Pub Date : 2026-03-01Epub Date: 2026-02-20DOI: 10.1016/j.phrs.2026.108150
Sofia Parrasia , Carlotta Paoli , Tatiana Varanita , Valentina Brillo , Mostafa A.L. Abdel-Salam , Alberto Ongaro , Claudia Honisch , Beatrice Angi , Magdalena Bachmann , Filippo Bergamin , Vincenzo Corbo , Elena Fiorini , Andrea Rossa , Giovanna Bossio , Erich Gulbins , Alessandro Carrer , Mario Zoratti , Andrea Mattarei , Paolo Ruzza , Lucia Biasutto , Ildiko Szabo
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). In vivo 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.
{"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 , Carlotta Paoli , Tatiana Varanita , Valentina Brillo , Mostafa A.L. Abdel-Salam , Alberto Ongaro , Claudia Honisch , Beatrice Angi , Magdalena Bachmann , Filippo Bergamin , Vincenzo Corbo , Elena Fiorini , Andrea Rossa , Giovanna Bossio , Erich Gulbins , Alessandro Carrer , Mario Zoratti , Andrea Mattarei , Paolo Ruzza , Lucia Biasutto , 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}
Pub Date : 2026-03-01Epub Date: 2026-02-06DOI: 10.1016/j.phrs.2026.108132
Sara Sultana, Yang Xie, Mir Shahriar Kamal, Wei Li
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.
{"title":"Pathophysiological significance of the TRPM2 ion channel as a potential target in cancer, neurological disorders, and ischemia/reperfusion injury","authors":"Sara Sultana, Yang Xie, Mir Shahriar Kamal, 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 Ca<sup>2+</sup> 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}
Pub Date : 2026-03-01Epub Date: 2026-02-08DOI: 10.1016/j.phrs.2026.108133
Shuhui Li , Jingjing He , Huxidanmu Tuoheniyazi , Junrui Ma , Zhenyu Li , Juanjuan Zheng , Yuxin Wang , Xiupan Gao , Xiaobao Yang , Danping Liu , Yanan Zhao , Tongxuan Su , Yibing Peng , Dakang Xu , Xuefeng Fei
Clostridium difficile infection (CDI) is a leading cause of antibiotic-associated diarrhea and pseudomembranous colitis, and there remains a significant unmet need for therapies specifically targeting C. difficile. 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 Zbtb16 protects mice from C. difficile-induced colitis by attenuating IL-1β-dependent inflammatory signaling. Mechanistic studies revealed that Zbtb16 deletion disrupts ASC oligomerization and speck formation, thereby selectively inhibiting inflammasome assembly and reducing mature IL-1β production in macrophages stimulated with C. difficile 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.
{"title":"ZBTB16 controls the onset of Clostridium difficile colitis through the Pyrin inflammasome","authors":"Shuhui Li , Jingjing He , Huxidanmu Tuoheniyazi , Junrui Ma , Zhenyu Li , Juanjuan Zheng , Yuxin Wang , Xiupan Gao , Xiaobao Yang , Danping Liu , Yanan Zhao , Tongxuan Su , Yibing Peng , Dakang Xu , 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}
Pub Date : 2026-03-01Epub Date: 2026-02-16DOI: 10.1016/j.phrs.2026.108142
Danielle McCartney , Christopher Irwin , Jonathon C. Arnold , Rebecca Gordon , Andrew J. McLachlan , Iain S. McGregor
Urine testing is used in a variety of contexts to identify cannabis use. Most tests target 11-nor-9-carboxy-Δ⁹-tetrahydrocannabinol (11-COOH-THC), the terminal metabolite of Δ⁹-tetrahydrocannabinol (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. Typical workplace threshold (15 ng/mL total 11-COOH-THC): Low single doses (i.e., 1.0–5.0 mg) and very low repeated doses (i.e., <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. World Anti-Doping Agency (WADA) Decision Limit (180 ng/mL total 11-COOH-THC): 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.
{"title":"Urinary Δ9-tetrahydrocannabinol and metabolite concentrations following cannabis use: A systematic review","authors":"Danielle McCartney , Christopher Irwin , Jonathon C. Arnold , Rebecca Gordon , Andrew J. McLachlan , 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., <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}
Pub Date : 2026-03-01Epub Date: 2026-02-19DOI: 10.1016/j.phrs.2026.108147
Ao Shang , Jiangang Shen
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 Bacteroidetes, Firmicutes, Proteobacteria and Actinomycetota, 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.
{"title":"Gut microbiota and their metabolites in stroke: From mechanistic study toward therapeutic perspectives","authors":"Ao Shang , 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}
Pub Date : 2026-03-01Epub Date: 2026-01-23DOI: 10.1016/j.phrs.2026.108108
Huimin Kang , Yongjia Feng , Baodong Wang , Zheng Chen , Jingya Li , Zhiyun Chen
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.
{"title":"From gasotransmitter to therapeutic insight: Unraveling the role of H₂S in the gut-liver axis during NAFLD","authors":"Huimin Kang , Yongjia Feng , Baodong Wang , Zheng Chen , Jingya Li , 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}
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. In vitro, 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. In vivo, 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, in vitro treatment with dynorphin enhanced the cytotoxic efficacy of docetaxel, accompanied by the inhibition of PI3K-Akt signaling, whereas in vivo 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.
{"title":"Pain signaling via sensory neurons drives breast cancer progression through neuropeptide release and κ-opioid counter-regulation","authors":"Hitoshi Makabe , Michiko Narita , Yasuyuki Nagumo , Masanori Fujiwara , Yusuke Hamada , Jion Takise , Takumi Yoshizawa , Sakura Sano , Shin Iizuka , Eri Asaba , Yukari Suda , Tomohisa Mori , Tsuyoshi Saitoh , Hiroshi Nagase , Vivianne L. Tawfik , Shigehiro Yagishita , Akinobu Hamada , Kan Yonemori , Shin Takayama , Masayuki Yoshida , 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}
Pub Date : 2026-03-01Epub Date: 2026-02-11DOI: 10.1016/j.phrs.2026.108134
Dong-Jun Fu, Yu-Jie Wu, Cong Chen, Cai Zhang, Ze-Qi Su, Ting Wang
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.
泛素酰化修饰是一种重要的翻译后修饰，泛素相关分子NEDD8在泛素酰化激活酶（NAE, E1）、E2偶联酶和E3连接酶的参与下，通过逐步的酶级联被添加到底物蛋白的赖氨酸残基上。在一些人类疾病中，许多重要的类neddyation蛋白都是高表达的，抑制类neddyation是开发治疗这些疾病的新药物的一个有吸引力的策略。尽管已经发现了多种靶向NEDDylation的小分子抑制剂，pevonedistat（也称为MLN4924）是迄今为止唯一进入III期临床试验的NEDDylation抑制剂。此外，许多临床前研究和40多项临床试验已经充分调查了佩维那司特的潜在治疗效果，它已被证明对人类疾病是安全的。在X-mol、Web of Science和PubMed中进行文献检索，检索关键词为pevonedistat和MLN4924。研究了参与neddyylation过程的逐步酶级联反应和pevonedistance与NAE结合的具体机制。重要的是，本文还详细介绍了pevonedistat的研究进展，包括发现过程和设计策略。通过抑制NEDDylation通路，pevonedistat可以缓解多种人类疾病，包括癌症、代谢性疾病、病毒性疾病、神经系统疾病、心脏疾病和自身免疫性疾病。综述为今后的研究提供了新的视角。通过对相关发现的系统理解，本综述强调了培酮远地治疗人类疾病的巨大潜力，并促进了靶向NEDDylation作为一种新的有效治疗策略的推广。
{"title":"Pevonedistat targeting NEDDylation activating enzyme for human diseases: Underlying mechanisms, clinical studies, and future directions","authors":"Dong-Jun Fu, Yu-Jie Wu, Cong Chen, Cai Zhang, Ze-Qi Su, 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}
Gastric cancer (GC) is a leading cause of cancer mortality due to late diagnosis, metastasis, and therapy resistance. Epigenetic modifications rewire the cytokine network, facilitating the development, progression, and chemoresistance of GC. Cytokines regulate immune and inflammatory responses through various pathways, including the IL-6/JAK/STAT pathway, MAP Kinase, NF-κB signaling, IL-8/NF-κB, and the TGF-β axis, which sustain persistent inflammation and oncogenic signaling. The expression of these regulatory molecules is tightly controlled by epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and miRNA sponging. In addition, this is influenced by long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), which impact the tumor microenvironment and tumor survival. H. pylori and EBV further remodel cytokine epigenetic networks, promoting tumor progression. LncRNA and circRNAs can play dual roles, acting as both oncogenic and tumor-suppressive agents, where oncogenic ncRNAs, via drug efflux, apoptosis inhibition, autophagy, PD-L1 stabilization, and CSC maintenance, whereas tumor-suppressive ncRNAs restore chemosensitivity and antitumor immunity by reactivating PTEN, MHC-I, and apoptosis, proving to be promising biomarkers and therapeutic targets. Various clinical trials are also discussed in this review.
{"title":"Cytokine epigenetics network for gastric cancer progression and chemoresistance","authors":"Ganji Purnachandra Nagaraju , Seema Kumari , Mundla Srilatha , Irina Nakashidze , Bassel F. El-Rayes","doi":"10.1016/j.phrs.2026.108136","DOIUrl":"10.1016/j.phrs.2026.108136","url":null,"abstract":"<div><div>Gastric cancer (GC) is a leading cause of cancer mortality due to late diagnosis, metastasis, and therapy resistance. Epigenetic modifications rewire the cytokine network, facilitating the development, progression, and chemoresistance of GC. Cytokines regulate immune and inflammatory responses through various pathways, including the IL-6/JAK/STAT pathway, MAP Kinase, NF-κB signaling, IL-8/NF-κB, and the TGF-β axis, which sustain persistent inflammation and oncogenic signaling. The expression of these regulatory molecules is tightly controlled by epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and miRNA sponging. In addition, this is influenced by long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), which impact the tumor microenvironment and tumor survival. <em>H. pylori</em> and EBV further remodel cytokine epigenetic networks, promoting tumor progression. LncRNA and circRNAs can play dual roles, acting as both oncogenic and tumor-suppressive agents, where oncogenic ncRNAs, via drug efflux, apoptosis inhibition, autophagy, PD-L1 stabilization, and CSC maintenance, whereas tumor-suppressive ncRNAs restore chemosensitivity and antitumor immunity by reactivating PTEN, MHC-I, and apoptosis, proving to be promising biomarkers and therapeutic targets. Various clinical trials are also discussed in this review.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108136"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195368","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}
Pub Date : 2026-03-01Epub Date: 2026-02-16DOI: 10.1016/j.phrs.2026.108143
Yirui Wang , Jiahui Ni , Guize Feng , Yan You , Keyuan You , Weilian Bao , Tongqing Chen , Lijie Zhang , Xinyue Cao , Xu Wang , Yuran Huang , Hong Li , Zhiwen Yang , Yuan Qi , Xiaoyan Shen
Dysplasia has been described in various inflammatory environments. However, the mechanisms underlying the dysplastic transformation of the intestinal epithelium and the increased risk of colorectal cancer in colitis patients are not yet fully understood. In this study, we observed that IL-10 was negatively correlated with aberrant proliferation and differentiation of colonic epithelium in colitis patients. Deficiency of myeloid IL-10 resulted in a marked accumulation of intestinal myeloid-derived suppressor cells (MDSCs) and colitis-associated dysplasia, which could be mitigated by intra-bone marrow injection of AAV9-mIL-10. Mechanistically, IL-10-deficient monocytic-MDSCs (M-MDSCs) displayed a distinct pro-inflammatory phenotype with unique metabolic properties characterized by HIF-1α overexpression-induced vibrant glycolysis. This metabolic shift was accompanied by DLL4 transcription through direct binding to its promoter and subsequently skewed the differentiation of intestinal stem cells (ISCs) toward absorptive enterocytes, thereby potentially contributing to intestinal dysplasia. Furthermore, a small-molecule drug screen identified the plant flavonoid Sophoraflavanone G (SG) as a potential DLL4 antagonist, which attenuated the abnormal lineage differentiation of ISCs and ameliorated dysplasia in colitis by inhibiting Notch1 signaling pathway overactivation. Our study highlights a critical role of myeloid IL-10 in monocyte development and homeostasis maintenance of the intestinal epithelium, suggesting potential complementary therapeutic strategies for intestinal dysplasia in colitis patients.
不典型增生在各种炎症环境中都有描述。然而，结肠炎患者肠上皮发育不良转化和结直肠癌风险增加的机制尚不完全清楚。在本研究中，我们观察到IL-10与结肠炎患者结肠上皮的异常增殖和分化呈负相关。骨髓IL-10的缺乏导致肠髓源性抑制细胞（MDSCs）的显著积累和结肠炎相关的发育不良，这可以通过骨髓内注射AAV9-mIL-10来缓解。在机制上，il -10缺陷单核细胞mdscs （M-MDSCs）表现出独特的促炎表型，具有独特的代谢特性，其特征是HIF-1α过表达诱导的活跃糖酵解。这种代谢转变伴随着DLL4的转录，通过直接结合其启动子，并随后扭曲肠干细胞（ISCs）向吸收性肠细胞的分化，从而可能导致肠道发育不良。此外，一项小分子药物筛选发现，植物类黄酮sophorafavanone G （SG）是一种潜在的DLL4拮抗剂，它通过抑制Notch1信号通路的过度激活，减轻ISCs的异常谱系分化，改善结肠炎的发育不良。我们的研究强调了髓样IL-10在肠上皮单核细胞发育和稳态维持中的关键作用，提示结肠炎患者肠道发育不良的潜在补充治疗策略。
{"title":"Manipulating metabolism-reprogrammed monocytic-MDSCs prevents colitis-associated dysplasia by IL-10/HIF-1α/DLL4 signaling","authors":"Yirui Wang , Jiahui Ni , Guize Feng , Yan You , Keyuan You , Weilian Bao , Tongqing Chen , Lijie Zhang , Xinyue Cao , Xu Wang , Yuran Huang , Hong Li , Zhiwen Yang , Yuan Qi , Xiaoyan Shen","doi":"10.1016/j.phrs.2026.108143","DOIUrl":"10.1016/j.phrs.2026.108143","url":null,"abstract":"<div><div>Dysplasia has been described in various inflammatory environments. However, the mechanisms underlying the dysplastic transformation of the intestinal epithelium and the increased risk of colorectal cancer in colitis patients are not yet fully understood. In this study, we observed that IL-10 was negatively correlated with aberrant proliferation and differentiation of colonic epithelium in colitis patients. Deficiency of myeloid IL-10 resulted in a marked accumulation of intestinal myeloid-derived suppressor cells (MDSCs) and colitis-associated dysplasia, which could be mitigated by intra-bone marrow injection of AAV9-mIL-10. Mechanistically, IL-10-deficient monocytic-MDSCs (M-MDSCs) displayed a distinct pro-inflammatory phenotype with unique metabolic properties characterized by HIF-1α overexpression-induced vibrant glycolysis. This metabolic shift was accompanied by DLL4 transcription through direct binding to its promoter and subsequently skewed the differentiation of intestinal stem cells (ISCs) toward absorptive enterocytes, thereby potentially contributing to intestinal dysplasia. Furthermore, a small-molecule drug screen identified the plant flavonoid Sophoraflavanone G (SG) as a potential DLL4 antagonist, which attenuated the abnormal lineage differentiation of ISCs and ameliorated dysplasia in colitis by inhibiting Notch1 signaling pathway overactivation. Our study highlights a critical role of myeloid IL-10 in monocyte development and homeostasis maintenance of the intestinal epithelium, suggesting potential complementary therapeutic strategies for intestinal dysplasia in colitis patients.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108143"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146219106","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}
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