British Journal of Pharmacology最新文献

{"title":"Pathway-level mutational signatures predict breast cancer outcomes and reveal therapeutic targets.","authors":"Máté Posta, Balázs Győrffy","doi":"10.1111/bph.70215","DOIUrl":"https://doi.org/10.1111/bph.70215","url":null,"abstract":"<p><strong>Background and purpose: </strong>In order to significantly improve the therapeutic treatment of breast cancer, the exploration of underlying genetic and molecular differences is absolutely necessary. Here, our goal was to integrate mutational status of entire pathways to reveal molecular pathway interactions determining survival.</p><p><strong>Experimental approach: </strong>A comprehensive analysis of breast cancer mutations was conducted by integrating data from three distinct databases with a total of 4586 samples encompassing over 25,000 genes. For each gene, we filtered mutations that disruptively affect the protein structure. Cox proportional hazard regression was employed to link altered pathways to outcome. We also identified the co-occurring and mutually exclusive disruptive mutations.</p><p><strong>Key results: </strong>We identified 17 genes, the mutation status of which alone seriously affects relapse-free survival. The three most significant genes were TP53 (HR: 2.04, p: 4.65 × 10^-33), CARD11 (HR: 2.59, p: 1.54 × 10^-5) and PIK3R1 (HR: 2.27, p: 3.66 × 10^-5). The five most significant biological processes and KEGG pathways affecting relapse-free survival include negative regulation of cell population proliferation, positive regulation of DNA-templated transcription, protein stabilisation, and MicroRNAs in cancer, hepatocellular carcinoma, and breast cancer. Co-mutation and mutual exclusivity analysis identified significant enrichment in 241 gene pairs. Finally, we also established an online platform to enable future analysis of the established cohort for any selected pathway.</p><p><strong>Conclusions and implications: </strong>We assembled a comprehensive database of breast cancer samples and used this cohort to identify cancer-specific disruptive mutation signatures linked to altered survival outcomes.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243751","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":"A quad-cistronic fluorescent biosensor system for real-time detection of subcellular Ca²⁺ signals.","authors":"Anna Lischnig, Yusuf C Erdoğan, Benjamin Gottschalk, Michael Gruber, Andrea Groselj-Strele, Sandra Burgstaller, Wolfgang F Graier, Roland Malli","doi":"10.1111/bph.70211","DOIUrl":"https://doi.org/10.1111/bph.70211","url":null,"abstract":"<p><strong>Background and purpose: </strong>The calcium ion (Ca²⁺) is a versatile cellular messenger regulating a variety of biological processes. Compounds modulating subcellular Ca²⁺ signals hold substantial pharmacological potential. Advances in fluorescent biosensors have revolutionised Ca²⁺ imaging. However, co-expression of targeted biosensors for simultaneous measurement of Ca²⁺ signals in multiple cellular compartments is still complicated by heterogeneous expression levels of the various sensors.</p><p><strong>Experimental approach: </strong>We developed the ribosomal skipping-based quad-cistronic fluorescent biosensor system CARMEN, enabling high-content Ca²⁺ imaging across three compartments. CARMEN allows proportional co-expression of spectrally distinct Ca²⁺ biosensors: the near-infrared Ca²⁺ biosensor for the cytosol (NIR-GECO2G-NES), the green Ca²⁺ biosensor for mitochondria (CEPIA3mt) and the red Ca²⁺ biosensor for the endoplasmic reticulum (R-CEPIA1er), along with a Ca²⁺-insensitive blue fluorescent protein targeted to the nucleus (NLS-mTagBFP2), serving as a normalisation reference.</p><p><strong>Key results: </strong>CARMEN allows spatiotemporal correlation of Ca²⁺ signals across the cytosol, endoplasmic reticulum and mitochondria, revealing distinct dynamics. We noted delayed mitochondrial Ca²⁺ uptake compared to the other compartments. We validated CARMEN across three cell types and tested two recently identified mitochondrial Ca²⁺ uniporter inhibitors (MCUis), MCUi4 and MCUi11, showcasing the potential of CARMEN for its application in pharmacological research. Our results show that while both MCUi4 and MCUi11 inhibited mitochondrial Ca²⁺ uptake in HeLa S3 cells, MCUi4 reduced cytosolic Ca²⁺ signals and oscillations, whereas MCUi11 had opposing effects.</p><p><strong>Conclusions and implications: </strong>CARMEN is a powerful tool for real-time, multiplexed analysis of compartment-specific Ca²⁺ signals, with the potential for automation in high-content drug screening.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211864","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":"Acetaminophen aggravates valproate-induced hepatic lipid accumulation and apoptosis by facilitating valproate retention.","authors":"Xiaoyun Liu, Anqin Li, Jie Wang, Luxin Pang, Jingwen Li, Luyong Zhang, Zhenzhou Jiang, Shusheng Fan","doi":"10.1111/bph.70214","DOIUrl":"https://doi.org/10.1111/bph.70214","url":null,"abstract":"<p><strong>Background and purpose: </strong>Hepatic steatosis is characteristic of valproate (VPA) induced hepatotoxicity. Drug-drug interactions of VPA and acetaminophen (APAP) have been associated with liver injury, but have not attracted sufficient attention. The present study aimed to elucidate the effect of VPA and APAP co-administration on liver lipid accumulation and apoptosis.</p><p><strong>Experimental approach: </strong>Liver lipid accumulation and apoptosis were studied in vivo and in vitro. The concentration of VPA and its metabolite 4-ene-VPA, as well as changes in free fatty acids (FFAs), were detected by liquid chromatography-mass spectrometry (LC-MS). Additionally, lipid accumulation and mitochondrial damage caused by VPA and 4-ene-VPA were evaluated in vitro.</p><p><strong>Key results: </strong>Liver lipid accumulation after VPA and APAP co-administration appeared earlier than liver injury in mice. VPA caused fatty acid accumulation by damaging mitochondria, increased triglyceride (TG) synthesis by up-regulating DGAT1/2 expression, and impaired TG transport by inhibiting expression of microsomal triglyceride transfer protein (MTTP). APAP inhibited the β-oxidation process by inhibiting CPT1α. During VPA and APAP co-administration, APAP inhibition of β-oxidation of VPA resulted in VPA retention and production of its toxic metabolite 4-ene-VPA, which caused further lipid accumulation and hepatocyte apoptosis.</p><p><strong>Conclusions and implications: </strong>VPA is the main factor contributing to intrahepatic lipid accumulation, but did not induce apoptosis of hepatocytes. APAP inhibited β-oxidation of VPA and caused VPA retention, which aggravated and prolonged the lipid accumulation and finally resulted in hepatocyte apoptosis. We provide evidence and guidance on the use of VPA and APAP in the clinic.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211781","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":"The potential for biased signalling in the P2Y receptor family of GPCRs.","authors":"Claudia M Sisk, Simon Pitchford, Graham Ladds","doi":"10.1111/bph.70213","DOIUrl":"https://doi.org/10.1111/bph.70213","url":null,"abstract":"<p><p>The purinergic receptor family is primarily activated by nucleotides, and contains members of both the G protein coupled-receptor (GPCR) superfamily (P1 and P2Y) and ligand-gated ion channels (P2X). The P2Y receptors are widely expressed in the human body, and given the ubiquitous nature of nucleotides, purinergic signalling is involved with a plethora of molecular physiological functions. The widespread nature of P2Y receptors make them a viable therapeutic target, but with the negative risk of on-target side effects. Some of the side effects associated with P1 and P2Y receptors arise due to the pleiotropic nature of many GPCRs, because a singular GPCR can activate several G proteins, as well as recruit β-arrestins. The utilisation of ligands that exhibit downstream pathway-specific activation, also known as biased signalling, at the P2Y receptors could circumvent these issues. This review will cover the signalling nature and impact of the P2Y family, with an emphasis on individual activity patterns of the P2Y receptors. This review also discusses current literature on the development of biased ligands for these receptors, with an aim to highlight the most beneficial targets and outcomes.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211784","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":"Resolution of inflammation in pulmonary arterial hypertension, the influence of sex-An IUPHAR immunopharmacology committee review.","authors":"Chloe Landy, Miles J De Blasio, Owen L Woodman, Pasquale Maffia, Hong Yong Peh, Cheng Xue Qin","doi":"10.1111/bph.70207","DOIUrl":"https://doi.org/10.1111/bph.70207","url":null,"abstract":"<p><p>Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease with limited treatment options. Sex differences are apparent in PAH, specifically in the pathophysiology, prognoses and pharmacological responses of patients. Inflammation and its resolution, which often differ between sexes, are dysregulated in chronic inflammatory conditions such as PAH. Inflammation is yet to be directly targeted by available PAH therapies despite its association with poor patient outcomes. Emerging research highlights the resolution of inflammation, an active process that restores tissue homeostasis, as a therapeutic avenue for treating chronic inflammatory diseases. This review encompasses the key pro-resolving ligands and G protein-coupled receptors involved in the active resolution of inflammation. We explore their dysregulation in PAH and evaluate their therapeutic potential, with a focus on how sex-specific immune responses may influence both preclinical findings and clinical outcomes. Signalling pathways involved in the resolution of inflammation present many therapeutically relevant targets for the development of novel PAH therapies.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205621","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":"Silencing the fibronectin gene (FN1) improves NaCl-induced cardiac fibrosis via ferritinophagy-mediated ferroptosis in a nuclear receptor coactivator 4 (NCOA4)-dependent manner.","authors":"Yawei Dai, Yong Li, Xiaoliang Yang, Yu Zhou, Yukang Mao, Yang Chuanxi, Peng Li, Kun Zhao","doi":"10.1111/bph.70205","DOIUrl":"https://doi.org/10.1111/bph.70205","url":null,"abstract":"<p><strong>Background and purpose: </strong>High-salt diet (HSD) induces heart damage, including cardiac fibrosis, independent of blood pressure. Exploring the underlying molecular mechanisms is of significant clinical value.</p><p><strong>Experimental approach: </strong>Male rats or neonatal rat cardiac fibroblasts (NRCFs) were treated with HSD or sodium chloride (NaCl) to induce cardiac fibrosis in vivo and in vitro, respectively. Exosome high-throughput sequencing was performed from exosomes isolated from culture supernatants of NRCFs treated with/without NaCl.</p><p><strong>Key results: </strong>First, HSD and NaCl induced myocardial fibrosis and ferroptosis in vivo and in vitro, respectively. The results of exosome high-throughput sequencing, along with validation experiments, showed that NaCl increased fibronectin gene (Fn1) expression via post-transcriptional regulation in NRCFs. Cardiac-specific silencing of Fn1attenuated HSD-induced cardiac fibrosis and ferroptosis, while Fn1 overexpression counteracted these effects. Also, GW4869-mediated exosome depletion reduced extracellular FN-1 but did not rescue NaCl-induced cardiac fibrosis. Moreover, silencing Fn1 inhibited NaCl-induced increase of nuclear receptor coactivator 4 (NCOA4). Fn1 loss exacerbated NCOA4 degradation. Next, inhibition of NOCA4-mediated ferritinophagy improved HSD-induced cardiac fibrosis, whereas NCOA4 overexpression hampered the antifibrotic effects of silencing Fn1in NaCl-induced NRCFs. Besides, autophagy inhibitor 3-MA ameliorated NaCl-induced cardiac fibrosis and ferroptosis, indicating that autophagy was essential for NCOA4-mediated ferroptosis.</p><p><strong>Conclusion and implications: </strong>Overall, our finding identified that silencing Fn1 possessed beneficial effects against NaCl-induced cardiac fibrosis through downregulating the ferroptosis of NRCFs, which was attributed to the inhibition of NOCA4-mediated ferritinophagy.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191155","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":"Optochemical modulation of corneal cold nerve terminal impulse activity with a photochromic ion channel blocker.","authors":"David Ares-Suárez, Almudena Iñigo-Portugués, Enrique Velasco, Susana Quirce, Fernando Aleixandre-Carrera, Ariadna Díaz-Tahoces, M Carmen Acosta, Wan-Chen Lin, Richard H Kramer, Carlos Belmonte, Juana Gallar, Victor Meseguer","doi":"10.1111/bph.70189","DOIUrl":"https://doi.org/10.1111/bph.70189","url":null,"abstract":"<p><strong>Background and purpose: </strong>The functional organization of corneal cold nerve endings, critical structures in maintaining the ocular surface, remains poorly understood. Here, the photoisomerizable small-molecule diethylamine-azobenzene-quaternary ammonium (DENAQ) was used to photomodulate activity of cold-sensing nerve terminals in control and chronic tear-deficient corneas. Furthermore, DENAQ was used for in vivo photochemical regulation of the thermally induced blink reflex.</p><p><strong>Experimental approach: </strong>Extracellular nerve terminal impulse activity was recorded on cold terminals in excised corneas of naïve and tear-deficient guinea pigs pre-incubated with DENAQ. Pulses of light at a wavelength of 460 nm were delivered to the perfused corneas. The thermally induced blink reflex was assessed using orbicularis oculi electromyography in anaesthetised rats after topical administration of DENAQ to the eye under blue light and darkness conditions.</p><p><strong>Key results: </strong>Exposure to blue light robustly reduced spontaneous activity of both naïve and tear-deficient cold nerve terminals pre-incubated with DENAQ, while cold-evoked responses remained unaffected. Pre-incubation of excised corneas with DENAQ, along with pharmacological P2X receptor antagonists, prevented the DENAQ-mediated photoreduction of the cold nerve terminal spontaneous activity. In addition, blue light increased cold-evoked reflex blink in eyes pre-treated with DENAQ.</p><p><strong>Conclusion and implications: </strong>DENAQ enters guinea pig cold sensory nerve endings primarily through P2X channels in excised corneas. Subsequently, DENAQ decreases the spontaneous nerve terminal impulse activity upon light irradiation by modulating voltage-gated potassium (K_V) channel activity. Furthermore, the cold-evoked blink reflex is modulated by light in DENAQ-treated eyes. Chemical photoswitches like DENAQ might be potential new treatments for ocular discomfort and pain in dry eye disease.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184621","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":"Oral administration of low-molecular-weight heparin ameliorates colitis by enhancing the gut mucus barrier via microbial tryptophan metabolites.","authors":"Dekai Zheng, Shuze Chen, Hanxiao Feng, Shaoheng Zhang, Cangui Zhang, Ying Wang, Weihao Tan, Qing Qing, Le Liu, Xiuying Liu, Zhi Wang, Liping Liang, Jian Sun, Ye Chen","doi":"10.1111/bph.70209","DOIUrl":"https://doi.org/10.1111/bph.70209","url":null,"abstract":"<p><strong>Background and purpose: </strong>Previous studies have reported that oral low-molecular-weight heparin (LMWH) ameliorated colitis by undefined mechanisms in ulcerative colitis (UC) patients. Our study explored the mechanisms of LMWH on colitis from the perspective of gut microbiota and its metabolites.</p><p><strong>Experimental approach: </strong>Dextran sulfate sodium (DSS; 2.5%) was used to induce colitis in mouse model, and LMWH was administered by either oral gavage, intracolonic delivery or subcutaneous injection to compare their therapeutic effects. Pseudo-germ-free mice was established by using antibiotic cocktail, and faecal microbial transplantation (FMT) was performed to verify the role of microbiota in LMWH actions. Alcian blue staining, fluorescence in situ hybridization of EUB338 and immunohistochemical staining were performed to evaluate the integrity of gut mucus barrier. Amplicon sequencing, transcriptome sequencing and untargeted metabolome studies were used to explore LMWH mechanisms. The ameliorating effect of indole-3-propionic acid (IPA) was verified in vitro and in vivo.</p><p><strong>Key results: </strong>Oral, but not subcutaneous, administration of LMWH alleviated colitis and enhanced the gut mucus barrier. Pseudo-germ-free mice and FMT assays confirmed that therapeutic effects of oral LMWH were dependent on gut microbiota. Oral LMWH increased Firmicutes abundance and decreased Escherichia/Shigella abundance, subsequently increasing microbial tryptophan metabolites, especially IPA. The protective effects of oral LMWH were reproduced by IPA supplementation, with mucus barrier enhancing through regulating the Wnt/β-catenin pathway.</p><p><strong>Conclusion and implications: </strong>The results provide new insights into the signalling mechanisms associated with the therapeutic potential of LMWH in colitis, and highlight the application of IPA for UC treatment.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184550","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":"Is there a role for cannabidiol in obesity, metabolic syndrome and binge eating?","authors":"Luca Botticelli, Emanuela Micioni Di Bonaventura, Giacomo Einaudi, Gustavo Provensi, Alessia Costa, Claudio D'Addario, Carlo Cifani, Maria Vittoria Micioni Di Bonaventura","doi":"10.1111/bph.70196","DOIUrl":"https://doi.org/10.1111/bph.70196","url":null,"abstract":"<p><p>Cannabidiol (CBD) is one of the most abundant phytocannabinoids isolated from the Cannabis sativa plant. CBD is a lipophilic, non-intoxicating substance that differently from Δ⁹-tetrahydrocannabinol (Δ⁹-THC) does not present the typical profile of a drug of abuse. It shows powerful anti-inflammatory and anti-oxidative properties that might be helpful for treating several pathologies. The aim of this review is to describe the potential role of CBD in the control of food intake and metabolism, with implications for the treatment of obesity and metabolic syndrome, and to discuss the underlying potential mechanisms of action. The preclinical evidence mentioned reveals that CBD influences eating behaviour, exerting anorexigenic effects and affecting the non-homeostatic aspect of food intake, via modulation of dopamine signalling in the brain reward system. Data from animal models of diet-induced obesity (DIO) and metabolic syndrome show that CBD improves glucose and lipid metabolism, inflammation and ameliorates psychiatric alterations not only in obese animals but also in the offspring born from obese mothers. These effects are achieved targeting multiple proteins expressed both in the central nervous system and peripheral tissues. The evidence collected from preclinical research, together with preliminary findings from clinical studies, supports further investigation of CBD in the context of obesity, metabolic syndrome and binge eating behaviour. Future studies are strongly required to highlight the potential role of CBD in these pathologies, specifically to better understand its mechanism of action, and how factors like sex differences, route of administration and formulation might influence the therapeutic activity of CBD.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145173453","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":"Nuclear factor, erythroid 2 like 2 (NRF2)-mediated disruption of iron homeostasis drives myocardial infarction progression.","authors":"Deepthy Jayakumar, Kishore Kumar S Narasimhan, Navvi Chandrasekar, Abinayaa Rajkumar, Gokulprasanth Panchalingam, Varsha C Ravikumar, Kalaiselvi Periandavan","doi":"10.1111/bph.70198","DOIUrl":"https://doi.org/10.1111/bph.70198","url":null,"abstract":"<p><strong>Background and purpose: </strong>Disruptions in iron homeostasis are a hallmark of myocardial infarction (MI). Recent studies have implicated NRF2, a key transcriptional regulator of antioxidant and detoxification genes, in the regulation of iron metabolism, particularly in murine models of hepatic iron overload. Emerging evidence suggests that the NRF2/hepcidin/ferroportin axis plays a central role in co-ordinating cardiac iron and redox homeostasis. However, the underlying mechanisms remain poorly understood.</p><p><strong>Experimental approach: </strong>In this study, we investigated the role of NRF2 in vivo using isoprenaline-induced MI and in vitro under cobalt chloride (CoCl₂)-induced hypoxia in H9c2 cardiomyocytes.</p><p><strong>Key results: </strong>Our results show that MI activates NRF2 signalling through increased nuclear NRF2 levels and upregulation of its downstream targets, accompanied by elevated hepcidin expression without ferroportin1 (IREG1) changes, suggesting enhanced iron sequestration in myocardial tissue and cardiomyocytes. We observed that iron regulatory protein 1 (IRP1) was significantly down-regulated while IRP2 was up-regulated in isoprenaline-treated myocardium and hypoxia-exposed H9c2 cells. In vivo brusatol administration ameliorated isoprenaline-induced cardiac remodelling, shown by reduced infarct size and ECG alterations. Transcriptomic analysis of MI rats with brusatol showed downregulation of pathways in cardiac remodelling, fibrosis, hypoxia, inflammation, iron/glutathione metabolism, necroptosis and ferroptosis. In H9c2 cardiomyocytes under hypoxic conditions, brusatol increased ferroportin1 expression, decreased hepcidin levels and reduced intracellular labile iron, inhibiting ferritinophagy and cardiomyocyte death.</p><p><strong>Conclusion: </strong>Together, our findings uncover a novel regulatory role for NRF2 in myocardial iron metabolism under stress conditions, highlighting potential therapeutic avenues targeting the NRF2 pathway in MI.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145129970","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}