2 also mediates different neurological disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and epilepsy, and contributes to ischemia/reperfusion (I/R) injury. This review provides a comprehensive summary of the pathophysiological significance of TRPM2, covering the structural features, regulation, and oxidative stress signaling, with a major focus on the mechanistic pathways that link TRPM2 to these diseases. We discuss the therapeutic potential of TRPM2, its long non-coding antisense RNA (TRPM2-AS), and provide a comprehensive overview of currently available TRPM2 inhibitors, including adenosine diphosphate ribose (ADPR) analogs, small molecules, and peptides. This review covers an in-depth analysis of the structural activity relationships (SAR), pharmacokinetic (PK) properties of these TRPM2 inhibitors, detailing their preclinical efficacy studies, and outlining their shortcomings. Overall, we conclude that TRPM2 represents a promising drug target for effective therapies in several major disease indications.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108132"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZBTB16 controls the onset of Clostridium difficile colitis through the Pyrin inflammasome","authors":"Shuhui Li ,&nbsp;Jingjing He ,&nbsp;Huxidanmu Tuoheniyazi ,&nbsp;Junrui Ma ,&nbsp;Zhenyu Li ,&nbsp;Juanjuan Zheng ,&nbsp;Yuxin Wang ,&nbsp;Xiupan Gao ,&nbsp;Xiaobao Yang ,&nbsp;Danping Liu ,&nbsp;Yanan Zhao ,&nbsp;Tongxuan Su ,&nbsp;Yibing Peng ,&nbsp;Dakang Xu ,&nbsp;Xuefeng Fei","doi":"10.1016/j.phrs.2026.108133","DOIUrl":"10.1016/j.phrs.2026.108133","url":null,"abstract":"<div><div><em>Clostridium difficile</em> infection (CDI) is a leading cause of antibiotic-associated diarrhea and pseudomembranous colitis, and there remains a significant unmet need for therapies specifically targeting <em>C. difficile</em>. The Pyrin inflammasome, activated by bacterial toxins, plays a critical role in driving macrophage-mediated intestinal inflammation during CDI. In this study, we report that myeloid-specific deficiency of <em>Zbtb16</em> protects mice from <em>C. difficile</em>-induced colitis by attenuating IL-1β-dependent inflammatory signaling. Mechanistic studies revealed that <em>Zbtb16</em> deletion disrupts ASC oligomerization and speck formation, thereby selectively inhibiting inflammasome assembly and reducing mature IL-1β production in macrophages stimulated with <em>C. difficile</em> culture supernatant or purified TcdB toxin. Importantly, pharmacological degradation of ZBTB16 using the cereblon E3 ligase modulating drug CC-3060 significantly ameliorated colitis severity in a murine model of CDI. Our findings establish ZBTB16 as a key regulator of Pyrin inflammasome activation in macrophages, highlighting the therapeutic promise of ZBTB16 degradation as a novel strategy for treating CDI.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108133"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146157720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urinary Δ9-tetrahydrocannabinol and metabolite concentrations following cannabis use: A systematic review","authors":"Danielle McCartney ,&nbsp;Christopher Irwin ,&nbsp;Jonathon C. Arnold ,&nbsp;Rebecca Gordon ,&nbsp;Andrew J. McLachlan ,&nbsp;Iain S. McGregor","doi":"10.1016/j.phrs.2026.108142","DOIUrl":"10.1016/j.phrs.2026.108142","url":null,"abstract":"<div><div>Urine testing is used in a variety of contexts to identify cannabis use. Most tests target <em>11-nor-9-carboxy-Δ⁹-tetrahydrocannabinol</em> (11-COOH-THC), the terminal metabolite of <em>Δ⁹-tetrahydrocannabinol</em> (THC), the principal intoxicant in cannabis. Different authorities use different threshold concentrations to define a positive test. This systematic review synthesised the urinary THC and THC-metabolite concentrations reported in prior studies involving administration of cannabis/cannabis-based products (acute and repeated dosing) and users of such products (during use and extended abstinence). The overall objectives were to: (1) clarify how different use patterns affect these concentrations; and (2) contextualise the thresholds applied in key contexts – specifically, workplaces (and workplace-aligned contexts, e.g., criminal justice) and competitive sport. Ninety-two eligible studies were identified and included. <em>Typical workplace threshold (15 ng/mL total 11-COOH-THC):</em> Low single doses (i.e., 1.0–5.0 mg) and very low repeated doses (i.e., &lt;1.0 mg/day) of THC were sometimes sufficient to exceed the workplace threshold, particularly with oral ingestion. Weekly to daily cannabis users could remain above this threshold for weeks following cessation. <em>World Anti-Doping Agency (WADA) Decision Limit (180 ng/mL total 11-COOH-THC):</em> Low-to-moderate oral doses (i.e., 10 mg) and moderate inhaled doses (i.e., 15–20 mg) of THC were sometimes sufficient to exceed the WADA Decision Limit, as was weekly cannabis use. Weekly to daily cannabis users often fell below this threshold within a week of cessation, although heavy users took longer. This synthesis may assist policymakers in selecting appropriate urine-testing thresholds and in educating individuals about the risks of testing positive following different patterns of cannabis use.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108142"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146219613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiota and their metabolites in stroke: From mechanistic study toward therapeutic perspectives","authors":"Ao Shang ,&nbsp;Jiangang Shen","doi":"10.1016/j.phrs.2026.108147","DOIUrl":"10.1016/j.phrs.2026.108147","url":null,"abstract":"<div><div>Stroke is a medical emergency with high incidence, mortality, disability rate, and multiple complications, which place a serious burden on families and society. Clinically, gastrointestinal dysfunction has been observed in a significant percentage of stroke patients, suggesting that gut microbiota may be a viable target for stroke prevention and therapy. In this review, we summarized the alterations in the intestinal environment following stroke across clinical and preclinical models, highlighting the changes in the major bacterial communities, including <em>Bacteroidetes</em>, <em>Firmicutes</em>, <em>Proteobacteria</em> and <em>Actinomycetota</em>, etc. Considering the connection between the brain-gut axis, we discussed the therapeutic potential for treating ischemic stroke by modulating the gut microbiota, including protection of the blood-brain barrier (BBB) and the intestinal barrier, as well as the application of fecal microbiota transplantation (FMT). Furthermore, we highlighted the main mechanisms of regulating gut microbiota to improve stroke outcomes, involving intestinal metabolites such as short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and phenylacetylglutamine (PAGln), endotoxin, hormones, and amino acids, as well as factors related to immunity, inflammation, and oxidative stress. Finally, we summarized potential targeted therapeutic approaches, such as natural small molecules, engineered probiotics, and bile acid-nanoparticles, etc. Collectively, these insights support the gut microbiota as a promising target for mitigating stroke risk, attenuating acute injury, and enhancing recovery.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108147"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From gasotransmitter to therapeutic insight: Unraveling the role of H₂S in the gut-liver axis during NAFLD","authors":"Huimin Kang ,&nbsp;Yongjia Feng ,&nbsp;Baodong Wang ,&nbsp;Zheng Chen ,&nbsp;Jingya Li ,&nbsp;Zhiyun Chen","doi":"10.1016/j.phrs.2026.108108","DOIUrl":"10.1016/j.phrs.2026.108108","url":null,"abstract":"<div><div>Non-alcoholic fatty liver disease (NAFLD) is a widespread chronic liver condition with intricate pathogenesis and poses substantial challenges for clinical management. The gut-liver axis is integral to the pathogenesis of NAFLD, and hydrogen sulfide (H₂S), a gaseous signaling molecule, offers novel insights into its pathophysiology. This review investigates the characteristics of H₂S within the gut and liver at the gut-liver axis level, examines the role of gut-liver interactions in NAFLD, and evaluates the potential function of H₂S as a crucial link in the pathogenesis of NAFLD via the gut-liver axis. By analyzing the role of H₂S within the gut-liver axis, this review highlights its potential therapeutic value in NAFLD, thereby providing a critical theoretical foundation for advancing the understanding of NAFLD's pathophysiological mechanisms and the development of novel targeted therapies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108108"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pain signaling via sensory neurons drives breast cancer progression through neuropeptide release and κ-opioid counter-regulation","authors":"Hitoshi Makabe ,&nbsp;Michiko Narita ,&nbsp;Yasuyuki Nagumo ,&nbsp;Masanori Fujiwara ,&nbsp;Yusuke Hamada ,&nbsp;Jion Takise ,&nbsp;Takumi Yoshizawa ,&nbsp;Sakura Sano ,&nbsp;Shin Iizuka ,&nbsp;Eri Asaba ,&nbsp;Yukari Suda ,&nbsp;Tomohisa Mori ,&nbsp;Tsuyoshi Saitoh ,&nbsp;Hiroshi Nagase ,&nbsp;Vivianne L. Tawfik ,&nbsp;Shigehiro Yagishita ,&nbsp;Akinobu Hamada ,&nbsp;Kan Yonemori ,&nbsp;Shin Takayama ,&nbsp;Masayuki Yoshida ,&nbsp;Minoru Narita","doi":"10.1016/j.phrs.2026.108113","DOIUrl":"10.1016/j.phrs.2026.108113","url":null,"abstract":"<div><div>Severe pain in patients with breast cancer is associated with poorer survival outcomes, yet the mechanisms linking nociceptive signaling to tumor progression remain unclear. In a clinical cohort, breast cancer patients whose moderate or severe pain improved under specialized palliative care exhibited significantly longer survival than those with persistent pain. Serum levels of calcitonin gene-related peptide (CGRP) and substance P (SP), neuropeptides that can be released from sensory neurons, were elevated in breast cancer patients with uncontrolled pain, correlating positively with pain intensity and negatively with overall survival. <em>In vitro</em>, supernatants from depolarized human iPSC-derived sensory neurons containing CGRP, SP, and the endogenous κ-opioid receptor (KOR) ligand dynorphin attenuated docetaxel efficacy, promoted epithelial-mesenchymal transition, and enhanced migration in human triple-negative breast cancer (TNBC) cells, accompanied by Gi protein-coupled activation of the PI3K-Akt signaling pathway. <em>In vivo</em>, optogenetic activation of sensory neurons significantly accelerated tumor growth following orthotopic transplantation of murine TNBC cells, whereas combined blockade of CGRP and SP receptors suppressed this effect. Similarly, in patient-derived xenograft models of TNBC, dual receptor blockade effectively abrogated tumor progression. Conversely, <em>in vitro</em> treatment with dynorphin enhanced the cytotoxic efficacy of docetaxel, accompanied by the inhibition of PI3K-Akt signaling, whereas <em>in vivo</em> administration of the peripherally restricted KOR agonist nalfurafine methiodide markedly suppressed tumor growth. These findings establish a bidirectional neural-tumor axis in breast cancer progression. Therapeutically, combined blockade of CGRP/SP signaling with peripheral KOR agonism may present a novel strategy to enhance chemotherapy efficacy in TNBC patients.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108113"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pevonedistat targeting NEDDylation activating enzyme for human diseases: Underlying mechanisms, clinical studies, and future directions","authors":"Dong-Jun Fu,&nbsp;Yu-Jie Wu,&nbsp;Cong Chen,&nbsp;Cai Zhang,&nbsp;Ze-Qi Su,&nbsp;Ting Wang","doi":"10.1016/j.phrs.2026.108134","DOIUrl":"10.1016/j.phrs.2026.108134","url":null,"abstract":"<div><div>NEDDylation is a crucial post-translational modification wherein the ubiquitin-related molecule NEDD8 is added to lysine residues in substrate proteins via a stepwise enzymatic cascade with the participation of the NEDDylation activating enzyme (NAE, E1), E2 conjugating enzymes, and E3 ligases. Many significant proteins in the NEDDylation process are highly expressed in several human diseases, and suppression of NEDDylation is an attractive strategy to develop novel therapeutic drugs for these diseases. Although a variety of small-molecule inhibitors targeting NEDDylation have been discovered, pevonedistat (also known as MLN4924) is the only NEDDylation inhibitor to date to enter phase III clinical trials. Moreover, many preclinical studies and over 40 clinical trials have fully investigated the potential therapeutic effects of pevonedistat, which has been proven safe for human diseases. A literature search was conducted in X-mol, Web of Science and PubMed, and the keywords to retrieve the literature were pevonedistat and MLN4924. Stepwise enzymatic cascades involved in the NEDDylation process and specific mechanisms underlying pevonedistat binding to NAE were investigated. Crucially, this review also details the research progress of pevonedistat, including the discovery process and design strategies. Through the inhibition of NEDDylation pathway, pevonedistat can alleviate various human diseases, including cancers, metabolic diseases, viral diseases, neurological disorders, cardiac diseases, and autoimmune diseases. Review offers new perspectives for the future research on pevonedistat. By a systematic understanding of relevant findings, this review highlights the immense potential of pevonedistat for human diseases and facilitates the promotion of targeting NEDDylation as a new and effective therapeutic strategy.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108134"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}