European journal of pharmacology最新文献

{"title":"Bexarotene alleviates aberrant activation of microglia in early life by regulating the RXRα-PPARγ-NF-κB axis","authors":"Shijie Zhang,&nbsp;Xinqi Wang,&nbsp;Senyue Yang,&nbsp;Ziye Zang,&nbsp;Xiang Li,&nbsp;Jianhong Li","doi":"10.1016/j.ejphar.2026.179155","DOIUrl":"10.1016/j.ejphar.2026.179155","url":null,"abstract":"<div><div>The early developmental window is a critical period for the structural establishment and functional maturation of the central nervous system. During this stage, the proliferation, morphological remodeling, and phenotypic transformation of microglia are essential for neurogenesis, synaptic pruning, and refinement of neural circuits, and their dysregulation is implicated in multiple neurodevelopmental disorders. However, the molecular mechanisms governing early microglial development remain unclear. Retinoid X receptor α (RXRα), a nuclear receptor with key roles in development and immune regulation, has not been fully characterized in this context. Here, we used a mouse model of early-life stress (maternal separation) to assess its impact on hippocampal microglial development and inflammation, and to delineate the role of RXRα. Early-life stress reduced body weight and increased plasma corticosterone in juvenile mice, decreased microglial branching and induced aberrant activation, and elevated hippocampal IL-1β, IL-6, and NF-κB subunits P50 and P65. Treatment with the RXR agonist bexarotene upregulated hippocampal RXRα, partially restored microglial morphological complexity, and markedly suppressed pro-inflammatory cytokines and NF-κB pathway gene expression. In an in vitro microglial inflammation model, the anti-inflammatory effect of bexarotene was dependent on peroxisome proliferator-activated receptor γ (PPARγ), as inhibition of PPARγ attenuated its actions. These findings identify RXRα as a critical transcriptional regulator maintaining early microglial homeostasis and limiting inflammation and provide a theoretical basis for the application of bexarotene in the treatment of neuroinflammatory damage caused by early-life trauma.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179155"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469675","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":"Cerebrospinal fluid metabolites and brain imaging in epilepsy subtypes: Mendelian randomization and multi-omics analysis","authors":"Huaiyu Sun,&nbsp;Xuewei Li,&nbsp;Weixuan Zhao,&nbsp;Hongmei Meng,&nbsp;Wuqiong Zhang","doi":"10.1016/j.ejphar.2026.179095","DOIUrl":"10.1016/j.ejphar.2026.179095","url":null,"abstract":"<div><h3>Background</h3><div>Epilepsy is a complex neurological disorder significantly influenced by genetic factors. Observational studies can identify associations, but cannot establish causality. Mendelian randomization (MR) offers a robust tool for identifying etiology. Therefore, using multi-omics, we explored genetically proxied associations among cerebrospinal fluid metabolites, neuroimaging phenotypes, and epilepsy to prioritize candidate genes and potential therapeutic targets.</div></div><div><h3>Methods</h3><div>Leveraging data from genome-wide association studies, gene expression databases, and the UK Biobank, we performed two-sample MR analyses. Immune infiltration was assessed using multiple algorithms, transcription factors predicted using RcisTarget, and key genes prioritized through single-nucleotide polymorphism annotation and localization using single-cell RNA sequencing.</div></div><div><h3>Results</h3><div>We identified genetically proxied associations between 14 cerebrospinal fluid metabolites and focal epilepsy (11 protective, three risk-associated), with 13 confirmed using reverse MR. Additionally, 259 neuroimaging phenotypes showed significant associations with focal epilepsy. <em>DAB1</em>, <em>ITGA8</em>, and <em>RORA</em> were the top-ranked genes, localized to inhibitory neurons, oligodendrocyte precursor cells, and astrocytes, respectively.</div></div><div><h3>Discussion</h3><div>These findings demonstrate cell-specific pathology beyond standard neuronal activity. Mechanistically, <em>DAB1</em> contributes to defects in inhibitory circuits, potentially disrupting excitation–inhibition balance, <em>ITGA8</em> to matrix or myelin abnormalities in oligodendrocyte precursor cells, and <em>RORA</em> to astrocyte-mediated metabolic regulation and neuroinflammation. These robust metabolic and structural associations suggest that these features may represent early endophenotypes preceding clinical symptoms.</div></div><div><h3>Conclusion</h3><div>By integrating multi-omics data, we identified a candidate gene–metabolite–imaging feature network potentially involved in epileptogenesis. The prioritized glial and neuronal targets offer hypothesis-generating insights for future mechanistic studies, precision medicine approaches, and translational research in epilepsy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179095"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338354","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":"Sodium ferulate prevents breast cancer metastasis by remodeling the bloodstream microenvironment","authors":"Mengting Lin,&nbsp;Shanshan He,&nbsp;Chunlian Zhong,&nbsp;Weiyu Wang,&nbsp;Yinyin Yao,&nbsp;Lin Luo,&nbsp;Jundan Xu,&nbsp;Lei Ma,&nbsp;Xinyi Zhao,&nbsp;Chengbin Fu,&nbsp;Mingqing Huang,&nbsp;Yusheng Lu","doi":"10.1016/j.ejphar.2026.179092","DOIUrl":"10.1016/j.ejphar.2026.179092","url":null,"abstract":"<div><div>Metastasis remains the leading cause of mortality in breast cancer, and effective prevention strategies are urgently needed. Sodium ferulate (SF), a bioactive compound derived from ferulic acid, has demonstrated diverse pharmacological activities, yet its role in suppressing cancer metastasis remains unclear. In this study, we demonstrate that SF significantly inhibits breast cancer metastasis through comprehensive modulation of the bloodstream microenvironment. At non-toxic concentrations, SF inhibited the migration and invasion of MCF-7 and MDA-MB-231 cells by suppressing the BMP4/Smad1/5/9 signaling pathway, reversing epithelial-mesenchymal transition (EMT), and disrupting cell cycle progression. SF also enhanced the sensitivity of breast cancer cells to paclitaxel. In addition, SF reduced tumor cell adhesion to endothelial cells by blocking TNF-α-induced expression of ICAM-1 and VCAM-1 through inhibition of NF-κB signaling cascade. Furthermore, SF attenuated platelet activation and angiogenesis, two key processes involved in metastatic dissemination and colonization. In 4T1 mouse metastasis model, SF treatment significantly decreased pulmonary metastatic nodules without causing organ toxicity. Immunohistochemical analysis further confirmed decreased expression of BMP4, PI3K, and N-cadherin in lung tissues following SF treatment. Additionally, SF enhanced systemic immunity by increasing the proportion of cytotoxic T cells and natural killer cells in peripheral blood. Collectively, these findings reveal that SF exerts potent anti-metastatic effects by modulating tumor-bloodstream-immune interactions rather than direct cytotoxicity. By remodeling the bloodstream microenvironment and enhancing immune defense, SF may represent a promising and safe candidate for the prevention of breast cancer metastasis.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179092"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148327690","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":"Diammonium glycyrrhizinate attenuates neuroinflammation after intracerebral hemorrhage by suppressing VCAM-1 expression via the PI3K-Akt pathway","authors":"Mengzhao Feng,&nbsp;Kaiyuan Zhang,&nbsp;Fang Wang,&nbsp;Han Wu,&nbsp;Qi Qin","doi":"10.1016/j.ejphar.2026.179094","DOIUrl":"10.1016/j.ejphar.2026.179094","url":null,"abstract":"<div><div>Intracerebral hemorrhage (ICH) is a devastating stroke subtype with limited therapeutic options, and excessive neuroinflammation plays a critical role in secondary brain injury following ICH. Here, we investigated whether diammonium glycyrrhizinate (DG), a clinically approved anti-inflammatory agent, confers neuroprotection in a mouse model of ICH and explored the underlying mechanisms. Adult male C57BL/6J mice subjected to collagenase-induced ICH were treated with DG or vehicle, and we assessed neurological function, brain water content, hematoma volume, and blood–brain barrier (BBB) integrity at 3 days post-ICH. DG treatment significantly reduced brain edema, hematoma volume, and BBB leakage while improving neurological outcomes. RNA sequencing revealed that DG downregulated 94 genes, with enrichment in cell surface receptor activity pathways, and identified Vascular cell adhesion molecule-1 (VCAM-1) as a key downstream target. VCAM-1 upregulation in brain microvascular endothelial cells after ICH was markedly suppressed by DG, accompanied by reduced neutrophil infiltration, attenuated microglial M1 polarization, and decreased production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), matrix metalloproteinase-9, oxidative stress markers, and apoptotic factors. Mechanistically, DG activated the PI3K-Akt signaling pathway, and this activation was associated with suppression of VCAM-1 expression and subsequent attenuation of neuroinflammation. These findings demonstrate that DG attenuates neuroinflammation and secondary brain injury after ICH by activating the PI3K-Akt pathway to suppress VCAM-1 expression, thereby limiting peripheral immune cell infiltration and modulating microglial polarization. The PI3K-Akt/VCAM-1 axis represents a promising therapeutic target, and DG may serve as a potential candidate for ICH management.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179094"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338302","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":"VER155008 rescues cognitive impairment in P301S tauopathy mice by promoting HSPA8-mediated lipophagy","authors":"Hongxiu Guo,&nbsp;Siyi Zheng,&nbsp;Xueying Shi,&nbsp;Xiufeng Wang,&nbsp;Rong Ma,&nbsp;Gang Li","doi":"10.1016/j.ejphar.2026.179107","DOIUrl":"10.1016/j.ejphar.2026.179107","url":null,"abstract":"<div><div>Alzheimer's disease (AD) features tau accumulation and pathogenic lipid droplet (LD) buildup, driving neurodegeneration through oxidative stress and neuroinflammation. The chaperone heat shock protein family A member 8 (HSPA8) is upregulated in AD, which may have implications for impaired LD clearance via lipophagy. We investigated whether targeting HSPA8 with the small-molecule antagonist VER155008 alleviates tau pathology and cognitive deficits by activating lipophagy in P301S tauopathy models. P301S tau transgenic mice and HEK293T-P301S cells were utilized. Western blotting, immunohistochemistry, and immunofluorescence were performed to assess HSPA8 levels, lipophagy, tau proteins, and inflammatory markers. VER155008 or vehicle control was administered to P301S mice for four weeks, starting at seven months of age. Cognitive function was evaluated using the Morris water maze and novel object recognition tests. Synaptic density was assessed through Golgi staining and electron microscopy. HSPA8 was elevated in P301S mice, correlating with impaired lipophagy and suppressed AMP-activated protein kinase (AMPK) activity. VER155008 treatment restored cognitive function and synaptic density. Critically, it activated lipophagy and reduced hippocampal LDs and tau pathology. Moreover, HSPA8 overexpression suppressed lipophagy and increased both LD accumulation and tau pathology. Inhibition of HSPA8 by VER155008 activates AMPK-mediated lipophagy, concurrently reducing tau pathology, oxidative stress, and neuroinflammation in AD models. These beneficial effects were eliminated by treatment with the AMPK inhibitor Compound C. This identifies the HSPA8-lipophagy axis as a promising therapeutic target for tauopathies.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179107"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148375001","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":"Taxifolin attenuates doxorubicin-induced heart, liver, and kidney toxicity in mice via targeting TLR4","authors":"Mengting Jiang,&nbsp;Shunlei Jiang,&nbsp;Xiaofeng Ye,&nbsp;Xin Qian,&nbsp;Jixu Li","doi":"10.1016/j.ejphar.2026.179136","DOIUrl":"10.1016/j.ejphar.2026.179136","url":null,"abstract":"<div><div>Doxorubicin (DOX) is an effective anthracycline chemotherapeutic agent widely used for treating lymphoma, leukemia, and sarcoma, but its clinical application is severely restricted by dose-dependent cardiotoxicity, hepatotoxicity, and nephrotoxicity. This study aimed to investigate the mechanisms underlying DOX-induced multi-organ toxicity and identify targeted therapeutic natural compounds through an integrated approach combining network toxicology, virtual screening, molecular docking, molecular dynamics simulation, and <em>in vivo</em> validation. Potential targets were obtained by intersecting drug targets from SwissTargetPrediction, SuperPred, PharmMapper, DrugBank, TTD, ChEMBL, PubChem, and DGIdb databases with injury-related targets from GeneCards, OMIM, and TTD databases. Ten protein-protein interaction network analyses were performed to identify core targets, revealing 24 potential targets involved in DOX-induced toxicity. Gene Ontology enrichment analysis identified 1515 biological processes, 44 cellular components, and 90 molecular functions, while KEGG analysis highlighted 107 significant pathways including lipid and atherosclerosis-related signaling. TLR4 was prioritized as the top hub target, and reverse virtual screening of the natural product database identified taxifolin as a high-affinity candidate with favorable ADMET properties. Molecular docking and dynamics simulations confirmed stable taxifolin-TLR4 complex formation. <em>In vivo</em> experiments using a mouse model demonstrated that taxifolin significantly ameliorated serum biomarker elevations and histopathological damage in heart, liver, and kidney tissues while effectively suppressing TLR4 protein expression. These findings establish taxifolin as a promising TLR4-targeted natural therapeutic agent for mitigating DOX-induced multi-organ toxicity.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179136"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419845","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 lipid metabolism enzymes in breast cancer: Mechanistic basis and therapeutic vulnerabilities","authors":"Xinpeng Li,&nbsp;Hua Hao","doi":"10.1016/j.ejphar.2026.179131","DOIUrl":"10.1016/j.ejphar.2026.179131","url":null,"abstract":"<div><div>Breast cancer constitutes a metabolically heterogeneous disorder wherein enzymes associated with lipid metabolism are instrumental in tumor progression, adaptation to the microenvironment, and therapeutic response. Beyond their catalytic roles in fatty acid, cholesterol, and phospholipid metabolism, these enzymes may function as regulatory nodes linking lipid flux to membrane remodeling, lipid peroxide detoxification, autophagy-dependent recycling, epithelial–mesenchymal plasticity, tumor–macrophage crosstalk, epigenetic stabilization, and multidrug resistance (MDR). This review adopts a subtype-aware, node-based framework to analyze lipid metabolic enzymes as context-dependent drivers of malignant phenotypes and treatment resistance. Furthermore, pharmacological strategies targeting lipid metabolic pathways—including fatty acid synthase (FASN) inhibition, ferroptosis induction, blockade of fatty acid oxidation, modulation of cholesterol metabolism, and interference with lipid uptake—are examined. The majority of these strategies are currently at preclinical or early translational stages, encountering significant challenges such as toxicity, metabolic compensation, subtype heterogeneity, and inadequate biomarker-guided patient selection. This review emphasizes lipid-metabolism enzymes as potential therapeutic vulnerabilities and underscores the necessity for mechanistic validation, rational combination therapies, and biomarker-driven metabolic stratification in breast cancer.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179131"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419891","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":"Drug repurposing of glucosamine to ameliorate alcoholic liver disease and delay liver aging through activation of AMPK signaling pathway","authors":"Yihe Song,&nbsp;Wei Li,&nbsp;Qiqi Shao,&nbsp;Junyang Huang,&nbsp;Xiaobo Guo,&nbsp;Xicheng Wang,&nbsp;Chao Gu,&nbsp;Jiahui Ke,&nbsp;Tong Zhu,&nbsp;Xiaojie Gao,&nbsp;Wenwen Liu,&nbsp;Manjiong Wang,&nbsp;Jian Li,&nbsp;Yixiang Xu,&nbsp;Xiaokang Li","doi":"10.1016/j.ejphar.2026.179143","DOIUrl":"10.1016/j.ejphar.2026.179143","url":null,"abstract":"<div><div>Alcohol consumption is a major etiological factor for alcoholic liver disease (ALD) and accelerates liver aging, representing a progressive condition with limited therapeutic options. Recent evidence suggests that targeting hepatocellular senescence represents a promising therapeutic strategy, particularly through repurposing approved drugs capable of simultaneously ameliorating hepatic steatosis, inflammation, and liver aging. In this study, we screened reported anti-aging molecules and identified glucosamine (GlcN) as a candidate with the potential to mitigate both ALD and liver aging. In both acute and chronic mouse models of ALD, GlcN administration significantly reduced hepatic lipid accumulation, pro-inflammatory cytokine expression, and cellular senescence markers. Mechanistically, GlcN activated AMPK signaling, which subsequently suppressed the senescence-associated secretory phenotype (SASP) through modulation of the p38 MAPK pathway, and improved lipid metabolism by regulating the SREBP1/FAS and ACC pathways. These findings illustrate the multifaceted role of GlcN in ameliorating both cellular senescence and dysregulated lipid metabolism, thereby attenuating ALD progression. Our results support the repurposing of GlcN as a potential candidate for ALD and alcohol-associated liver aging.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179143"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148445115","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":"DGAT2: A key therapeutic target in lipid synthesis regulation and metabolic diseases","authors":"Jun-Yao Cheng,&nbsp;Hui-Xuan Gu,&nbsp;Cheng-Hai He,&nbsp;Wen-Yan Gong,&nbsp;Kai-Jing Yang,&nbsp;Ying-Ying Liu,&nbsp;Zhen Chen,&nbsp;Qi-Bin Jiao,&nbsp;Xing-Wei Zhang,&nbsp;Hui Luo","doi":"10.1016/j.ejphar.2026.179145","DOIUrl":"10.1016/j.ejphar.2026.179145","url":null,"abstract":"<div><div>Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final committed step in the intracellular triglyceride (TG) synthesis pathway. It plays a critical role in energy metabolism by catalyzing the esterification of diacylglycerol (DG) into TG for storage. DGAT2 differs significantly from DGAT1—an unrelated enzyme from a distinct gene family that catalyzes the same biochemical reaction—in terms of structure, expression, and function. While DGAT2 is essential for skin barrier integrity (whose global absence is lethal in mice), its role in intracellular lipid storage in other tissues can often be compensated for by DGAT1. The expression and activity of DGAT2 are subject to complex multilevel regulation, including transcriptional control and post-translational modifications. Dysregulation of DGAT2 is a critical factor in the pathogenesis of several metabolic disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D). Given its substantial pathophysiological significance, DGAT2 has emerged as a key therapeutic target for metabolic diseases. Current therapeutic strategies include small-molecule inhibitors that directly suppress the enzyme activity of DGAT2, as well as nucleic acid–based approaches that silence DGAT2 mRNA expression. Here, we highlight the physiological and pathological roles of DGAT2, as well as the current therapeutic strategies targeting DGAT2 for the treatment of metabolic disorders.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179145"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148455161","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":"Trilobatin ameliorates pulmonary fibrosis by directly targeting MEK1 to antagonize TGF-β-driven epithelial-mesenchymal transition","authors":"Yuzhe Zhao,&nbsp;Sanwei Gu,&nbsp;Xia Zhang,&nbsp;Mengyuan Zhang,&nbsp;Lu Liu,&nbsp;Tingting Wang,&nbsp;Lei Song,&nbsp;Chao Wang,&nbsp;Dan Li","doi":"10.1016/j.ejphar.2026.179161","DOIUrl":"10.1016/j.ejphar.2026.179161","url":null,"abstract":"<div><div>Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by limited therapeutic options and a poor prognosis. Trilobatin (TLB), a natural dihydrochalcone extracted from <em>Lithocarpus polystachyus</em>, possesses diverse bioactivities; however, its anti-fibrotic potential and underlying mechanisms remain poorly defined. Here, we demonstrate that TLB effectively mitigates bleomycin (BLM)-induced pulmonary fibrosis in vivo and suppresses transforming growth factor-beta 1 (TGF-β1)-driven epithelial-mesenchymal transition (EMT) <em>in vitro</em>. In fibrotic mice, TLB treatment significantly attenuated pro-inflammatory cytokine secretion, limited inflammatory cell infiltration, preserved alveolar architecture, and decreased collagen deposition, ultimately leading to improved survival rates. Through network pharmacology and molecular docking, we identified MEK1 as a primary molecular target of TLB, an interaction subsequently validated by the Cellular Thermal Shift Assay (CETSA). Mechanistically, TLB directly uncoupled the TGF-β-induced ERK signaling cascade by selectively inhibiting the phosphorylation of MEK1 and ERK1/2, without affecting the upstream activation of Raf1. Furthermore, pharmacological hyperactivation of MEK1 via forskolin abrogated the protective effects of TLB against EMT and fibrogenesis. Collectively, our findings reveal a previously unrecognized anti-fibrotic mechanism of TLB, suggesting that this natural small molecule is a promising therapeutic candidate for IPF by specifically targeting MEK1-dependent ERK signaling.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179161"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148548259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}