European journal of pharmacology最新文献

{"title":"Neuroprotective alpha-linolenic acid derived from black pepper targets PGK1 and activates the Nrf2 pathway in PC12 cells and mice","authors":"Chunyan Sun ,&nbsp;Xiaoying Cai ,&nbsp;Xueqin Jiang ,&nbsp;Feiyan Wen ,&nbsp;Li Wan","doi":"10.1016/j.ejphar.2025.178154","DOIUrl":"10.1016/j.ejphar.2025.178154","url":null,"abstract":"<div><h3>Background</h3><div>Oxidative stress is a significant contributor to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Nuclear factor E2-related factor 2 (Nrf2), a pivotal regulator of antioxidant responses, is an emerging therapeutic target for these conditions. Our study assessed the neuroprotective effects of monomeric compounds derived from black pepper against hydrogen peroxide (H₂O₂)-induced damage in neuron-like PC12 cells. Alpha-linolenic acid (ALA) demonstrated superior protective effects.</div></div><div><h3>Purpose</h3><div>The aim of this study was to investigate the mechanism underlying the neuroprotective activity of ALA derived from black pepper.</div></div><div><h3>Methods</h3><div>H₂O₂ induces oxidative stress in vitro, and MPTP induces Parkinson's syndrome in vivo. Proliferation and apoptosis assays, fluorescent dye staining, Western blotting, real-time PCR, immunofluorescence, luciferase reporter assays, behavioural experiments, and immunohistochemistry were performed to investigate the effects of ALA and the underlying mechanism in vitro and in vivo.</div></div><div><h3>Results</h3><div>Our findings indicate that the ROS-scavenging and cytoprotective properties of ALA are likely mediated through Nrf2 activation and the upregulation of phase II antioxidant enzymes, including HO-1 and NQO1. Drug affinity responsive target stability (DARTS) assays revealed that ALA interacts with the PGK1 protein, potentially inhibiting its activity to promote Nrf2 activation. In vivo, the oral administration of ALA (60 and 120 mg/kg) significantly mitigated the behavioural deficits associated with Parkinson's disease, preserved dopaminergic neurons in an MPTP-induced mouse model of PD, and relieved nerve inflammation.</div></div><div><h3>Conclusion</h3><div>Our data suggest that ALA may be a candidate neuroprotective agent for the treatment of neurodegenerative diseases, offering novel insights and potential therapeutic targets for future interventions.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178154"},"PeriodicalIF":4.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging-related epigenetic instability in lncRNAs and miRNAs mediates the development of hypertension","authors":"M. Chandhru ,&nbsp;Karthikeyan Ramamurthy ,&nbsp;Gokul Sudhakaran ,&nbsp;Ki Choon Choi ,&nbsp;M. Valan Arasu ,&nbsp;Jesu Arockiaraj","doi":"10.1016/j.ejphar.2025.178150","DOIUrl":"10.1016/j.ejphar.2025.178150","url":null,"abstract":"<div><div>Hypertension is a complex, age-related condition that markedly elevates the risk of cardiovascular problems and mortality globally. With the aging global population, understanding the molecular foundations of hypertension is essential. Emerging evidence highlights the essential roles of non-coding RNAs, particularly Long non-coding RNAs and microRNAs, in regulating gene expression linked to vascular health and blood pressure control. This review examines the impact of aging on the expression and synthesis of key ncRNAs, which leads to malfunction in three pivotal systems: vascular smooth muscle cells, the renin-angiotensin-aldosterone system, and endothelial cells. Dysregulated ncRNAs impair nitric oxide bioavailability, enhance inflammation, and modify vascular tone, resulting in arterial stiffness and increased blood pressure. Crosstalk between lncRNAs and miRNAs, as exemplified by MALAT1–miR-145 and H19–let-7b, reveals a complex regulatory network that affects vascular remodeling and homeostasis. This review highlights new molecular targets for early diagnosis and therapeutic treatment of age-related hypertension, incorporating recent findings on miRNA and lncRNA interactions.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178150"},"PeriodicalIF":4.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YN1548: A novel small-molecule agonist of human glucagon-like peptide-1 receptor for the treatment of type 2 diabetes mellitus and obesity","authors":"In-Gyu Je ,&nbsp;Tae-Kwang Kim ,&nbsp;Hyeong Jun Lee ,&nbsp;Mi-Young Lee ,&nbsp;Kyung-Mi An ,&nbsp;Joon-Tae Park ,&nbsp;Ki-Young Kim","doi":"10.1016/j.ejphar.2025.178143","DOIUrl":"10.1016/j.ejphar.2025.178143","url":null,"abstract":"<div><div>Type 2 diabetes mellitus (T2DM) and obesity are the major global health concerns. Glucagon-like peptide-1 (GLP-1) receptor agonists are effective incretin-based treatments for T2DM and obesity. The patient compliance of peptide-based GLP-1 receptor agonists is limited due to subcutaneous administration. This study aimed to develop small-molecule GLP-1 receptor agonists that can be administered orally. Pharmacological properties of YN1548 were evaluated using <em>in vitro</em> assays in Chinese hamster ovary (CHO) cells expressing GLP-1 receptor and diabetic monkey models. YN1548 demonstrated potent binding to human GLP-1 receptor and activation of the cyclic adenosine monophosphate (cAMP) signaling pathway at a half-maximal effective concentration of 4.59, 24.28, and 2.20 nM in CHO cells expressing various levels of human GLP-1 receptor. The maximal efficacy, ranging from 101.0 % to 103.9 %, was comparable to GLP-1 (7–36) amide. YN1548 exhibited biased agonism, preferentially activating cAMP response over β-arrestin recruitment, as well as selectivity for primate GLP-1 receptor. Pharmacokinetic evaluations indicated that YN1548 is suitable for oral administration. In diabetic monkeys, oral administration of YN1548 reduced blood glucose levels and enhanced insulin secretion in a concentration-dependent manner. YN1548 also reduced food intake and induced weight loss comparable to liraglutide, injectable GLP-1 receptor agonists. Toxicological studies in rats and monkeys revealed that YN1548 was well-tolerated up to 1000 and 500 mg/kg/day, respectively, with reversible and non-adverse changes in clinical pathology parameters. YN1548, a novel small-molecule GLP-1 receptor agonist, is a promising therapeutic candidate for the management of T2DM and obesity, addressing the unmet need for long-term and convenient oral treatments.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178143"},"PeriodicalIF":4.7,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic insights into the therapeutic potential of hydrogen sulfide","authors":"James J.R. Brady ,&nbsp;William R. Reay","doi":"10.1016/j.ejphar.2025.178135","DOIUrl":"10.1016/j.ejphar.2025.178135","url":null,"abstract":"<div><div>Hydrogen sulfide (H₂S) is a chalcogen-hydrogen gas that can be endogenously synthesized and is the third known bioactive gaseous signalling molecule (gasotransmitter). H₂S has diverse physiological roles, such as with cell division, neurotransmission and inflammation. Its involvement with a variety of disease-related processes has spurred growing interest in its therapeutic potential. We propose that variants in genes implicit in regulating cellular H₂S availability could help prioritise conditions for exploration of H₂S as a therapeutic target. Here, we present the first systematic genetic investigation of H₂S biology across thousands of human disease endpoints and clinical measures, leveraging common frequency genetic variants associated with gene expression and rare predicted loss-of-function variants. These analyses revealed a broad phenotypic spectrum of association signals with H₂S related variants, in line with the complexity and pleiotropy of genes involved in this system. Notably, genetically predicted expression of <em>SUOX</em> (sulfite oxidase) showed strong associations with several diseases, including type 1 diabetes and other autoimmune diseases. Polygenic enrichment of common variant signals provided some evidence of a link between H₂S biology and cerebrovascular disease. Our findings reveal new insights into genetic influences on H₂S signalling and its relevance to human disease, highlighting genetic variation as a tool to prioritise indications for H₂S-targeted therapies.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178135"},"PeriodicalIF":4.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated network pharmacology and in vivo experimental approaches unveil the modulatory effect of telmisartan on autophagy in a rat model of nonalcoholic steatohepatitis","authors":"Sami S. Metwally ,&nbsp;Rasha H. Abdel-Ghany ,&nbsp;Atef S. Elgharbawy ,&nbsp;Mohamed Mohsen ,&nbsp;Amira Ebrahim Alsemeh ,&nbsp;Esraa M. Zakaria","doi":"10.1016/j.ejphar.2025.178136","DOIUrl":"10.1016/j.ejphar.2025.178136","url":null,"abstract":"<div><div>Defective autophagy contributes to the progression of various diseases, including nonalcoholic steatohepatitis (NASH). While telmisartan's hepatoprotective effects are well established, its impact on hepatic autophagy in NASH remains unclear. This study employed network pharmacology combined with <em>in vivo</em> experiments to predict and validate telmisartan's effects on hepatic autophagy in a rat model of NASH. Additionally, we investigated whether telmisartan could augment pioglitazone's protective effects.</div><div>Network pharmacology identified 97 common molecular targets shared by telmisartan and NASH. Key targets included Signal Transducer and Activator of Transcription 3 (STAT3), B-cell lymphoma 2 (Bcl2), and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), regulators of cellular autophagy, suggesting telmisartan's potential interaction with autophagy-related pathways. To validate these findings, NASH was induced in adult male rats via an 18-week high fructose, fat, and salt diet, with telmisartan, pioglitazone, or their combination administered orally during the final 10 weeks. Blood pressure, glycemic, lipid, and liver function parameters were quantified in serum. Besides, hepatic markers of autophagy (Beclin1, LC3, and p62), inflammation, oxidative stress, fibrosis, and apoptosis were measured. Moreover, liver histology and collagen deposition were examined.</div><div>Telmisartan significantly enhanced hepatic autophagy more than pioglitazone. Furthermore, combination therapy synergistically increased autophagy beyond the effects of either drug alone. Both drugs similarly ameliorated hepatic inflammation and oxidative stress markers. These results demonstrate that telmisartan's hepatoprotective effects are partly mediated by restoration of hepatic autophagy. Moreover, the data suggest that combined telmisartan and pioglitazone therapy may provide enhanced benefit in NASH treatment, warranting further clinical investigation.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178136"},"PeriodicalIF":4.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxymatrine attenuates the type 1 diabetes mellitus via negative regulation of the follicular helper T cells","authors":"Xiaoqi Yue,&nbsp;Shuo Wang,&nbsp;Zhenhua Cui,&nbsp;Yanli Zhang","doi":"10.1016/j.ejphar.2025.178127","DOIUrl":"10.1016/j.ejphar.2025.178127","url":null,"abstract":"<div><div>Type 1 diabetes mellitus (T1DM) is an autoimmune disorder in which autoantibodies cause the immune system to attack and destroy pancreatic β-cells, leading to insufficient insulin production and impaired blood glucose control. T follicular helper (Tfh) cells are recognized as a group of CD4⁺ T cells that help B cells to produce high-affinity antibodies. Our previous research found that oxymatrine (OMT) exhibits excellent immunomodulatory properties on Tfh cells in autoimmune diseases. Based on the aforementioned research, we investigated whether OMT can modulate Tfh cells to reduce autoantibodies and thereby protect pancreatic β-cells in T1DM. Thus, we collected clinical laboratory examination indices from T1DM patients and utilized the well-known non-obese diabetic (NOD/LtJ) mouse model. Flow cytometry was used to detect changes in Tfh (CD4⁺CXCR5⁺ICOS⁺PD1⁺) cells, and the correlation between the Tfh cells percentage and serum factors was analyzed. We also measured changes in blood glucose, oral glucose tolerance, insulin, spleen germinal center, liver and kidney function, pancreatic and kidney tissues in NOD/LtJ mice. We found that in T1DM patients, the frequency of Tfh cells in peripheral blood was increased and positively correlated with elevated levels of autoantibodies and serum cytokines. After OMT treatment, NOD/LtJ mice showed increased serum insulin levels, protection of pancreatic and kidney tissues, and a significant control of Tfh cells expansion in the spleen. In summary, OMT may have therapeutic effects on type 1 diabetes mellitus via negatively regulating T follicular helper cells to protect pancreatic islets β cells.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178127"},"PeriodicalIF":4.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improving the efficacy and targeting of carvedilol for the management of diabetes-accelerated atherosclerosis: An in vitro and in vivo assessment","authors":"Marwa M. Nagib ,&nbsp;Ala Hussain Haider ,&nbsp;Amr Gamal Fouad ,&nbsp;Sherif Faysal Abdelfattah Khalil ,&nbsp;Amany Belal ,&nbsp;Fahad H. Baali ,&nbsp;Nisreen Khalid Aref Albezrah ,&nbsp;Alaa Ismail ,&nbsp;Fatma I. Abo El-Ela","doi":"10.1016/j.ejphar.2025.178134","DOIUrl":"10.1016/j.ejphar.2025.178134","url":null,"abstract":"<div><div>Atherosclerosis is characterized by the accumulation of lipids and inflammation in large arteries. Diabetes mellitus significantly contributes to the initiation and progression of this condition. Carvedilol, an oral beta-adrenergic antagonist, is recognized for its ability to enhance arterial blood circulation and reduce hyperglycemia. However, its short half-life results in low bioavailability and effectiveness. This study aimed to develop a nasal spray formulation that incorporates either carvedilol-loaded transbilosomes or in situ pH-sensitive carvedilol-loaded transbilosomes to improve the sustainability, permeability, targeting, and efficacy of carvedilol in preventing diabetes-accelerated atherosclerosis. Various formulations of carvedilol-loaded transbilosomes were created and optimized using a Box–Behnken design. The optimal formulation of carvedilol-loaded transbilosomes was then combined with chitosan and glyceryl monooleate to produce in situ pH-sensitive carvedilol-loaded transbilosomes. Both the optimal carvedilol-loaded transbilosomes and the in situ pH-sensitive carvedilol-loaded transbilosomes were evaluated in vivo using a rat model of experimental diabetes and atherosclerosis. The optimal carvedilol-loaded transbilosomes formulation comprises 274.3 mg of phospholipid, 26.7 mg of Span 60, and 22.5 mg of sodium deoxycholate. Both the optimal carvedilol-loaded transbilosomes and the in situ pH-sensitive carvedilol-loaded transbilosome formulations exhibited greater sustainability, permeability, and targeting capabilities compared to free carvedilol. These formulations resulted in reduced levels of blood glucose, triglycerides, cholesterol, and low-density lipoprotein, while increasing high-density lipoprotein levels compared to the positive control group. In conclusion, the nasal delivery of the optimal carvedilol-loaded transbilosomes and the in situ pH-sensitive carvedilol-loaded transbilosomes shows promise as a strategy for treating diabetes-accelerated atherosclerosis.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178134"},"PeriodicalIF":4.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of cyclooxygenase-2 signaling mediates liraglutide-induced adipose lipolytic activity","authors":"Jingyi Li ,&nbsp;Hailian Wu ,&nbsp;Wenhui Ma ,&nbsp;Tao Yuan ,&nbsp;Xiaopan Chen ,&nbsp;Yong Pan","doi":"10.1016/j.ejphar.2025.178133","DOIUrl":"10.1016/j.ejphar.2025.178133","url":null,"abstract":"<div><div>Pharmacological benefits of glucagon like peptide-1 receptor agonist (GLP-1RA) were mainly contributed to body weight reduction. This study aims to identify the novel mechanisms by which liraglutide improves adipose tissue homeostasis through cyclooxygenase (COX)-2 signaling. Liraglutide's impact on metabolic parameters <em>in vivo</em> was assessed in high-fat diet (HFD)-induced obese mice received liraglutide (1 mg/kg/day) treatment. In <em>vitro</em> experiments were conducted with differentiated adipocytes, and non-targeted metabolomics sequenced to identify key metabolites and COX-2 involvement during cold exposure. Liraglutide improved metabolic insulin resistance, accompanied with reduction of body weight and individual fat weight. Liraglutide suppressed adipocyte hypertrophy whereas induced lipolytic activity, including upregulation of browning-related markers PGC1α, UCP1, and ATGL in obese adipose tissues and differentiated 3T3-L1 adipocytes. Metabolomics analysis revealed elevated activation of COX-2 signaling, including increasing levels of COX-2 signaling and prostaglandin levels in subcutaneous adipose tissue from liraglutide-treated obese mice. COX-2 inhibition abolished liraglutide's effects on adipogenesis and lipolysis, and impaired adaptive thermogenesis in response to cold. In conclusions, liraglutide suppressed adipocyte hypertrophy dependent on upregulation of COX-2 activity. Targeting COX-2 pathway in adipose tissue was one of clinical concerns when obese patient treated with GLP-1RA.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178133"},"PeriodicalIF":4.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145027163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Authentic learning environments for critical thinking and clinical reasoning skills in clinical pharmacology: a scoping review","authors":"Dani Rizali Firman ,&nbsp;Nada Abu Ezzat ,&nbsp;Jacqueline Bustraan ,&nbsp;Arnout Jan de Beaufort ,&nbsp;Anna Diewerke (Arianna) Pranger","doi":"10.1016/j.ejphar.2025.178124","DOIUrl":"10.1016/j.ejphar.2025.178124","url":null,"abstract":"<div><h3>Introduction</h3><div>Critical thinking and clinical reasoning are crucial skills for healthcare professionals, particularly in clinical pharmacology, where decision making directly impacts patient care. However, there is a gap in the literature on how to foster these skills effectively. Therefore, the aim of this study was to map and examine the evidence of authentic learning environments in healthcare education in developing critical thinking and clinical reasoning skills in pharmacology.</div></div><div><h3>Methods</h3><div>We conducted a comprehensive search of four electronic databases to identify relevant primary research studies. We focused on studies that have investigated and implemented various authentic learning environments. The analysis focused on studies that covered and assessed critical thinking and clinical reasoning skills in authentic learning contexts. The results were structured and reported in accordance with PRISMA-Scr. For this analysis, we used Herrington and Herrington's framework to identify the characteristics of authentic learning environments across studies.</div></div><div><h3>Results and discussion</h3><div>Of the 141 articles screened for eligibility, 31 were included. This analysis of authenticity reveals how each environment uniquely contributes to the development of critical thinking and clinical reasoning skills in pharmacology. Notably, environments that integrate simulation-based learning, case-based learning, and collaborative activities are linked to significant improvements in critical thinking and clinical reasoning skills. The variety of implementation influenced their effectiveness, suggesting that a deeper integration of authentic characteristics in the learning environment tends to enhance students' clinical decision-making capabilities. Overall, these findings indicate that authentic learning environments can substantially improve the application of clinical knowledge in real-world settings.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178124"},"PeriodicalIF":4.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the Skp2–Cks1 protein–protein interaction: structures, assays, and preclinical inhibitors","authors":"Emadeldin M. Kamel ,&nbsp;Sally Mostafa Khadrawy ,&nbsp;Ahmed A. Allam ,&nbsp;Noha A. Ahmed ,&nbsp;Faris F. Aba Alkhayl ,&nbsp;Al Mokhtar Lamsabhi","doi":"10.1016/j.ejphar.2025.178129","DOIUrl":"10.1016/j.ejphar.2025.178129","url":null,"abstract":"<div><div>The Skp2–Cks1 protein–protein interaction (PPI) within the SCF^Skp2 ubiquitin ligase acts as a co-receptor for phosphorylated CDK inhibitors—most prominently p27^Kip1—relieving CDK inhibition and advancing the cell cycle, a dependency accentuated in RB-pathway–defective cancers. Crystallographic and cryo-EM analyses delineate a composite pocket formed by the Skp2 leucine-rich-repeat groove and the phosphate-recognition site of Cks1; Cks1-centered open–closed motions further influence druggability. Using HTRF/TR-FRET and AlphaScreen biochemistry, alongside cell-based target-engagement readouts in some studies, three small-molecule classes have emerged that disrupt this PPI: 1,3-diphenyl-pyrazines and triazolo[1,5-a]pyrimidines (lead E35) with low-micromolar potency, and “Skp2E3LI” compounds with micromolar cellular activity. These agents elevate p27 (and in some reports p21), curb proliferation, and show in-vivo effects in defined models: diphenyl-pyrazines in prostate and gastric xenografts, E35 in gastric xenografts, and Skp2E3LIs in estrogen-driven endometrial hyperplasia. Additional strategies that impinge on the Skp2 axis—such as SKPin-C1 or neddylation blockade—suppress osteosarcoma and small-cell lung cancer models; doxorubicin combinations are synergistic in osteosarcoma, whereas neddylation combinations yield enhanced but not uniformly synergistic activity. Genetic validation comes from a Cks1^N45R knock-in that prevents Skp2–Cks1 binding, stabilizes p27, and phenocopies Skp2 loss without systemic lethality. Key needs include pushing potency into the sub-micromolar range, broad selectivity profiling, and defining long-term safety in proliferative tissues, with biomarker-guided development focused on RB1 loss, SKP2 overexpression, and nuclear p27 depletion. Degrader approaches (PROTACs/molecular glues) remain preclinical. This review synthesizes these advances and outlines priorities for translation.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178129"},"PeriodicalIF":4.7,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145020865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}