British Journal of Pharmacology最新文献

{"title":"Recent innovations in targeting redox biology for therapeutics.","authors":"Miriam M Cortese-Krott, Jon M Fukuto, Amrita Ahluwalia","doi":"10.1111/bph.70156","DOIUrl":"https://doi.org/10.1111/bph.70156","url":null,"abstract":"<p><p>Redox signalling governs key physiological and pathological processes, offering diverse therapeutic targets across disease contexts. This editorial introduces a special issue of the British Journal of Pharmacology highlighting recent advances in redox biology, including novel small molecules, non-canonical nitric oxide and hydrogen sulfide pathways, epigenetic modulation and immune regulation. Together, these contributions illustrate the translational potential of redox-targeted pharmacology and outline future directions for innovation in the field.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943695","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":"E3 ubiquitin ligase Pellino1 suppresses acinar cell necroptosis and alleviates severe acute pancreatitis by promoting ubiquitin-dependent receptor-interacting protein kinase 3 (RIP3) degradation.","authors":"Jiatong Chen, Zhiwei Huang, Pei Jing, Hao Shi, Shenglu Liu, Lu Feng, Yang Long, Mingxin Ye, Wenguang Fu, Peng Tan","doi":"10.1111/bph.70175","DOIUrl":"https://doi.org/10.1111/bph.70175","url":null,"abstract":"<p><strong>Background and purpose: </strong>Severe acute pancreatitis (SAP) is a critical abdominal condition with high mortality rates. The activation of necroptosis in acinar cells is an critical mechanism for SAP. Pellino1 (PELI1), as an E3 ubiquitin ligase, is involved in pathogenic mechanisms in various diseases. Its ubiquitination function also can regulate necroptosis. However, in SAP, there is a lack of research on upstream regulatory mechanisms and small molecule-targeted drug therapy of necroptosis. Therefore, it is of great significance to study the specific mechanism of PELI1 regulating necroptosis in SAP.</p><p><strong>Experimental approach: </strong>We designed animals and cells with overexpression and knockdown of PELI1 to study the role of PELI1 in SAP, detect the ubiquitination regulatory mechanism of PELI1 on necroptosis and explore the therapeutic effect of GSK-872 in SAP models in vitro and in vivo.</p><p><strong>Key results: </strong>We revealed that PELI1 expression was significantly down-regulated in SAP mouse models and in vitro SAP cell models. Additionally, the overexpression experiments at the cellular and animal levels confirmed the protective effect of PELI1 in SAP and its negative regulatory effect on necroptosis. Mechanistically, our investigation identified that PELI1 degraded RIP3 through K48-linked ubiquitination to inhibit necroptosis, and thereby promote acinar cell activity. Furthermore, we found that GSK-872 effectively inhibited necroptosis and alleviated pancreatic damage in SAP.</p><p><strong>Conclusions and implications: </strong>Our findings highlight the protective role of PELI1-mediated ubiquitination-dependent proteasomal degradation of RIP3 in SAP and propose pharmacological inhibition of RIP3 as a promising strategy to combat SAP.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943690","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":"In silico, in vitro and ex vivo characterization of cystic fibrosis transmembrane conductance regulator pathogenic variants localized in the fourth intracellular loop and their rescue by modulators.","authors":"Emanuela Pesce, Valeria Tomati, Valeria Capurro, Mariateresa Lena, Cristina Pastorino, Miro Astore, Serdar Kuyucak, Benoit Chevalier, Elvira Sondo, Federico Cresta, Alice Dighero, Vito Terlizzi, Cristina Fevola, Stefano Costa, Maria Cristina Lucanto, Valeria Daccò, Laura Claut, Francesca Ficili, Benedetta Fabrizzi, Renata Bocciardi, Federico Zara, Carlo Castellani, Luis J V Galietta, Shafagh A Waters, Alexandre Hinzpeter, Nicoletta Pedemonte","doi":"10.1111/bph.70176","DOIUrl":"10.1111/bph.70176","url":null,"abstract":"<p><strong>Background and purpose: </strong>Cystic fibrosis (CF) is due to loss-of-function variants of the CF transmembrane conductance regulator (CFTR) channel. The most effective treatment for people with CF carrying the F508del mutation is the triple combination of elexacaftor-tezacaftor-ivacaftor (ETI). ETI can correct the underlying defect(s) in other CFTR mutants. The use of disease-relevant predictive models such as patient-derived human nasal epithelial cells allow to investigate the response to CFTR modulators of specific genotypes, possibly supporting patients' access to treatment.</p><p><strong>Experimental approach: </strong>Using computational, biochemical and functional methodologies, a detailed analysis of selected variants in the intracellular loop 4 (ICL4) to understand their impact on CFTR structure and function.</p><p><strong>Key results: </strong>Mutations affecting L1065, R1066 and L1077 compromise structural stability of CFTR. Analyses of single variants expressed heterologously in immortalized bronchial cells showed that, upon ETI, rescued activity for both L1065P and R1066C was close to 50% of the wild-type CFTR activity. Biochemical studies of ICL4 variants expression pattern in CFBE41o-cells, following treatment for 24 h, demonstrate the appearance of the mature, fully glycosylated band, with no changes in the immature band. Finally, our study provides evidence in primary nasal cells from a cohort of people with CF that L1065P and R1066C can be effectively rescued by ETI up to 25%-45% of the activity measured in non-CF epithelia.</p><p><strong>Conclusion and implications: </strong>Although the observed rescue for L1065P and R1066C was smaller than that of the F508del, it should fall in a range predicted, by various studies, to provide a clinical benefit.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882157","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":"Elucidation of the zinc binding site in KCNQ channels.","authors":"Shuo Zhang, Xinhe Yang, Meng Yang, Yixue Cao, Sai Shi, Nikita Gamper, Haixia Gao","doi":"10.1111/bph.70177","DOIUrl":"10.1111/bph.70177","url":null,"abstract":"<p><strong>Background and purpose: </strong>KCNQ1-5 (Kv7.1-7.5) are members of a family of voltage-gated potassium channels with prominent function in the nervous and cardiovascular systems and in epithelia. KCNQ channels are activated by intracellular free zinc, but the molecular mechanism of this effect is poorly understood and zinc binding sites within KCNQ channels are elusive.</p><p><strong>Experimental approach: </strong>We used patch-clamp electrophysiology, site-directed mutagenesis and computational biology to investigate the action of zinc on KCNQ1 and its complexes with KCNE1 or KCNE3 auxiliary subunits.</p><p><strong>Key results: </strong>Zinc ionophores, zinc pyrithione (ZnPy) and pyrrolidinedithiocarbamate (PDTC), potently activated homotetrameric KCNQ1 channels. In contrast, heteromeric KCNQ1/KCNE1 and KCNQ1/KCNE3 channels were partially inhibited by ZnPy. Focussing on this difference, we identified a putative zinc coordination site in close proximity to the KCNQ1-KCNE interface and a binding site for the KCNQ channel cofactor, phosphatidylinositol 4,5-bisphosphate (PIP₂). The zinc coordination site in KCNQ1 contains histidines H126 and H240, and glutamic acid E170. Additional aspartic acid D242 acts as an effector site in coupling zinc binding with channel activation. The site is partially conserved with other KCNQ subunits, although the role of D242 appears to be unique for KCNQ1.</p><p><strong>Conclusions and implications: </strong>Our findings reveal a new structural modality for ligand-induced activation of an important potassium channel, which can be harnessed for development of KCNQ-targeting pharmaceutics.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882155","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":"Exploiting PP2A dependent and independent effects of forskolin for therapeutic targeting of KMT2A (MLL)-rearranged acute leukaemia.","authors":"Yoana Arroyo-Berdugo, Antonella Di Mambro, Volker Behrends, Michelle A Sahai, Luca Cozzuto, Immacolata Zollo, Julia Ponomarenko, Owen Williams, John Gribben, Yolanda Calle, Bela Patel, Maria Teresa Esposito","doi":"10.1111/bph.70158","DOIUrl":"10.1111/bph.70158","url":null,"abstract":"<p><strong>Background and purpose: </strong>Activation of Protein Phosphatase 2A (PP2A), via genetic and pharmacologic modulation of SET, has recently being identified as a promising strategy to therapeutically target acute myeloid leukaemia (AML) carrying KMT2A (MLL) chromosomal translocations (KMT2A-r AML).</p><p><strong>Experimental approach: </strong>In this study, we investigated the expression of PP2A subunits and the therapeutic potential of forskolin, a cyclic adenosine monophosphate (cAMP) elevating natural compound that has been reported as a PP2A activator.</p><p><strong>Key results: </strong>Our data show that PPP2CA encoding protein phosphatase 2 catalytic subunit α is abundantly expressed in KMT2A-r AML cells. Treatment with forskolin arrests proliferation; induces cell death; represses the expression of MYC, HOXA9 and HOXA10; stimulates PP2A activity; and attenuates the activity of ERK1/2 in KMT2A-r AML cells. Forskolin increases sensitivity to standard-of-care daunorubicin in KMT2A-AML cell lines and PDX. Silencing PPP2CA partially rescues the cytotoxic effect of forskolin, stimulates ERK1/2, inhibits GSK3β, and abolishes the forskolin-mediated repression of c-MYC and HOXA10, but it did not affect the potentiation of response to daunorubicin. This effect was also not dependent on increase of cAMP, but it was because of increase in the intracellular accumulation of daunorubicin, through inhibition of drug efflux pump P-glycoprotein 1 (multidrug resistance protein).</p><p><strong>Conclusions and implications: </strong>In conclusion, our findings highlight a novel mechanism of action for forskolin and support a potential role of this natural compound in combination with current conventional agent daunorubicin in the treatment of KMT2A-r AML.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144882156","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":"Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitors reduce vascular inflammation in vitro and in vivo.","authors":"Hiba Chaudhry, Ali A Zarban, Silvia Cellone Trevelin, Xenia Kodji, Camilla Cerutti, Xiaoqing Xiong, Fulye Argunhan, Ajay M Shah, Anne J Ridley, Susan D Brain","doi":"10.1111/bph.70152","DOIUrl":"10.1111/bph.70152","url":null,"abstract":"<p><strong>Background and purpose: </strong>Endothelial cells play central roles in increasing vascular permeability and leukocyte recruitment. Therapeutic approaches for treating endothelial cell barrier dysfunction to reduce unwanted fluid accumulation in tissues are limited. Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) enzymes are implicated in signalling inflammatory endothelial permeability and leukocyte recruitment. We investigated the ability of PI3K inhibitors to influence cutaneous oedema formation and neutrophil accumulation.</p><p><strong>Experimental approach: </strong>We used cultured endothelial cells to determine the effects of inflammatory mediators on permeability and vascular leakage, and a murine model of vascular inflammation in mouse skin in vivo. The effects of inflammatory mediators that induce vascular leakage and neutrophil accumulation (TNFα, IL-1β and C5a) were examined, with the neuropeptides substance P and α-CGRP used as controls. The ability of PI3K inhibitors to modulate inflammatory responses was studied.</p><p><strong>Key results: </strong>A broad spectrum PI3K inhibitor (PI-103) and a selective inhibitor of the class 1A p110α catalytic subunit (BYL-719/alpelisib) inhibited endothelial morphological changes and permeability induced by TNFα and IL-1β in vitro. In vivo, oedema and neutrophil accumulation induced by TNFα and IL-1β, but not by the complement fragment C5a, is inhibited by BYL-719, whereas PI-103 blocks effects of all three mediators. Neither influences the acute oedema formation induced by neuropeptides.</p><p><strong>Conclusions and implications: </strong>Selective p110α inhibition of vascular inflammation may provide a novel therapeutic pathway for limiting adverse tissue swelling. Moreover, the limited effect of BYL-719 on C5a-mediated responses implies that this innate component of the immune response will continue to provide essential defence activity during p110α blockade.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871561","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":"Activation of peripheral NOP receptors reduces periorbital mechanical allodynia evoked by CGRP in mice.","authors":"Chiara Sturaro, Pietro Pola, Michela Argentieri, Alessia Frezza, Matilde Marini, Francesco De Logu, Valentina Albanese, Marie Soukupova, Davide Malfacini, Nurulain T Zaveri, Romina Nassini, Dane D Jensen, Pierangelo Geppetti, Girolamo Calò, Chiara Ruzza","doi":"10.1111/bph.70162","DOIUrl":"https://doi.org/10.1111/bph.70162","url":null,"abstract":"<p><strong>Background and purpose: </strong>Migraine is a neurovascular disorder largely mediated by calcitonin gene-related peptide (CGRP). This study explores the role of the nociceptin/orphanin FQ (N/OFQ)-N/OFQ receptor (NOP) system in CGRP-induced periorbital mechanical allodynia (PMA) in mice.</p><p><strong>Experimental approach: </strong>Male or female wild type (NOP(+/+)) and NOP receptor knockout (NOP(-/-)) mice and CD-1 mice were used. The brain penetrant, AT-403, and the peripherally restricted, UFP-112, NOP agonists were tested for PMA prevention. To identify a potential site of action at the cellular level, the ability of N/OFQ to signal at membrane and endosomal level in NOP-expressing HEK293 cells, and to inhibit the increase in cyclic adenosine monophosphate (cAMP) induced by CGRP in human Schwann cells (hSCs) was investigated.</p><p><strong>Key results: </strong>CGRP-induced PMA was comparable in NOP(+/+) and NOP(-/-) mice. AT-403 and UFP-112 equally reduced CGRP-evoked PMA in CD-1 mice. In NOP-expressing cells, activation of NOP resulted in the internalisation and movement of NOP away from the plasma membrane marker CAAX and to early endosomes marker Rab5a. N/OFQ stimulated G_αi recruitment to NOP at the plasma membrane and from the endosomal compartment. N/OFQ attenuated cAMP increase elicited by CGRP in hSCs.</p><p><strong>Conclusions and implications: </strong>The peripherally restricted NOP agonist showed efficacy similar to the brain-penetrant compound, indicating that peripheral NOP activation is sufficient to alleviate CGRP-evoked PMA. Despite NOP ability to halt Gα_i recruitment and cAMP increase in cells, further studies are required to confirm that SCs are the cellular site where N/OFQ operates to attenuate the CGRP pro-migraine action.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858933","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":"Rethinking preclinical models in drug-resistant epilepsy: From seizures to side effects all at once","authors":"Emilio Russo","doi":"10.1111/bph.70182","DOIUrl":"10.1111/bph.70182","url":null,"abstract":"&lt;p&gt;C&lt;b&gt;ommentary&lt;/b&gt; on “Challenging the preclinical paradigm: Adverse effects of antiseizure medicines in male rats with drug-resistant epilepsy” by Guignet et al., &lt;i&gt;British Journal of Pharmacology&lt;/i&gt; (&lt;span&gt;2025&lt;/span&gt;); doi: 10.1111/bph.70076.&lt;/p&gt;&lt;p&gt;Drug-resistant epilepsy (DRE) remains a major unmet need in the area of epilepsy research (Chen et al., &lt;span&gt;2018&lt;/span&gt;); it affects nearly one-third of people with epilepsy despite the availability of over 30 antiseizure medications (ASMs), with most being authorized in the last 25 years (Chen et al., &lt;span&gt;2018&lt;/span&gt;). The persistence of this clinical burden raises critical questions about the translational validity of preclinical models traditionally employed in the discovery and evaluation of ASMs. This study by Guignet et al. (&lt;span&gt;2025&lt;/span&gt;), and others from the same group (Barker-Haliski &amp; White, &lt;span&gt;2020&lt;/span&gt;), further underline this problem while proposing and executing a paradigm change in how ASMs should be evaluated in animal models. Specifically, here, the first shift in the preclinical approach is based on moving from acute seizure induction in neurologically intact animals to chronic drug exposure in disease-relevant models that more accurately mimic human pharmaco-resistance (Guignet et al., &lt;span&gt;2025&lt;/span&gt;).&lt;/p&gt;&lt;p&gt;Furthermore, this study addresses a crucial gap in epilepsy research: the inadequacy of existing preclinical methodologies to predict efficacy and tolerability of ASMs in drug-resistant forms of epilepsy at the same time. In conventional screening models such as the maximal electroshock seizure (MES) and pentylenetetrazol (PTZ) tests, seizures are acutely evoked in otherwise healthy rodents, and compounds are evaluated for their ability to suppress these events. While these models are efficient in screening for antiseizure potential, they fail to capture the chronic and multifaceted nature of epilepsy, particularly the pathophysiological, pharmacokinetic and pharmacodynamic complexities inherent in DRE.&lt;/p&gt;&lt;p&gt;Guignet and colleagues present a refined approach using a kainic acid-induced status epilepticus model leading to spontaneous seizures, a well-established and widely used model of temporal lobe epilepsy in rodents. They administer ASMs via a chronic, steady-state oral dosing regimen embedded within food pellets, mimicking patients' real-world treatment. They further integrate continuous video-EEG monitoring, pharmacokinetic profiling and behavioural tolerability assessments, which are often neglected in preclinical epilepsy research but relevant for a meaningful clinical translation.&lt;/p&gt;&lt;p&gt;Three widely used ASMs (carbamazepine [CBZ], levetiracetam [LEV], and lamotrigine [LTG]) were tested in a cross-over design, allowing each animal to serve as its own control. This design is elegant and statistically robust, reducing inter-animal variability and allowing direct comparisons across treatments and doses. By including therapeutic drug monitoring, the ","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 21","pages":"5087-5089"},"PeriodicalIF":7.7,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70182","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to ‘P2Y14 receptor activation of platelets induces Ca2+ mobilization and Rho-GTPase-dependent motility that requires an interaction with P2Y1 receptors’","authors":"","doi":"10.1111/bph.70172","DOIUrl":"10.1111/bph.70172","url":null,"abstract":"<p>\u0000 <span>Hossain, M. M.</span>, <span>Pan, D.</span>, <span>Arkless, K. L.</span>, <span>Rahman, K. M.</span>, <span>Page, C. P.</span>, <span>Authi, K. S.</span>, &amp; <span>Pitchford, S. C.</span> (<span>2025</span>). <span>P2Y₁₄ receptor activation of platelets induces Ca²⁺ mobilization and Rho-GTPase-dependent motility that requires an interaction with P2Y₁ receptors</span> <i>British Journal of Pharmacology</i>, <span>182</span>(<span>13</span>), <span>2950</span>–<span>2967</span>. https://doi.org/10.1111/bph.70024.</p><p>We apologize for this error.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 19","pages":"4732-4733"},"PeriodicalIF":7.7,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70172","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HMC ameliorates myocardial ischaemia-reperfusion injury through suppressing cuproptosis via the de-ubiquitination and stabilization of ATP7A.","authors":"Jia-Bao Su, You-Yi Zhuang, Ming-Heng Liu, Guo Chen, Min Wei, Bing-Xin Chen, Le Yang, Yun-Feng Ji, Chuan Zhu, Xue-Xue Zhu, Ji-Ru Zhang, Hai-Jian Sun","doi":"10.1111/bph.70171","DOIUrl":"https://doi.org/10.1111/bph.70171","url":null,"abstract":"<p><strong>Background and purpose: </strong>Myocardial ischaemia-reperfusion injury (MI/RI) is a major contributor to poor prognosis following revascularization in myocardial infarction patients, yet targeted therapies remain elusive. While hesperidin methyl chalcone (HMC) demonstrates antioxidant and vasoprotective properties, its role in modulating regulated cell death pathways during MI/RI is undefined. This study investigates the cardioprotective effects of HMC against MI/RI and its underlying mechanisms.</p><p><strong>Experimental approach: </strong>Hypoxia/reoxygenation (H/R) models in H9c2 cardiomyocytes and a model of MI/RI in mice were employed. The effects of HMC on cardiac performance, copper flux analysis, ubiquitination assays and molecular docking, mitochondrial integrity and cell death modalities in response to MI/RI were examined.</p><p><strong>Key results: </strong>HMC pretreatment exhibited significant cardioprotection, reducing infarct size and improving cardiac function in MI/RI mice. Mechanistically, HMC specifically attenuated cuproptosis, as evidenced by decreased copper overload and downregulation of cuproptosis effectors, mimicking the action of the copper chelator ammonium tetrathiomolybdate (ATTM). Crucially, the cuproptosis inducer elesclomol-Cu (Es-Cu) abolished the cardioprotective effects of HMC. Furthermore, HMC interacted with the E3 ubiquitin ligase MARCHF7, and disrupted the complex of MARCHF7/ATP7A, thereby reducing ubiquitination and proteasomal degradation of the copper exporter ATP7A. The stabilization of ATP7A enhanced copper efflux, alleviating cuproptosis, oxidative stress, inflammation and mitochondrial damage induced by MI/RI.</p><p><strong>Conclusions and implications: </strong>Our work unveils a ubiquitin-regulated copper homeostasis axis in MI/RI. By targeting MARCHF7-ATP7A interaction, HMC sustains copper export machinery to combat cuproptosis-driven injury. These findings position HMC as a novel therapeutic candidate for MI/RI through regulating ubiquitination-dependent regulation of copper homeostasis.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854693","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}