European journal of pharmacology最新文献

{"title":"Salicylic acid inhibits Mas-related G protein-coupled receptor X2-mediated mast cell 2 activation and mitigates cutaneous pseudo-allergic reactions","authors":"Hongmei Zhou ,&nbsp;Xi Zhao ,&nbsp;Dan Ye ,&nbsp;Qiang Zhao ,&nbsp;Mengyao Yang ,&nbsp;Zhaoyang Wang ,&nbsp;Li Wang ,&nbsp;Chao wang ,&nbsp;Songmei Geng ,&nbsp;Weihui Zeng ,&nbsp;Zhao Wang","doi":"10.1016/j.ejphar.2025.178189","DOIUrl":"10.1016/j.ejphar.2025.178189","url":null,"abstract":"<div><h3>Background</h3><div>Pseudo-allergic reactions mediated by non-IgE mast cells (MCs) activation contribute to various dermatological conditions, with Mas-related G protein-coupled receptor X2 (MRGPRX2) recognized as a key receptor. Salicylic acid (SA) has long been applied in dermatology as a peeling agent with anti-inflammatory properties, but its role in MRGPRX2-associated pseudo-allergic responses remains unclear.</div></div><div><h3>Methods</h3><div>In vivo, a murine skin pseudo-allergic reaction model combined with Evans blue dye extravasation assay was employed in C57BL/6 mice. In vitro, human skin-derived MCs and LAD2 cells were activated with MRGPRX2 agonists compound 48/80 (c48/80) and substance P (SP). Degranulation and calcium influx were assessed via β-hexosaminidase release and calcium influx assays. RT-qPCR quantified mRNA expression, while kinase phosphorylation and reactive oxygen species (ROS) levels were evaluated using western blotting and flow cytometry, respectively. MRGPRX2 cell surface expression was analyzed by flow cytometry and immunofluorescence.</div></div><div><h3>Results</h3><div>In vivo, SA significantly reduced MRGPRX2-mediated skin edema and Evans blue dye extravasation. In vitro, SA inhibited MC degranulation and calcium influx in both human skin-derived MCs and LAD2 cells. It also suppressed the mRNA expression of inflammatory cytokines IL-4, IL-8, and TNF-α following MRGPRX2 activation. SA pre-treatment reduced ROS levels and inhibited extracellular signal-regulated kinase (ERK) phosphorylation. Additionally, prolonged SA exposure downregulated both MRGPRX2 mRNA and cell surface expression.</div></div><div><h3>Conclusions</h3><div>SA demonstrates a dual-phase inhibitory effect on MRGPRX2-mediated pseudo-allergic reactions. Short-term SA treatment suppresses MC degranulation and cytokine production, whereas long-term treatment further reduces MRGPRX2 expression, highlighting the therapeutic potential of SA for MRGPRX2-associated dermatological disorders.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178189"},"PeriodicalIF":4.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174153","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":"Exploring Prima-1MET as a single agent or in combination with tamoxifen in breast cancer cells in vitro","authors":"Ali Haider Alhammer,&nbsp;Shahad Ali Mudhafar,&nbsp;Shaimaa Yousif Abdulfattah","doi":"10.1016/j.ejphar.2025.178195","DOIUrl":"10.1016/j.ejphar.2025.178195","url":null,"abstract":"<div><div>The mutant tumor suppressor p53 (p53-mut) is expressed in approximately 1/3 of breast cancer cases and 2/3 of triple-negative breast cancer (TNBC). It is linked to metastasis and resistance to various cancer therapies. A p53 reactivator, Prima-1^MET (or APR-246), has shown potential synergy with certain conventional therapies against cancer cells with various p53 statuses across a range of cancer types. Moreover, the clinical form eprenetapopt is showing promise in clinical trials. Thus, we examined the cytotoxic effects of Prima-1^MET against a TNBC-derived p53-mut cell line (MDA-MB231) and an estrogen receptor-positive (ER+) cell line (MCF7) that expresses wild-type p53 (p53-wt), either as a monotherapy or in combination with tamoxifen (Tam). Viability, migration, morphology, apoptosis, and expression of the cell cycle gene <em>CCND1</em> were detected via standard in vitro methods. With CalcuSyn, the combination index (CI) was calculated to assess synergy. Both MDA-MB231 and MCF7 cells cocultured with Prima-1^MET alone exhibited an antiproliferative effect, which was linked to apoptosis and reduced migratory potential. Furthermore, upon exposure to the combination of 10 μM Prima-1^MET and 10 μM Tam, synergistic effects were detected, reflected by decreased viability, migration, altered morphology, and induction of apoptosis, along with downregulation of <em>CCND1</em>. Hence, these results emphasize the attractiveness of the combination of Prima-1^MET and Tam as a therapeutic approach for TNBC and ER + breast cancer, irrespective of p53 mutational status; therefore, these results encourage further preclinical and clinical studies, considering that the effective dose of Prima-1^MET is less than the reported clinically achievable plasma level (∼80 μg/ml).</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178195"},"PeriodicalIF":4.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174271","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":"Preclinical study on cynaroside as a selective granzyme B inhibitor in the treatment of atopic dermatitis","authors":"Seon Sook Kim ,&nbsp;Nam Kyoung Kim ,&nbsp;Ye Ji Heo ,&nbsp;Sanghwa Han ,&nbsp;Su Ryeon Seo","doi":"10.1016/j.ejphar.2025.178196","DOIUrl":"10.1016/j.ejphar.2025.178196","url":null,"abstract":"<div><div>Granzyme B (GrB) is a serine protease primarily involved in cytotoxic T lymphocyte (CTL)-mediated apoptosis through caspase activation. However, emerging evidence suggests that GrB also plays a role in inflammation and extracellular matrix (ECM) degradation, contributing to skin disorders such as atopic dermatitis (AD). GrB is expressed by various immune and non-immune cells, including mast cells, macrophages, and keratinocytes, where it functions independently of perforin to degrade ECM components like fibronectin and decorin. In AD, elevated GrB levels correlate with disease severity, and GrB-deficient mice exhibit reduced AD symptoms, suggesting that inhibiting GrB could be a promising therapeutic approach. Despite its pathological significance, selective GrB inhibitors remain scarce. In this study, we identified cynaroside, a flavonoid compound, as a novel natural inhibitor of GrB. Virtual screening and molecular docking analysis revealed that cynaroside interacts with the Asp88 residue of GrB, forming stable hydrogen bonds that interfere with its catalytic activity. Molecular dynamics (MD) simulations confirmed that this interaction remains stable over 200 ns. Additionally, cynaroside inhibited GrB activity <em>in vitro</em> and significantly reduced fibronectin cleavage. Immunohistochemical analysis further demonstrated decreased GrB expression and preserved fibronectin levels in cynaroside-treated AD mice. Moreover, cynaroside treatment led to a reduction in epidermal thickening and immune cell infiltration, including mast cells and Th2 cells—key indicators of AD severity. These findings highlight cynaroside's potential as a targeted GrB inhibitor for inflammatory skin diseases.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178196"},"PeriodicalIF":4.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145174285","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":"Design, synthesis, and preclinical evaluation of novel 1-benzylpiperidine derivatives as multitarget agents against Alzheimer's disease","authors":"Anu Kunnath Ramachandran ,&nbsp;Anusha Govindula ,&nbsp;Niraja Ranadive ,&nbsp;Sumit Raosaheb Birangal ,&nbsp;Varadaraj Bhat ,&nbsp;S.M. Fayaz ,&nbsp;Gautham G. Shenoy ,&nbsp;Jayesh Mudgal","doi":"10.1016/j.ejphar.2025.178192","DOIUrl":"10.1016/j.ejphar.2025.178192","url":null,"abstract":"<div><div>Small molecules targeting pathologies of Alzheimer's disease (AD) is a promising approach. Identification of potential molecules using computational techniques and their synthesis provides potential applications in the treatment of AD. 2D fingerprint similarity screening, using the Tanimoto coefficient, identified structurally similar molecules to donepezil for lead identification. A molecule with a Tanimoto coefficient of 0.7 was chosen, and derivatives were synthesized. <em>In silico</em> screening of the synthesized compounds indicated strong binding to acetylcholinesterase (AChE). All molecules met drug-likeness criteria and showed 100 % oral absorption. Key interactions with AChE were observed, crucial for inhibitory activity. Molecular dynamics simulations over 100 ns showed stable binding conformations. <em>In vitro</em> assays for AChE and amyloid β (Aβ) inhibition were conducted after the cytotoxicity testing in microglial cells for all four synthesized compounds. Among the tested compounds at 5 μM, (E)-2-(((1-benzylpiperidin-4-yl)imino)methyl)-4-methylphenol (5MeSA4ABP) with AChE (57.46 ± 2.140 %) and Aβ inhibition (57.83 ± 0.08 %), was selected for lipopolysaccharide-induced AD-like mouse model. Behavioural analysis using Morris water maze and open field tests revealed memory impairment in mice. Brain estimations were performed to study the effect of treatments on AD markers such as interleukin-6 (IL-6), Aβ and AChE. In mice with AD pathology, oral administration of 5MeSA4ABP resulted in improved cognitive function without any impact on locomotor activity. Except brain AChE activity, treatment with 5MeSA4ABP significantly reversed the elevated brain IL-6 and Aβ levels. Thus, synthesized hybrid pharmacophores, 5MeSA4ABP, exert its activity via reducing neuroinflammation and plaque deposition. Future investigation are warranted for safety and efficacy mechanisms of 5MeSA4ABP against AD.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178192"},"PeriodicalIF":4.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145155507","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":"Pharmacology education: putting more SoTL (Scholarship of Teaching and Learning) in the bottle.","authors":"Graham A Mackay, Ferdi Engels","doi":"10.1016/j.ejphar.2025.178186","DOIUrl":"https://doi.org/10.1016/j.ejphar.2025.178186","url":null,"abstract":"","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178186"},"PeriodicalIF":4.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148069","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":"HEC95468, a novel soluble guanylate cyclase stimulator, shows protection in the Dahl model of cardiorenal disorder","authors":"Fang-yuan Wu ,&nbsp;Jing Li ,&nbsp;Min-qiang Hu ,&nbsp;Jun-cheng Deng ,&nbsp;Shan-shan Liu ,&nbsp;Man Xiang ,&nbsp;Juan Wan ,&nbsp;Sheng-tian Cao ,&nbsp;Ying-lin Zuo ,&nbsp;Bao-hua Gu","doi":"10.1016/j.ejphar.2025.178190","DOIUrl":"10.1016/j.ejphar.2025.178190","url":null,"abstract":"<div><div>Nitric oxide (NO) signaling plays a vital role in the regulation of cardiovascular and renal function. As the main receptor of NO, soluble guanylate cyclase (sGC) catalyzes the production of cyclic guanosine monophosphate (cGMP) via NO-mediated activation. In conditions of cardiorenal disorder with reduced NO bioavailability, NO-independent sGC stimulation could be an effective way to restore the downstream signaling. In the present study, we aimed to investigate the effects of HEC95468 [methyl (4,6-diamino-2-(7-fluoro-1-(2-fluorobenzyl)-1<em>H</em>-indazol-3-yl)pyrimidin-5-yl)carbamate], a clinical-stage sGC stimulator, in a rat model of cardiorenal damage. In vitro, HEC95468 was demonstrated to stimulate cGMP production with a slightly higher activity than the classical drug vericiguat. In vivo, HEC95468 was studied in the Dahl salt-sensitive (DSS) rats with a high-salt (HS) diet. HEC95468 treatment lowered the systolic and diastolic blood pressure, reduced the relative left ventricular free wall plus ventricular septum (LV + S) weight, prevented HS-induced increase of plasma NT-proANP and NP-proBNP levels, and improved left ventricular interstitial fibrosis. In terms of renal function, HEC95468 treatment decreased the urine protein creatinine ratio, reduced the serum level of KIM-1 and creatinine, as well as attenuating the progression of glomerulosclerosis, renal tubular damage and interstitial fibrosis. In addition, the survival rate was significantly improved in HEC95468-treated rats. These data suggest that HEC95468, a novel and potent sGC stimulator, demonstrates significant protective effects against cardiorenal disorder in HS-induced DSS rat model.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178190"},"PeriodicalIF":4.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148132","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":"Lactobacillus reuteri attenuates methotrexate-induced liver injury via modulation of oxidative stress and inflammation through HO-1/GPX4 and NF-κB/NLRP3 pathways","authors":"Wen-Ru Li ,&nbsp;Yi-Ke Li ,&nbsp;Huan Ren ,&nbsp;Zhen Guo ,&nbsp;Chen-Lin Xiao ,&nbsp;Jian-Quan Luo","doi":"10.1016/j.ejphar.2025.178185","DOIUrl":"10.1016/j.ejphar.2025.178185","url":null,"abstract":"<div><div>Methotrexate (MTX) is a chemotherapeutic agent widely used in cancer and autoimmune diseases; however, its clinic use is considerably limited owing to its severe hepatotoxicity. Although gut microbiota is implicated in various liver diseases, its specific role and mechanism in MTX-induced liver injury remain unclear. We established a MTX-induced liver injury model in mice and assessed hepatic damage through biochemical markers and histopathological analysis. Gut microbiota depletion was conducted using an antibiotic cocktail (ABX) and microbial composition was analysed via 16S rRNA sequencing. We observed that MTX administration induced hepatic pathological and oxidative stress injury by increased hepatic MDA levels, elevated serum AST and ALT activities, and reduced SOD and GSH activities. Depletion of the gut microbiota using ABX resulted in comparable liver injury in MTX-treated and saline-treated mice, suggesting that gut microbiota contributed to MTX-induced liver injury. Further, 16S rRNA sequencing demonstrated that MTX reduced gut microbial diversity and disturbed gut microbial composition. Among the altered bacteria, <em>Lactobacillus reuteri</em> was negatively associated with liver injury index. Furthermore, <em>L. reuteri</em> supplementation attenuated MTX-induced hepatic pathological and oxidative stress injury by inhibiting hepatic MDA content, AST and ALT activities, and promoting the activities of SOD through enhancing the HO-1/GPX4 signalling pathway. In addition, <em>L. reuteri</em> alleviated hepatic inflammation responses by reducing pro-inflammatory cytokines through inhibiting the NF-κB/NLRP3 signalling pathway. In conclusion, our results demonstrated that MTX-induced liver injury is dependent on the gut microbiota and <em>L. reuteri</em> supplementation can help prevent MTX-induced liver injury.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178185"},"PeriodicalIF":4.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136713","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":"Harnessing AI for precision medicine and its applications in genomics, systems pharmacology, and drug discovery","authors":"Jane Dagher ,&nbsp;Moussa Nassar ,&nbsp;Wissam H. Faour","doi":"10.1016/j.ejphar.2025.178183","DOIUrl":"10.1016/j.ejphar.2025.178183","url":null,"abstract":"<div><div>Artificial intelligence and machine learning are revolutionizing pharmaceutical research by enabling the rapid analysis of complex datasets and automating critical tasks throughout the drug-development process. In this review, we surveyed how artificial intelligence accelerated target identification, guided lead-compound design and enhanced safety and efficacy profiling through predictive ADMET modeling and PK/PD simulations. We also explored downstream applications, including modelling complex biological interactions and leveraging real-world clinical data, while emphasizing the essential requirements for model validation and interpretability. While still in its early stages, AI in pharmacology is poised for rapid progress, driving future innovations.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178183"},"PeriodicalIF":4.7,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109398","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":"Phospholysine phosphohistidine inorganic pyrophosphate phosphatase suppresses glycolysis and proliferation of pulmonary artery smooth muscle cells in hypoxic pulmonary hypertension via inhibition of lactate dehydrogenase A","authors":"Yuhan Qin ,&nbsp;Ziqi Sha ,&nbsp;Yong Qiao ,&nbsp;Gaoliang Yan ,&nbsp;Dong Wang ,&nbsp;Chengchun Tang","doi":"10.1016/j.ejphar.2025.178172","DOIUrl":"10.1016/j.ejphar.2025.178172","url":null,"abstract":"<div><h3>Background</h3><div>Hypoxic pulmonary hypertension (HPH) is a progressive disorder marked by pulmonary vasculature remodeling, primarily driven by the overproliferation of pulmonary artery smooth muscle cells (PASMCs). Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) has been identified as a tumor suppressor in cancer. However, its role in the proliferation of PASMCs and its implications in HPH remain unexplored.</div></div><div><h3>Methods</h3><div>Hypoxia and SU5416 (SuHx) were used to establish HPH rat models. Rat and human PASMCs models with LHPP overexpression and silencing were constructed to evaluate the role of LHPP in HPH. Cell proliferation was assessed using both CCK-8 and EdU assays. LHPP targeting approach (siRNA, adenovirus, and adeno-associated virus AAV) was used for in vitro and in vivo experiments to investigate the impact of LHPP on PASMCs glycolysis. We measured lactate levels, and key glycolytic enzymes, focusing on LHPP's influence on lactate dehydrogenase A (LDHA). Additionally, the effect of methyltransferase-like 3 (METTL3) on the reduction of LHPP expression was examined.</div></div><div><h3>Results</h3><div>LHPP levels were significantly decreased in both the pulmonary arteries of rats with SuHx-induced HPH and in hypoxia-treated PASMCs. Overexpression of LHPP inhibited the hypoxia-induced increase in proliferation potential and alleviated pulmonary vascular remodeling (PVR) in vivo. Conversely, silencing LHPP promoted PASMCs proliferation. LHPP overexpression suppressed PASMCs glycolysis and proliferation by lactate dehydrogenase A (LDHA)-mediated glycolysis. Mechanistic studies revealed that METTL3 downregulated LHPP expression.</div></div><div><h3>Conclusion</h3><div>This study emphasizes the METTL3/LHPP/LDHA axis's role in enhancing PASMC proliferation and HPH. LHPP may represent a potential therapeutic target for the treatment of hypoxic pulmonary hypertension.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178172"},"PeriodicalIF":4.7,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145123962","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":"Dihydromyricetin exerts dual anti-acne actions by suppressing propionibacterium acnes proliferation and host inflammatory responses via TLR2/NF-κB/MAPK pathway inhibition","authors":"Liping Jin ,&nbsp;Rao Li ,&nbsp;Xingchen Zhou ,&nbsp;Wangqing Chen ,&nbsp;Xiang Chen ,&nbsp;Wu Zhu","doi":"10.1016/j.ejphar.2025.178161","DOIUrl":"10.1016/j.ejphar.2025.178161","url":null,"abstract":"<div><div>Acne is a common skin disorder, with <em>Propionibacterium acnes</em> (<em>P. acnes</em>) playing a central role in its pathogenesis. Despite the availability of various treatment options, current therapies are limited by safety concerns and reduced efficacy, highlighting the urgent need for the development of safer and more effective alternatives. This study demonstrated that dihydromyricetin (DMY), a natural flavonoid from Ampelopsis grossedentata, exhibited dual therapeutic actions against acne pathogenesis. DMY exerted potent bactericidal activity against <em>P. acnes</em> with a minimum inhibitory concentration of 0.5 mg/mL and minimum bactericidal concentration of 1 mg/mL, inducing bacterial membrane disruption. In <em>P. acnes</em>-stimulated human keratinocytes, DMY significantly reduced pro-inflammatory cytokine expression (<em>IL-1β, TNF-α, IL-8</em>) and suppressed Toll-like receptor 2 (TLR2) expression. Mechanistically, DMY inhibited phosphorylation of nuclear factor-kappa B (NF-κB) p65, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase (MAPK). In a murine acne model, topical application of 0.1 % DMY gel attenuated ear edema, decreased inflammatory cell infiltration (macrophages, neutrophils, CD4⁺ and CD8⁺ T cells), and reduced bacterial loads comparable to standard treatments (adapalene and clindamycin). Molecular docking revealed DMY binds TLR2 via hydrogen bonds with TYR-326 and LYS-347 residues. These findings establish DMY as a novel dual-functional agent against acne that simultaneously targets bacterial proliferation and host inflammatory pathways through TLR2/NF-κB/MAPK axis modulation.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178161"},"PeriodicalIF":4.7,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145112243","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}