British Journal of Pharmacology最新文献

{"title":"Peptide CIGB-552 has a synergistic effect on CFTR-F508del when combined with elexacaftor/tezacaftor/ivacaftor triple therapy for cystic fibrosis.","authors":"Benjamin Simonneau, Stéphanie Simon, Bénédicte Duriez, Aurélie Guguin, Frédéric Becq, Sandra Mirval, Christelle Coraux, Fanny Degrugillier, Bruno Costes, Maribel G Vallespi, Pascale Fanen, Abdel Aissat","doi":"10.1111/bph.70169","DOIUrl":"https://doi.org/10.1111/bph.70169","url":null,"abstract":"<p><strong>Background and purpose: </strong>Cystic fibrosis is an autosomal recessive disease caused by mutations in the CFTR gene, leading to progressive respiratory decline and reduced life expectancy. The most common mutation, CFTR-F508del, results in mislocalised and non-functional protein. Although triple therapy with elexacaftor/tezacaftor/ivacaftor (ETI) is prescribed for patients carrying this mutation, some biological defects remain unresolved. We previously identified COMMD1 as a potential therapeutic target, as its overexpression enhances CFTR-WT plasma membrane localisation. CIGB-552, a cell-penetrating peptide discovered in 2013, stabilises COMMD1. This study evaluates its therapeutic potential in cystic fibrosis.</p><p><strong>Experimental approach: </strong>CIGB-552 was tested, with and without ETI, in CFBE and HEK cells stably expressing CFTR-WT or CFTR-F508del, and in primary human bronchial cells. CFTR function was assessed using YFP quenching and short-circuit current assays. Peptide uptake was evaluated using FITC-labelled CIGB-552 in submerged and air-liquid interface models. Plasma membrane density of CFTR was measured in CFBE CFTR-HA cells, and western blotting assessed CFTR maturation and COMMD1 expression.</p><p><strong>Key results: </strong>CIGB-552 was non-toxic and preferentially entered CFBE CFTR-F508del cells rather than CFBE CFTR-WT cells, without altering COMMD1 expression or localisation. Although not a corrector or potentiator alone, CIGB-552 synergised with ETI, enhancing CFTR-F508del-mediated chloride efflux, confirmed in primary cells. CIGB-552 also increased YFP quenching of CFTR-WT and CFTR-G551D, in combination with ivacaftor. This effect required COMMD1.</p><p><strong>Conclusions and implications: </strong>COMMD1 expression was necessary for CIGB-552 to affect CFTR function positively. Its synergy with the triple therapy offers a promising strategy for improving CF treatment.</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":"144854694","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":"Inhibition of the calcineurin/forkhead box O1/fatty acid binding protein 4 pathway prevents SERCA2 dysfunction-induced foam cell formation and atherosclerosis.","authors":"Beibei Zhu, Shuangxue Luo, Hang Su, Wanping Zhang, Qingqiu Chen, Yiping Zhang, Chenyuan Liu, Pan Li, Tingting Wang, Xiaoyong Tong, Pingping Hu","doi":"10.1111/bph.70170","DOIUrl":"https://doi.org/10.1111/bph.70170","url":null,"abstract":"<p><strong>Background and purpose: </strong>The cysteine residue 674 (C674) of sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase 2 (SERCA2) is pivotal in maintaining SERCA2 activity. The C674S mutation leads to SERCA2 dysfunction and exacerbates atherosclerosis by inducing endoplasmic reticulum stress and inflammation in bone marrow-derived macrophages (BMDMs) and endothelial cells (ECs). This study aimed to explore if SERCA2 dysfunction aggravates atherosclerosis, by disrupting fatty acid metabolism and promoting the formation of macrophage foam cells.</p><p><strong>Experimental approach: </strong>Heterozygous SERCA2 C674S gene mutation knock-in (SKI) mice were used to simulate SERCA2 dysfunction under pathological conditions. Serum from SKI mice and their littermate wild-type mice were taken for metabolomic testing. The entire aorta and aortic root were isolated for histological analysis. BMDMs were used for protein expression, lipid uptake and accumulation analysis.</p><p><strong>Key results: </strong>In SKI BMDMs, SERCA2 dysfunction induced the expression of calcineurin (CaN), which promoted nuclear translocation of forkhead box O1 (FoxO1) and transcription of its downstream target fatty acid-binding protein 4 (FABP4), leading to increased fatty acid synthesis and foam cell formation. Inhibition of the CaN/FoxO1/FABP4 pathway corrects aberrant lipid metabolism and inhibits the formation of foam cells in SKI BMDMs. Pharmacological interventions targeting either FoxO1 or FABP4, or FABP4 partial deficiency, significantly ameliorated atherosclerosis progression.</p><p><strong>Conclusions and implications: </strong>SERCA2 dysfunction accelerates the progression of atherosclerotic lesions by stimulating the CaN/FoxO1/FABP4 pathway and promoting the formation of foam cells. Our findings highlight the importance of SERCA2 function in the context of atherosclerosis and reveal a novel therapeutic strategy to combat lipid accumulation and atherosclerosis.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834088","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":"GCN2 regulates paclitaxel-induced neuropathic pain.","authors":"Alexander R Mikesell, Angela R Meyer, Guadalupe García, Luke R Frietze, Cheryl L Stucky, Tao Pan, Zachary T Campbell","doi":"10.1111/bph.70154","DOIUrl":"https://doi.org/10.1111/bph.70154","url":null,"abstract":"<p><strong>Background and purpose: </strong>Neuropathic pain is debilitating and pervasive. Chemotherapeutic agents commonly induce chronic neuropathic pain. Paclitaxel is a prototypical example, causing painful peripheral neuropathy in a majority of patients. Paclitaxel triggers persistent changes in the excitability of sensory neurons resulting in hypersensitivity to sensory cues. The molecular mechanisms underlying paclitaxel-induced maladaptive plasticity are unclear. Here, we demonstrate a role for the Integrated Stress Response (ISR)-a key translational control mechanism-and its activating kinase, general control non-derepressible 2 kinase (GCN2), in paclitaxel-induced neuropathic pain (PINP).</p><p><strong>Experimental approach: </strong>We used genetic and pharmacological techniques, including sensory neuron-specific GCN2 conditional knockout mice and the selective GCN2 inhibitor GCN2-IN-7. Behavioural assays assessed mechanical and cold hypersensitivity, while primary DRG neuron cultures were used to evaluate neuronal excitability via calcium imaging and protein translation by puromycin incorporation (surface sensing of translation, SUnSET). tRNA charging and abundance were measured using MSR-seq.</p><p><strong>Key results: </strong>Paclitaxel robustly activated the ISR via GCN2 in mouse DRG sensory neurons, shown by increased eIF2α phosphorylation, elevated ATF4 levels and reduced global translation rates. Genetic deletion or pharmacological inhibition of GCN2 blocked paclitaxel-induced sensory neuron sensitisation and significantly attenuated mechanical and cold hypersensitivity in vivo. Mechanistically, paclitaxel reduced global tRNA charging and abundance in DRGs, providing a molecular basis for GCN2 activation.</p><p><strong>Conclusions and implications: </strong>These findings demonstrate that GCN2-dependent ISR activation is critical for PINP. Targeting GCN2 may represent a promising therapeutic strategy for preventing or alleviating chemotherapy-induced peripheral neuropathy, potentially improving patient quality of life and chemotherapy tolerance.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844504","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":"Sigma non-opioid intracellular receptor 1 activation relieves post-stroke cognitive impairment via suppressing AIM2-driven inflammatory response.","authors":"Hui Ma, Yue Chen, Yi-Mo Zhang, Yue Zhang, Xiao-Juan Hou, Hai-Long Li, Yi-Xin Yang, Qian Long, Xin Qiao, Yun-Feng Li","doi":"10.1111/bph.70134","DOIUrl":"https://doi.org/10.1111/bph.70134","url":null,"abstract":"<p><strong>Background and purpose: </strong>Ischaemic stroke is one of the most critical causes of death and disability worldwide, but its pharmacotherapies are currently lacking. This study aimed to investigate the effects of the sigma non-opioid intracellular receptor 1 agonist hypidone hydrochloride (YL-0919) on ischaemic stroke as well as the underlying mechanisms.</p><p><strong>Experimental approach: </strong>Male mice were subjected to a middle cerebral artery occlusion (MCAO)/reperfusion (R) model to mimic ischaemic stroke injury. Neurological and cognitive functions were evaluated, and neuroinflammatory pathways in the medial prefrontal cortex and hippocampus were detected.</p><p><strong>Key results: </strong>Mice subjected to MCAO exhibited obvious neurological and motor deficits, increased infarct volume and neuronal death in the acute phase, and severe cognitive impairment in the chronic phase. Administration of YL-0919 for seven consecutive days beginning within 7 h after MCAO significantly ameliorated the pathological changes described above. Further studies demonstrated that YL-0919 exerted its effect by suppressing absent in melanoma 2 (AIM2)-related inflammatory signals in MCAO mice and alleviated the neuronal deficits in the medial prefrontal cortex and hippocampus, thereby ameliorating chronic post-stroke cognitive impairment. This effect was eliminated by AIM2 overexpression in the medial prefrontal cortex and hippocampus.</p><p><strong>Conclusions and implications: </strong>This study highlights the extended therapeutic window for sigma non-opioid intracellular receptor 1 agonist administration during the acute phase of ischaemic stroke and further demonstrates that targeted inhibition of AIM2-mediated neuroinflammatory pathways may promote sustained cognitive rehabilitation in post-stroke survivors.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144844505","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":"Astragaloside IV alleviates hypoxic pulmonary hypertension by inhibiting RELM-β to reduce PINK1/Parkin-mediated mitophagy in pulmonary artery smooth muscle cells (PASMCs).","authors":"Rongzhen Ding, Haiping Xie, Shuliu Sang, Li Qin, Yinhui Sun, Chao Zhang, Jian Yi, Hui Liu, Jianmin Fan, Guoran Peng, BeiBei Cheng, Lan Song, Aiguo Dai","doi":"10.1111/bph.70166","DOIUrl":"https://doi.org/10.1111/bph.70166","url":null,"abstract":"<p><strong>Background and purpose: </strong>Hypoxic pulmonary hypertension (HPH) is a chronic disorder marked by irreversible pulmonary vascular remodelling (PVR) and pulmonary artery smooth muscle cell (PASMC) dysfunction. Astragaloside IV (AS-IV), a natural saponin from Astragalus, shows potential in HPH management. This study explores AS-IV's protective effect on PVR in HPH.</p><p><strong>Experimental approach: </strong>HPH mouse model was established by 28 days of hypoxia and AS-IV was administered daily. The effect of AS-IV on the HPH model was evaluated by haemodynamic parameters, echocardiography and pathological changes in the pulmonary arteries. In vitro, CCK8, EdU, scratch and transwell assays assessed cell proliferation and migration. Transmission electron microscopy, immunofluorescence and Seahorse XFe24 were employed to detect mitochondrial morphology and function. Retnlb^-/- mice were constructed to assess the effect of RELM-β in HPH. The impact of AS-IV on RELM-β expression and mitophagy at the cellular level was evaluated through lentivirus overexpression.</p><p><strong>Key results: </strong>AS-IV ameliorated HPH in mice by reducing right ventricular systolic pressure (RVSP), attenuating right ventricular hypertrophy and inhibiting vascular remodelling. AS-IV improves hypoxia-induced proliferation, migration and phenotypic transformation of PASMC in vitro. AS-IV reduced hypoxia-induced increases in RELM-β, PINK1, Parkin and excessive mitophagy. Retnlb (RELM-β) knockdown amended mitophagy and PVR under hypoxia. However, the overexpression of RETNLB (RELM-β) hindered the regulatory effect of AS-IV on mitophagy mediated by PINK1/Parkin pathways.</p><p><strong>Conclusions and implications: </strong>AS-IV attenuated the hypoxia-induced increase of PASMC RELM-β expression and suppressed PINK1/Parkin-mediated mitophagy, resulting in the amelioration of PVR. This study unveils the potential of AS-IV as a therapeutic approach for HPH.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834087","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":"Bilirubin prevents hyperlipidaemic acute pancreatitis by inhibiting aryl hydrocarbon receptor-mediated acinar cell pyroptosis.","authors":"Wenjie Liang, Hanxiao Lu, Bo Wu, Hongnian Shen, Li-Long Pan, Xiaoliang Dong, Jun Yang","doi":"10.1111/bph.70168","DOIUrl":"https://doi.org/10.1111/bph.70168","url":null,"abstract":"<p><strong>Background and purpose: </strong>Hyperlipidaemia-induced acute pancreatitis (HLAP) represents a specific subtype of acute pancreatitis (AP) characterised by elevated serum triglyceride levels. However, the precise pathophysiological mechanisms underlying HLAP remain unclear. Bilirubin, an essential haem metabolite, displays significant capabilities in neutralising oxidative stress and modulating inflammatory responses. Here, we investigate the role of bilirubin in mediating HLAP.</p><p><strong>Experimental approach: </strong>We analysed the serum from 627 AP patients, including 160 HLAP patients and 467 non-HLAP patients. Using an experimental HLAP mouse model, knockout mice and an aryl hydrocarbon receptor (AHR) inhibitor, we evaluated the role and underlying mechanism of bilirubin during HLAP development.</p><p><strong>Key results: </strong>Bilirubin levels were significantly down-regulated in HLAP patients, and this decrease is correlated positively with the severity of the disease. Additionally, in the HLAP mouse model, we found that bilirubin supplementation mitigates lipid dysregulation and reduces pancreatic inflammation. Moreover, the Nrf2/HO-1 pathway is an upstream activator of bilirubin accumulation. Our data showed that Nrf2^-/- HLAP mice exhibited enhanced pancreatic injuries compared with control mice. Furthermore, transcriptome analysis demonstrated marked elevation of the NOD-like receptor pathway in pancreatic tissue of HLAP mice, and bilirubin supplementation notably inhibited pancreatic pyroptosis. In addition, using an aryl hydrocarbon receptor (AHR) inhibitor and a pancreatic acinar cell line, we demonstrated that bilirubin prevents HLAP by inhibiting AHR-mediated pyroptosis.</p><p><strong>Conclusions and implications: </strong>Our data demonstrated that bilirubin protects against HLAP by suppressing AHR-mediated pyroptosis, highlighting bilirubin modulation as a potential therapeutic target for clinical intervention.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815840","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 opioid partial agonist PPL-138 reduces alcohol self-administration in rats susceptible to post-traumatic stress disorder.","authors":"Andrea Cippitelli, Yong Zhang, Kylie Kealoha, Ali Idriss, Panini S Patankar, Benjamin Carper, Lawrence Toll, Kelly M Standifer","doi":"10.1111/bph.70151","DOIUrl":"https://doi.org/10.1111/bph.70151","url":null,"abstract":"<p><strong>Background and purpose: </strong>Post-traumatic stress disorder (PTSD) is a significant challenge in the military population and civilians exposed to danger and violence. Alcohol use disorder (AUD) and pain are common PTSD comorbidities, with a higher incidence in PTSD patients than the general population. Approved pharmacotherapies for these disorders are often ineffective and adverse effect potential limits use. No current drugs address both PTSD and alcohol use disorder. This study examines whether the opioid partial agonist PPL-138 (BU10038) alleviates preclinical behaviours associated with PTSD such as anxiety, pain and comorbid alcohol use.</p><p><strong>Experimental approach: </strong>The single prolonged stress (SPS) model induced PTSD-like phenotypes in male and female Sprague-Dawley rats. As PTSD afflicts only a subset of humans exposed to trauma, the effect of PPL-138 on alcohol self-administration was tested in SPS susceptible and resilient rat populations (defined by anxiety phenotype and escalation of alcohol-related responses).</p><p><strong>Key results: </strong>PPL-138 effectively reduces anxiety-like behaviour, tactile allodynia and thermal hyperalgesia induced by SPS. It also decreases escalated alcohol consumption in male rats exhibiting comorbid anxiety-like behaviour, leaving alcohol intake unaltered in non-anxious phenotypes or in rats not exposed to traumatic-like stress. The compound has a similar effect in female rats, as it reduces alcohol self-administration selectively in anxious female rats.</p><p><strong>Conclusions and implications: </strong>Results support the efficacy of PPL-138 to attenuate behavioural traits attributable to PTSD and alcohol consumption associated with elevated anxiety in an AUD-PTSD population.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803663","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":"Synthesis and evaluation of a novel inhibitor for the α5-GABA_A receptor in the treatment of peripheral neuralgia: Evidence from MD simulation and in vivo studies.","authors":"Yanming Chen, Jiaxu Zhou, Yue Tian, Xiangyu Zhang, Yiqiao Liu, Weiping Lyu, Dehua Lu, Jie Cai, Xia Li, Cheng Shi, Guogang Xing, Zhenming Liu","doi":"10.1111/bph.70150","DOIUrl":"https://doi.org/10.1111/bph.70150","url":null,"abstract":"<p><strong>Background and purpose: </strong>Peripheral neuropathic pain (PNP) remains challenging to treat, because of the limited efficacy of current therapies and their central nervous system side effects. Targeting the α5-GABA_A receptor (GABRA5) has shown potential in addressing the limitations of existing therapies. This study aimed to develop and evaluate SR-419, a novel GABRA5 inhibitor, for its potential therapeutic application in PNP.</p><p><strong>Experimental approach: </strong>SR-419 was synthesised via an optimised route and characterised using nuclear magnetic resonance (NMR). Molecular docking and molecular dynamics (MD) simulations were performed to predict its binding mode. Analgesic efficacy was assessed in rat models of post-herpetic neuralgia (PHN) and spared nerve injury (SNI). Mechanistic studies included cellular thermal shift assays (CETSA) and pharmacological validation using QH-II-66, a GABRA5-selective agonist.</p><p><strong>Key results: </strong>The results of NMR analysis confirmed that we had successfully developed a novel chemistry route to synthesise the target compound. SR-419 bound stably to GABRA5 in silico and showed high selectivity in vitro. CETSA confirmed direct engagement of SR-419 with intracellular GABRA5. SR-419 produced dose-dependent analgesia in vivo, without crossing the blood-brain barrier or causing sedation or motor impairment. Its analgesic effect was abolished by QH-II-66, confirming GABRA5 involvement. Toxicology studies revealed excellent safety in acute and chronic settings.</p><p><strong>Conclusions and implications: </strong>SR-419 is a peripherally acting GABRA5 inhibitor with potent analgesic efficacy and a favourable safety profile. Its target-specific mechanism suggests that it is a promising candidate for treating PNP and avoiding central side effects.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803662","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":"β-elemene ameliorates metabolic dysfunction-associated steatohepatitis by targeting PPARα in experimental diet-induced models.","authors":"Yongqiang Xiong, Wu Luo, Jiaxi Ye, Yaqian Cui, Xiangsheng Zheng, Leiming Jin, Shuaijie Lou, Qianhui Zhang, Ao Wang, Yi Fang, Tianyang Jin, Mengsha Lin, Hui Dong, Guang Liang, Xiang Hu, Weiwei Zhu","doi":"10.1111/bph.70161","DOIUrl":"https://doi.org/10.1111/bph.70161","url":null,"abstract":"<p><strong>Background and purpose: </strong>Metabolic dysfunction-associated steatohepatitis (MASH) is an escalating global health concern with few effective pharmacological treatment options available. β-elemene (ELE) is a natural product derived from Curcuma Rhizoma, which has anti-tumour and anti-inflammatory effects. However, its efficacy and molecular mechanism in MASH have not been elucidated.</p><p><strong>Experimental approach: </strong>Two diet-induced MASH models were used to evaluate the therapeutic potential of ELE in vivo. Additionally, RNA sequencing, network pharmacological analysis, and target validation were performed to elucidate the underlying mechanisms.</p><p><strong>Key results: </strong>ELE markedly ameliorated lipid dysfunction and the inflammatory response in MASH mice and fatty acids-stimulated hepatocytes. RNA-sequencing analysis indicated that ELE exerted its therapeutic effects through activating the PPARα signalling pathway. Particularly, we found that ELE directly binds to PPARα protein, preventing its degradation via K48-linked polyubiquitination. Notably, the protective effects of ELE on MASH were abolished in the absence of PPARα.</p><p><strong>Conclusion and implications: </strong>Our studies reveal that ELE is a novel stabiliser of PPARα, effectively inhibiting its ubiquitin-mediated degradation in MASH. By preserving the PPARα signalling pathway, ELE enhances lipid homeostasis and relieves the inflammation. Therefore, ELE holds significant potential as a therapeutic candidate for the treatment of MASH.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144798259","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":"Grifolic acid, a FFAR4 agonist, identified as a dual antagonist of voltage-gated sodium and Ca_V2.2 channels with potent antinociceptive effects.","authors":"Miao Zhao, Yuchen Jin, Jun Wu, Jimei Liu, Min Li, Jungui Dai, Haibo Yu","doi":"10.1111/bph.70165","DOIUrl":"https://doi.org/10.1111/bph.70165","url":null,"abstract":"<p><strong>Background and purpose: </strong>Chronic pain affects nearly 30% of the global population. Because of significant adverse effects of opioids, alternative therapies are urgently needed. In a drug discovery project, we identified grifolic acid (GA) as a potent Na_V1.7 antagonist. Here, we have evaluated its biophysical properties and efficacy in animal pain models.</p><p><strong>Experimental approach: </strong>A mechanistic investigation of GA was carried out on dorsal root ganglion (DRG) neurons, and various stable cell lines, using whole-cell patch clamp techniques. Site-directed mutagenesis and molecular docking analyses also were performed to identify the binding pocket of GA on Na_V1.7. The antinociceptive efficacy of GA was evaluated in inflammatory pain models.</p><p><strong>Key results: </strong>GA exhibited state-dependent blockade of Na_V1.7 channels and modulated channel gating kinetics. It suppressed native Na_V currents and action potential (AP) firing in DRG neurons. GA inhibited the increase in action potential firing frequency in DRG neurons induced by inflammatory mediators. Mutational and molecular docking studies revealed that GA and bupivacaine targeted anaesthetics binding sites, with their use-dependent properties almost abolished in the F1737A mutant. In formalin and CFA-induced inflammatory pain models in male mice, GA demonstrated analgesic effects comparable to, or exceeding, those of the indomethacin, lidocaine and carbamazepine. GA showed minimal effects on skeletal muscle function but exhibited an inhibitory effect on the Ca_V2.2 channel.</p><p><strong>Conclusions and implications: </strong>GA is a state-dependent sodium channel and Ca_V2.2 channel antagonist with potent analgesic effects. These findings support its potential as an antinociceptive agent in the treatment of chronic pain conditions.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144793509","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}