European journal of pharmacology最新文献

{"title":"Troxerutin Attenuates Paclitaxel-induced Cardiotoxicity Through Modulation of Ferroptosis and GRP78/ATF6/CHOP Signaling in Rats.","authors":"Yasmine M El-Naggar, Sara El Wakeel, Mina Y George, Doaa A Elsherbiny","doi":"10.1016/j.ejphar.2026.178944","DOIUrl":"https://doi.org/10.1016/j.ejphar.2026.178944","url":null,"abstract":"<p><p>Paclitaxel (PXT) is an effective chemotherapeutic agent whose clinical use is limited by serious cardiotoxic effects, including arrhythmias, myocardial infarction, and heart failure. Troxerutin (TXR) is a bioflavonoid with demonstrated cardioprotective properties in various cardiac injury models, including cardioprotective effects in doxorubicin-induced myocardial injury, as well as diabetic myocardiopathy. This study, therefore, investigates whether TXR can mitigate PXT-induced cardiotoxicity and explores the underlying protective mechanisms. Male Wistar rats were treated with either PXT (7.5 mg/kg/week, i.p.) and/or TXR (150 mg/kg/day, oral) for 28 days. TXR restored the histological structure of the myocardial tissues, as well as heart weight and heart index, which were disrupted following PXT treatment. In addition, TXR alleviated PXT-induced elevation of cardiac damage indicators such as Troponin I and CK-MB. Furthermore, TXR counteracted the PXT effect on cardiac iron deposits and mitigated PXT-induced imbalance of redox homeostasis as evidenced by the abridged reactive oxygen species level, raised levels of the antioxidant enzymes glutathione peroxidase-4, catalase and superoxide dismutase, attenuating ferroptosis induced by PXT. Besides, TXR ameliorated PXT-induced endoplasmic reticulum (ER) stress as indicated by reduced ER stress markers C/EBP homologous protein, activating transcription factor-6, and glucose regulatory protein-78. Moreover, TXR hindered apoptosis induced by PXT, as evidenced by its effect on the BAX and BCL-2 expressions. Importantly, TXR did not abrogate the anticancer activity of PXT in cultured human MDA-MB cells. In conclusion, TXR hindered the cardiotoxicity of PXT and showed cardioprotective effects via its inhibitory actions on ER stress, ferroptosis, oxidative stress, and apoptosis.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178944"},"PeriodicalIF":4.7,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147856073","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":"Neuroprotective effects of cinnamaldehyde and naltrexone on morphine-induced hippocampal neurotoxicity: Behavioral, biochemical, ultrastructural evaluations.","authors":"Seyede Soraya Mahmoudi, Amir Abbas Farshid, Esmaeal Tamaddonfard, Amir Erfanparast, Mehdi Imani","doi":"10.1016/j.ejphar.2026.178932","DOIUrl":"https://doi.org/10.1016/j.ejphar.2026.178932","url":null,"abstract":"<p><p>Chronic consumption of opiates such as morphine can exert serious adverse effects such as cognitive disturbances. Cinnamaldehyde has a potent neuroprotective property. The current study was targeted to explore the effect of cinnamaldehyde on morphine-induced behavioral and hippocampal biochemistry, histopathology and ultrastructure outcomes and molecular changes. Thirty rats were divided into five groups of six rats in each for receiving normal saline + normal saline, normal saline + morphine 40 mg/kg, cinnamaldehyde 10 mg/kg + morphine 40 mg/kg, cinnamaldehyde 20 mg/kg + morphine 40 mg/kg and naltrexone (an opioid receptor antagonist) 5 mg/kg + morphine 40 mg/kg. Another 24 rats were divided into four groups of six for treating with the above-mentioned treatments in the absence of morphine. Weekly body weight, behavioral tests and hippocampal tissue biochemical, histopathological, ultrastructural alterations were determined. Morphine-induced body weight loss and cognitive deficits, as measured with the Morris water maze (MWM) and elevated plus maze-transfer latency (EPM-TL) tests, were improved by cinnamaldehyde and naltrexone. Hippocampal malondialdehyde (MDA), superoxide dismutase (SOD), total antioxidant (TAC), tumor necrosis factor-α (TNF-α), caspase-3, and acetylcholinesterase (AChE) content alterations were restored by cinnamaldehyde and naltrexone. Neuronal shrinkage, vacuolation and loss and mitochondrial vacuolation and myelin sheath lamellar spacing in the hippocampus were improved. No significant differences were observed in normal saline, cinnamaldehyde and naltrexone treatments in the absence of morphine. These results indicated that cinnamaldehyde and naltrexone exert neuroprotective effects against morphine-induced cognitive deficits through antioxidant, anti-inflammatory, anti-apoptotic and anti-AChE mechanisms in the hippocampus.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178932"},"PeriodicalIF":4.7,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835446","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":"The Pulmonary Circadian Rhythms (Diurnal Rhythms) Role of the Bmal1/Per2 Axis in Mitigating Ventilator-Induced Lung Injury and Fibrosis through Nrf2 Antioxidant Pathway Activation.","authors":"De-Chao Li, Ming-Hui Wu, Hong-Yan Ruan","doi":"10.1016/j.ejphar.2026.178929","DOIUrl":"https://doi.org/10.1016/j.ejphar.2026.178929","url":null,"abstract":"<p><strong>Backgrounds: </strong>While lung-protective ventilation strategies are standard care, effective adjunctive pharmacotherapies for ventilator-induced lung injury (VILI) remain lacking. Disruption of circadian (diurnal) rhythms is implicated in various lung pathologies, and the exploration of circadian regulation in VILI has emerged as a clinically relevant research direction for optimizing mechanical ventilation strategies. We hypothesized that the pulmonary Bmal1/Per2 axis confers protection against VILI by activating the Nrf2 antioxidant pathway.</p><p><strong>Methods: </strong>A murine model of VILI was established via high-tidal volume ventilation. Lung epithelial cell-specific Bmal1 knockout mice (Bmal1^fl/fl; *SPC-CreERT2*) and wild-type littermates were used to define the role of the Bmal1/Per2 axis. Lung injury was assessed histologically, by bronchoalveolar lavage fluid protein, and wet/dry weight ratio. Fibrosis was evaluated after a recovery period using hydroxyproline assay and Masson's trichrome staining. Molecular mechanisms were analyzed by qPCR, western blot, and immunohistochemistry. The specific Nrf2 inhibitor ML385 was employed to validate pathway involvement.</p><p><strong>Results: </strong>VILI significantly disrupted pulmonary circadian rhythms, suppressing rhythmic Bmal1 and Per2 expression. Bmal1 deficiency markedly exacerbated VILI, increasing lung injury scores by approximately 2-fold, alveolar permeability by 1.8-fold, and edema. These mice subsequently developed more severe pulmonary fibrosis. This aggravated phenotype was associated with a blunted activation of the Nrf2-mediated antioxidant response, demonstrated by reduced expression of Nrf2 and its downstream targets HO-1 and NQO1. Pharmacological inhibition of Nrf2 with ML385 in wild-type mice abolished the protective effect, resulting in injury and fibrosis severity comparable to Bmal1-deficient animals.</p><p><strong>Conclusion: </strong>This study establishes a crucial functional link between the circadian clock and oxidative stress in mechanical lung injury, identifying the Bmal1/Per2-Nrf2 axis as a potential target for chronotherapeutic intervention. Notably, this work is the first to define the specific Bmal1/Per2 regulatory module and its direct causal connection with the Nrf2 pathway in mediating VILI-induced pulmonary fibrosis, extending prior observations of general circadian rhythm disruption in lung injury to a mechanistically actionable signaling axis.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178929"},"PeriodicalIF":4.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835402","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":"Citral exerts a more pronounced antinociceptive effect in obese adult male C57BL/6J mice mediated through the CB2 receptor.","authors":"Felipe Lima Dario, Maria Luiza Alves Aquino, Maycon Tavares Emílio-Silva, Felipe Leonardo Fagundes, Laura Vitória Fortunato de Oliveira, Isabela Galende Guidolin, Mariana Moraes Fioravanti, Renata Assunção, Vinícius Peixoto Rodrigues, Gabriela Bueno, Catarine Massucato Nishijima, Clelia Akiko Hiruma-Lima","doi":"10.1016/j.ejphar.2026.178894","DOIUrl":"https://doi.org/10.1016/j.ejphar.2026.178894","url":null,"abstract":"<p><strong>Background: </strong>Obesity is a prevalent chronic disease strongly associated with pain, primarily due to low-grade systemic inflammation that sensitizes nociceptive neurons.</p><p><strong>Objective: </strong>To evaluate the effects of citral, an acyclic monoterpene, present in essential oils such as Cymbopogon citratus (lemongrass), on nociception in obese mice and identify the mechanisms involved.</p><p><strong>Methods: </strong>Adult male C57BL/6J mice (n=232) were fed a standard diet (SD) or a high-fat diet (HFD) for 12 weeks. Metabolic alterations were confirmed using an oral glucose tolerance test. Nociception was assessed using the formalin test to evaluate both neurogenic (phase I) and inflammatory (phase II) pain. Citral (100 or 300 mg/kg) was orally administered. Carrageenan-induced paw edema was utilized to investigate anti-inflammatory properties. Antagonists for 5-HT2A (ketanserin, 1 mg/kg, i.p.) and CB2 (AM630, 1 mg/kg, i.p.) receptors were used. The vehicle group received 1% Tween 80 (10 mL/kg, orally). Statistical significance was set at p < 0.05.</p><p><strong>Results: </strong>HFD-fed mice developed obesity, hyperglycemia, and increased thermal sensitivity. Citral (300 mg/kg) significantly reduced nociception in both phases of the formalin test in SD and HFD mice, with a greater effect in the HFD group. CB2 receptor antagonism reversed the antinociceptive effects of citral in both phases of the formalin test, whereas 5-HT2A antagonism produced no change. LPS did not influence citral-induced antinociception only in obese mice, and citral showed no effect in the hot-plate test.</p><p><strong>Conclusion: </strong>Citral exerts antinociceptive effects in both eutrophic and obese mice, with enhanced efficacy in obese mice. Its action is mediated, at least in part, by CB2 receptor modulation, which reduces both neurogenic and inflammatory pain. These findings suggest that citral is a potential therapeutic candidate for pain management in obesity-related conditions.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178894"},"PeriodicalIF":4.7,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835385","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":"Transcriptomic alterations upon nuclear XIAP overexpression reveal IGFBP6/Wnt as a regulatory axis in breast cancer cell survival and chemoresistance.","authors":"Bruna Dos Santos Mendonça, Renata Binato, Eliana Abdelhay, Nathalia Silva Lima, Wallace Martins de Araujo, Raquel Ciuvalschi Maia, Renato Sampaio Carvalho, Gabriela Nestal de Moraes","doi":"10.1016/j.ejphar.2026.178876","DOIUrl":"https://doi.org/10.1016/j.ejphar.2026.178876","url":null,"abstract":"<p><p>X-linked inhibitor of apoptosis protein (XIAP) is an antiapoptotic protein which plays canonical functions in the cytoplasm. However, we have previously demonstrated that nuclear XIAP is associated with increased cell growth and drug resistance as well as unfavorable outcomes in breast cancer. Therefore, this work aimed to investigate the non-canonical molecular functions associated with abnormal XIAP nuclear localization in breast cancer. To address this, we have performed both transcriptomic and proteomic large-scale approaches with breast cancer cell line models overexpressing HA-tagged ectopic XIAP (WT, H467A, ΔRING and NLS mutants) in distinct subcellular locations. Nuclear XIAP overexpressing cells (XIAP^NLS) have been shown enriched for genes implicated in cellular processes other than apoptosis inhibition, such as proliferation, transport, locomotion, migration, cell motility, and protein phosphorylation. Interestingly, the validation analysis has shown differential expression of genes associated with the Wingless-related integration site (Wnt)/β-catenin pathway, as well as the insulin-like growth factor-binding protein 6 (IGFBP6) tumor suppressor gene. IGFBP6 transcript levels have been found reduced in XIAP^NLS-overexpressing cells, as well as invasive breast cancer patients. Notably, IGFBP6 knockdown modulated long-term cell proliferation and doxorubicin sensitivity in cells overexpressing nuclear XIAP, further suggesting that nuclear XIAP might indirectly target the IGFBP6 pathway to promote chemoresistance. Finally, Wnt signaling effectors were identified in nuclear XIAP interactomes, closely linked to activation of β-catenin transcriptional activity in XIAP^NLS-overexpressing cells. Our data establishes a non-canonical role for XIAP in the regulation of pathways related to cell growth in the nucleus, with Wnt/IGFBP6 emerging as a potential regulatory node associated with nuclear XIAP effects in breast cancer.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178876"},"PeriodicalIF":4.7,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147812339","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":"Corrigendum to “CT2-3 induces cell cycle arrest and apoptosis in rheumatoid arthritis fibroblast-like synoviocytes through regulating PI3K/AKT pathway” [Eur. J. Pharmacol. 956 (2023) 175871]","authors":"Jian Chen ,&nbsp;Xian Lin ,&nbsp;Kangdi Liu ,&nbsp;Juan He ,&nbsp;Xin Li ,&nbsp;Chuchu Zhang ,&nbsp;Yongxing Deng ,&nbsp;Lianxiang Luo ,&nbsp;Cheng Tao ,&nbsp;Qingwen Wang","doi":"10.1016/j.ejphar.2026.178839","DOIUrl":"10.1016/j.ejphar.2026.178839","url":null,"abstract":"","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1022 ","pages":"Article 178839"},"PeriodicalIF":4.7,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147671611","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 Houttuyfonate Alleviates Monocrotaline-induced Pulmonary Hypertension by Regulating Canonical Transient Receptor Potential Channel Proteins via CHIP.","authors":"Suya Zhang, Gaojia Ju, Jun Zhang, Fang Dong","doi":"10.1016/j.ejphar.2026.178874","DOIUrl":"https://doi.org/10.1016/j.ejphar.2026.178874","url":null,"abstract":"<p><p>The influx of extracellular Ca²⁺ through store-operated Ca²⁺ channels (SOCCs), known as store-operated calcium entry (SOCE), significantly contributes to the elevation of intracellular Ca²⁺ concentration ([Ca²⁺]_i) in pulmonary arterial smooth muscle cells (PASMCs), which plays a crucial role in pulmonary hypertension (PH). Canonical transient receptor potential channel (TRPC) proteins are the crucial constituents of SOCCs. Sodium houttuyfonate (SH) is a compound derived from the combination of sodium bisulfite and houttuynin. Our recent study demonstrates that SH alleviates monocrotaline (MCT)-induced PH (MCT-PH) by suppressing pulmonary arterial smooth muscle cell (PASMC) proliferation via TRPC1,4,6-SOCE-[Ca²⁺]_i signaling pathway. In this study, we investigated the contributions of Carboxyl terminus of Hsc70-interacting protein (CHIP) to TRPC1,4,6-SOCE-[Ca²⁺]_i signaling pathway and PASMC proliferation. Furthermore, based on the actions of CHIP, we explored the mechanism by which SH regulates TRPC1,4,6-SOCE-[Ca²⁺]_i signaling pathway. The results revealed that: 1) CHIP promotes MCT-induced PASMC proliferation by enhancing TRPC1,4,6-SOCE-[Ca²⁺]_i signaling pathway; 2) SH significantly downregulates CHIP expression in distal pulmonary arteries (PAs) and cultured PASMCs from MCT-PH rats. 3) Overexpression of CHIP attenuated the inhibitory effect of SH on MCT-elevated TRPC1,4,6-SOCE-[Ca²⁺]_i signaling pathway and PASMC proliferation. Collectively, these findings provide compelling evidence that SH effectively mitigates MCT-PH by inhibiting PASMC proliferation through the TRPC1,4,6-SOCE-[Ca²⁺]_i pathway, likely mediated by CHIP.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"178874"},"PeriodicalIF":4.7,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147722250","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":"Obesity-associated metabolic dysregulation aggravates myocardial ischemia-reperfusion injury through Gls2-mediated ferroptosis","authors":"Taotao Zhou ,&nbsp;Yang Liu ,&nbsp;Rong Xiao ,&nbsp;Baodong Xie ,&nbsp;Wandong Xie ,&nbsp;Xionghai Qin ,&nbsp;Xu Zhan ,&nbsp;Haobo Sun ,&nbsp;Donghui Liu ,&nbsp;Sida Qin ,&nbsp;Changfu Li ,&nbsp;Lihua Sun ,&nbsp;Kai Kang","doi":"10.1016/j.ejphar.2026.178739","DOIUrl":"10.1016/j.ejphar.2026.178739","url":null,"abstract":"<div><div>Metabolic diseases, including obesity, are becoming increasingly prevalent worldwide. However, the extent to which obesity-associated metabolic dysregulation exacerbates myocardial ischemia-reperfusion (IR) injury, and its specific impact on the patterns of cell death in this context, remain insufficiently understood. In this study, we demonstrate that obesity-associated metabolic dysregulation leads to more severe cardiac IR injury. This effect is not due to increased IR-mediated myocardial apoptosis, but rather to enhanced IR-induced ferroptosis. Our findings indicate that obesity-associated metabolic dysregulation aggravates cardiac ferroptosis primarily by upregulating glutaminase 2 (Gls2) expression in the heart. Furthermore, inhibition of Gls2 may attenuate IR injury exacerbated by obesity-associated metabolic dysregulation.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1019 ","pages":"Article 178739"},"PeriodicalIF":4.7,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147443109","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":"Corrigendum to “GZR18, a novel long-acting GLP-1 analog, demonstrated positive in vitro and in vivo pharmacokinetic and pharmacodynamic characteristics in animal models” [Europ. J. Pharmacol. 928 (2022) 175107]","authors":"Man Zhang ,&nbsp;Yining Zhang ,&nbsp;Xiaohong Peng ,&nbsp;Anshun He ,&nbsp;Yue Wang ,&nbsp;Ying Deng ,&nbsp;Cheng Cui ,&nbsp;Fangkai Xue ,&nbsp;Bing Wei ,&nbsp;Wancai Xing ,&nbsp;Yuzhen Qian ,&nbsp;Michelle Mazuranic ,&nbsp;Wei Chen","doi":"10.1016/j.ejphar.2026.178742","DOIUrl":"10.1016/j.ejphar.2026.178742","url":null,"abstract":"","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1019 ","pages":"Article 178742"},"PeriodicalIF":4.7,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147431585","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":"Repositioning of nonsedating antihistamine Ebastine for anti-lung adenocarcinoma based on EGFR/ERBB2 dual-targeting strategy","authors":"Yuehua Yu ,&nbsp;Zixuan Li ,&nbsp;Yuan He ,&nbsp;Ji Huang,&nbsp;Zhenxiao Sun","doi":"10.1016/j.ejphar.2026.178774","DOIUrl":"10.1016/j.ejphar.2026.178774","url":null,"abstract":"<div><div>Lung adenocarcinoma is a highly fatal carcinoma worldwide with limited therapeutic options. We identified EGFR/ERBB2 as promising dual targets through integrative analysis of clinical data and TCGA database. Molecular docking and cytotoxicity screening of FDA-approved drugs identified Ebastine as a potent dual-targeting agent. Ebastine significantly inhibited NCI-H1975 cell viability (EGFR-mutant with high EGFR/ERBB2 expression), induced ROS elevation, decreased mitochondrial membrane integrity, and triggered apoptosis. Western blot revealed that Ebastine suppressed phosphorylation of EGFR, ERBB2, ERK1/2 and AKT. In xenograft models, Ebastine significantly inhibited NCI-H1975 tumor growth with no significant impact on body weight. Histopathological and immunohistochemical analyses showed reduced Ki67 expression and increased tumor cell apoptosis in Ebastine-treated tumors. Notably, Ebastine promoted macrophage infiltration and M1 polarization both <em>in vivo</em> and <em>in vitro</em>. Our findings establish Ebastine as a promising therapeutic candidate for EGFR/ERBB2-mutant lung adenocarcinoma through a unique dual-targeting approach that combines direct tumor cell inhibition with enhancement of anti-tumor immunity.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1019 ","pages":"Article 178774"},"PeriodicalIF":4.7,"publicationDate":"2026-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462771","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}