Chronic kidney disease (CKD) refers to a pathological change characterized by the progressive and irreversible loss of renal function. Renal fibrosis is the final pathological outcome of CKD without effective treatment. Persistent inflammation is one of the most important factors in the occurrence and development of fibrosis. FK2, a 9-amino-acid-residue peptide originating from the silk of Zea mays L., was reported to have anti-inflammatory effects on mice. In this study, we verified for the first time that FK2 has an inhibitory effect on the process of renal fibrosis both in vivo and in vitro. Mechanistically, we identified IKKβ as a direct target of FK2. By binding to IKKβ, FK2 concurrently suppresses the IKKβ/NF-κB and TGF-β1/Smad2/3 signaling axes, thereby effectively mitigating the associated inflammatory response and key cellular processes including macrophage-to-myofibroblast transition (MMT) and epithelial-mesenchymal transition (EMT). Our research provides a promising candidate molecule for the development of anti-renal fibrosis drugs, and targeting IKKβ presents a viable strategy for treating kidney fibrosis.
{"title":"Peptide FK2 attenuates inflammation and pro-fibrotic cellular transitions via targeting the IKKβ/NF-κB/TGF-β1 axis in renal fibrosis","authors":"Runling Yang, Xiaocui Feng, Jianfeng Zhang, Tianyi Chen, Wenqian Wang, Yangrui Liu, Wanru Chen, Jingya Bai, Bangzhi Zhang","doi":"10.1016/j.ejphar.2026.178567","DOIUrl":"10.1016/j.ejphar.2026.178567","url":null,"abstract":"<div><div>Chronic kidney disease (CKD) refers to a pathological change characterized by the progressive and irreversible loss of renal function. Renal fibrosis is the final pathological outcome of CKD without effective treatment. Persistent inflammation is one of the most important factors in the occurrence and development of fibrosis. FK2, a 9-amino-acid-residue peptide originating from the silk of <em>Zea mays L</em>., was reported to have anti-inflammatory effects on mice. In this study, we verified for the first time that FK2 has an inhibitory effect on the process of renal fibrosis both in vivo and in vitro. Mechanistically, we identified IKKβ as a direct target of FK2. By binding to IKKβ, FK2 concurrently suppresses the IKKβ/NF-κB and TGF-β1/Smad2/3 signaling axes, thereby effectively mitigating the associated inflammatory response and key cellular processes including macrophage-to-myofibroblast transition (MMT) and epithelial-mesenchymal transition (EMT). Our research provides a promising candidate molecule for the development of anti-renal fibrosis drugs, and targeting IKKβ presents a viable strategy for treating kidney fibrosis.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178567"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017867","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}
Pub Date : 2026-02-15Epub Date: 2026-01-22DOI: 10.1016/j.ejphar.2026.178587
Shenyue Zhang , Shengbo Niu , Shengli An , Xinghai Cai , Xiangqian Lao
Background
Semaglutide has demonstrated significant weight loss benefits, but comprehensive evidence on its long-term efficacy and safety in non-diabetic adults with overweight or obesity remains limited. This meta-analysis provides updated evidence by incorporating oral semaglutide data, extended follow-up duration, and comprehensive subgroup analyses.
Methods
We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov databases from inception to April 30, 2024. Randomized controlled trials comparing semaglutide with placebo in non-diabetic adults with BMI ≥27 kg/m2 were included in this study. The Cochrane Risk of Bias 2 tool was used for quality assessment. Data were analyzed using RevMan v5.4. Sensitivity analyses were used to explore the sources of heterogeneity.
Results
Seven RCTs involving 5411 participants were included in this review. Semaglutide significantly reduced absolute weight (WMD -12.24 kg, 95 % CI -13.25 to −11.22), percentage weight change (WMD -12.15 %, 95 % CI -13.63 to −10.67), BMI (WMD -4.32 kg/m2, 95 % CI -4.75 to −3.89), and waist circumference (WMD -9.32 cm, 95 % CI -9.87 to −8.78). Semaglutide increased likelihood of achieving ≥5 % weight loss (RR 2.63, 95 % CI 2.12–3.25). Total adverse events were modestly but significantly elevated (RR 1.05, 95 % CI 1.01–1.09), primarily gastrointestinal symptoms. Serious adverse reactions were also higher (RR 1.33, 95 % CI 1.08–1.63).
Conclusions
Both oral and subcutaneous semaglutide significantly improve weight management in non-diabetic adults. While the safety profile is generally acceptable, elevated serious adverse events warrant careful patient selection and monitoring. Optimal outcomes occur with lifestyle interventions at doses ≥2.4 mg weekly.
背景：Semaglutide已显示出显著的减肥效果，但关于其对超重或肥胖的非糖尿病成人的长期疗效和安全性的综合证据仍然有限。本荟萃分析通过纳入口服西马鲁肽数据、延长随访时间和全面亚组分析提供了最新证据。方法：系统检索PubMed、Embase、Cochrane Library、Web of Science和ClinicalTrials.gov数据库，检索时间从成立到2024年4月30日。在BMI≥27 kg/m2的非糖尿病成年人中比较西马鲁肽和安慰剂的随机对照试验纳入了本研究。采用Cochrane风险偏倚2工具进行质量评估。使用RevMan v5.4对数据进行分析。敏感性分析用于探索异质性的来源。结果：本综述纳入了7项随机对照试验，涉及5,411名受试者。Semaglutide显著降低绝对体重（WMD -12.24 kg, 95% CI -13.25 ~ -11.22）、体重变化百分比（WMD -12.15%, 95% CI -13.63 ~ -10.67）、BMI （WMD -4.32 kg/m2, 95% CI -4.75 ~ -3.89）和腰围（WMD -9.32 cm, 95% CI -9.87 ~ -8.78）。Semaglutide增加了达到≥5%体重减轻的可能性（RR 2.63, 95% CI 2.12-3.25）。总不良事件轻微但显著升高（RR 1.05, 95% CI 1.01-1.09），主要是胃肠道症状。严重不良反应也较高（RR 1.33, 95% CI 1.08-1.63）。结论：口服和皮下注射西马鲁肽均可显著改善非糖尿病成人的体重管理。虽然安全性一般可以接受，但严重不良事件的增加需要仔细选择和监测患者。最佳结果发生在剂量≥2.4 mg每周的生活方式干预。
{"title":"Efficacy and safety of semaglutide in non-diabetic adults with overweight or obesity: A meta-analysis of randomized controlled trials","authors":"Shenyue Zhang , Shengbo Niu , Shengli An , Xinghai Cai , Xiangqian Lao","doi":"10.1016/j.ejphar.2026.178587","DOIUrl":"10.1016/j.ejphar.2026.178587","url":null,"abstract":"<div><h3>Background</h3><div>Semaglutide has demonstrated significant weight loss benefits, but comprehensive evidence on its long-term efficacy and safety in non-diabetic adults with overweight or obesity remains limited. This meta-analysis provides updated evidence by incorporating oral semaglutide data, extended follow-up duration, and comprehensive subgroup analyses.</div></div><div><h3>Methods</h3><div>We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and <span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> databases from inception to April 30, 2024. Randomized controlled trials comparing semaglutide with placebo in non-diabetic adults with BMI ≥27 kg/m<sup>2</sup> were included in this study. The Cochrane Risk of Bias 2 tool was used for quality assessment. Data were analyzed using RevMan v5.4. Sensitivity analyses were used to explore the sources of heterogeneity.</div></div><div><h3>Results</h3><div>Seven RCTs involving 5411 participants were included in this review. Semaglutide significantly reduced absolute weight (WMD -12.24 kg, 95 % CI -13.25 to −11.22), percentage weight change (WMD -12.15 %, 95 % CI -13.63 to −10.67), BMI (WMD -4.32 kg/m<sup>2</sup>, 95 % CI -4.75 to −3.89), and waist circumference (WMD -9.32 cm, 95 % CI -9.87 to −8.78). Semaglutide increased likelihood of achieving ≥5 % weight loss (RR 2.63, 95 % CI 2.12–3.25). Total adverse events were modestly but significantly elevated (RR 1.05, 95 % CI 1.01–1.09), primarily gastrointestinal symptoms. Serious adverse reactions were also higher (RR 1.33, 95 % CI 1.08–1.63).</div></div><div><h3>Conclusions</h3><div>Both oral and subcutaneous semaglutide significantly improve weight management in non-diabetic adults. While the safety profile is generally acceptable, elevated serious adverse events warrant careful patient selection and monitoring. Optimal outcomes occur with lifestyle interventions at doses ≥2.4 mg weekly.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178587"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043992","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}
Pub Date : 2026-02-15Epub Date: 2026-01-22DOI: 10.1016/j.ejphar.2026.178586
Liangyu Chen , Xiaojun Liu , Ying Guo , Ying Liu , Xin Zheng , Shi Yin , Yifei Wang , Hui Xue , Jiamei Liu
Globally, traumatic brain injury (TBI) and stroke are the primary contributors to mortality and disability. In recent years, C-C chemokine receptor 5 (CCR5) has attracted much attention as a potential therapeutic target for stroke and TBI. Therefore, we performed a meta-analysis of animal models of stroke or TBI to assess the therapeutic effects of CCR5 inhibition. The PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), VIP Chinese Journal Service Platform (VIP), Ovid MEDLINE, Wanfang Data Knowledge Service Platform (Wanfang), and China Biomedical Literature Database (CBM) databases were searched, and twelve studies were included. The program Stata 17.0 was used to perform the statistical analysis. Overall, the results revealed that CCR5 inhibition reduced infarct volume, neurological deficit scores, and microglial activation and increased cAMP response element-binding protein (CREB) expression levels in animal models of stroke or TBI; however, there was no significant effect on astrocytes or the number of apoptotic cells. Subgroup analyses revealed that inhibition of CCR5 was more effective at reducing lesion volume in animal models of TBI, with CCR5 inhibitors, after the onset of stroke or TBI, and at intervention durations of 1–3 days. Furthermore, the results of this study suggest that the CCR5/PKA/CREB signaling pathway may be involved in the treatment of stroke and traumatic brain injury. These results suggest that CCR5 inhibition may have significant therapeutic uses in the management of TBI and stroke. However, further preclinical research is needed to assess the safety and effectiveness of CCR5 inhibitors with greater accuracy.
在全球范围内，创伤性脑损伤（TBI）和中风是导致死亡和残疾的主要原因。近年来，C-C趋化因子受体5 （CCR5）作为脑卒中和脑外伤的潜在治疗靶点备受关注。因此，我们对脑卒中或脑外伤动物模型进行了荟萃分析，以评估CCR5抑制的治疗效果。检索PubMed、Cochrane图书馆、Web of Science、中国知网（CNKI）、维普中文期刊服务平台（VIP）、Ovid MEDLINE、万方数据知识服务平台（Wanfang）、中国生物医学文献数据库（CBM）等数据库，共纳入12篇研究。采用Stata 17.0软件进行统计分析。总体而言，结果显示CCR5抑制减少脑卒中或TBI动物模型中的梗死体积、神经功能缺损评分和小胶质细胞激活，并增加cAMP反应元件结合蛋白（CREB）表达水平；但对星形胶质细胞及凋亡细胞数量无明显影响。亚组分析显示，CCR5抑制剂在脑卒中或TBI发病后，干预时间为1-3天，在TBI动物模型中，CCR5抑制剂在减少病变体积方面更有效。此外，本研究结果提示CCR5/PKA/CREB信号通路可能参与脑卒中和创伤性脑损伤的治疗。这些结果表明，CCR5抑制可能在TBI和卒中的治疗中具有重要的治疗作用。然而，需要进一步的临床前研究来更准确地评估CCR5抑制剂的安全性和有效性。
{"title":"The therapeutic effect of inhibition of CCR5 on animal models of stroke or traumatic brain injury: A systematic review and meta-analysis","authors":"Liangyu Chen , Xiaojun Liu , Ying Guo , Ying Liu , Xin Zheng , Shi Yin , Yifei Wang , Hui Xue , Jiamei Liu","doi":"10.1016/j.ejphar.2026.178586","DOIUrl":"10.1016/j.ejphar.2026.178586","url":null,"abstract":"<div><div>Globally, traumatic brain injury (TBI) and stroke are the primary contributors to mortality and disability. In recent years, C-C chemokine receptor 5 (CCR5) has attracted much attention as a potential therapeutic target for stroke and TBI. Therefore, we performed a meta-analysis of animal models of stroke or TBI to assess the therapeutic effects of CCR5 inhibition. The PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), VIP Chinese Journal Service Platform (VIP), Ovid MEDLINE, Wanfang Data Knowledge Service Platform (Wanfang), and China Biomedical Literature Database (CBM) databases were searched, and twelve studies were included. The program Stata 17.0 was used to perform the statistical analysis. Overall, the results revealed that CCR5 inhibition reduced infarct volume, neurological deficit scores, and microglial activation and increased cAMP response element-binding protein (CREB) expression levels in animal models of stroke or TBI; however, there was no significant effect on astrocytes or the number of apoptotic cells. Subgroup analyses revealed that inhibition of CCR5 was more effective at reducing lesion volume in animal models of TBI, with CCR5 inhibitors, after the onset of stroke or TBI, and at intervention durations of 1–3 days. Furthermore, the results of this study suggest that the CCR5/PKA/CREB signaling pathway may be involved in the treatment of stroke and traumatic brain injury. These results suggest that CCR5 inhibition may have significant therapeutic uses in the management of TBI and stroke. However, further preclinical research is needed to assess the safety and effectiveness of CCR5 inhibitors with greater accuracy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178586"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044025","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}
Pub Date : 2026-02-15Epub Date: 2026-01-21DOI: 10.1016/j.ejphar.2026.178585
Maria Sofia Anastácio , Francisco Veiga , Ana Cláudia Paiva-Santos , Patrícia C. Pires
Nanotechnology has emerged as an innovative tool capable of overcoming the limitations of traditional drug delivery systems, by enabling enhanced drug solubility and stability, controlled drug release, and improved drug targeting. Additionally, nanosystems can allow the co-encapsulation of multiple drugs simultaneously, harnessing their synergistic pharmacological effects, leading to increased therapeutic efficacy and safety. The purpose of this review is to critically analyze studies that have developed triple drug-loaded nanosystems, exploring various different nanoplatforms, such as polymeric nanoparticles, lipid nanoparticles, microcapsules, nanoemulsions, nanoemulgels, thermosensitive hydrogels, and nanocomposite hydrogels. Triple drug co-encapsulation has been achieved for non-steroidal anti-inflammatory drugs such as indomethacin, analgesic and antipyretic drugs such as paracetamol, immunosuppressant drugs such as methotrexate, antiretroviral drugs such as efavirenz, lopinavir, ritonavir, and tenofovir, antibacterial drugs such as amoxicillin and clarithromycin, antiulcer drugs such as omeprazole and famotidine, ion channel antagonists such as lomerizine hydrochloride, oxidized adenosine triphosphate, and zonampanel monohydrate, photosensitive molecules such as indocyanine green, genetic material such as MMP-9 siRNA, enzymes such as catalase, and/or plant-derived bioactive compounds such as curcumin, resveratrol, sinomenine, and thymoquinone. These molecules’ triple co-encapsulation into nanometric formulations has led to controlled and sustained drug release, extended circulation time, enhanced bioavailability, and reduced systemic toxicity, with an overall improvement in drug targeting and therapeutic outcomes in rheumatoid arthritis, psoriasis and other inflammation-based conditions, HIV and Helicobacter pylori infection, and trauma-induced central nervous system secondary degeneration, ultimately opening a door for improved patient compliance due to simplified dosing regimens.
{"title":"Triple drug co-delivery within nanosystems for synergistic anti-infective, anti-inflammatory, antinociceptive and neuroregenerative therapeutic effects: a focus on pharmacological and nanotechnological aspects","authors":"Maria Sofia Anastácio , Francisco Veiga , Ana Cláudia Paiva-Santos , Patrícia C. Pires","doi":"10.1016/j.ejphar.2026.178585","DOIUrl":"10.1016/j.ejphar.2026.178585","url":null,"abstract":"<div><div>Nanotechnology has emerged as an innovative tool capable of overcoming the limitations of traditional drug delivery systems, by enabling enhanced drug solubility and stability, controlled drug release, and improved drug targeting. Additionally, nanosystems can allow the co-encapsulation of multiple drugs simultaneously, harnessing their synergistic pharmacological effects, leading to increased therapeutic efficacy and safety. The purpose of this review is to critically analyze studies that have developed triple drug-loaded nanosystems, exploring various different nanoplatforms, such as polymeric nanoparticles, lipid nanoparticles, microcapsules, nanoemulsions, nanoemulgels, thermosensitive hydrogels, and nanocomposite hydrogels. Triple drug co-encapsulation has been achieved for non-steroidal anti-inflammatory drugs such as indomethacin, analgesic and antipyretic drugs such as paracetamol, immunosuppressant drugs such as methotrexate, antiretroviral drugs such as efavirenz, lopinavir, ritonavir, and tenofovir, antibacterial drugs such as amoxicillin and clarithromycin, antiulcer drugs such as omeprazole and famotidine, ion channel antagonists such as lomerizine hydrochloride, oxidized adenosine triphosphate, and zonampanel monohydrate, photosensitive molecules such as indocyanine green, genetic material such as MMP-9 siRNA, enzymes such as catalase, and/or plant-derived bioactive compounds such as curcumin, resveratrol, sinomenine, and thymoquinone. These molecules’ triple co-encapsulation into nanometric formulations has led to controlled and sustained drug release, extended circulation time, enhanced bioavailability, and reduced systemic toxicity, with an overall improvement in drug targeting and therapeutic outcomes in rheumatoid arthritis, psoriasis and other inflammation-based conditions, HIV and <em>Helicobacter pylori</em> infection, and trauma-induced central nervous system secondary degeneration, ultimately opening a door for improved patient compliance due to simplified dosing regimens.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178585"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040784","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}
Pub Date : 2026-02-15Epub Date: 2026-01-16DOI: 10.1016/j.ejphar.2026.178569
Shaocong Sang , Huiming Han , Mingyue Liu , Nan Zhang , Yanrui Cui , Kaidong Liu , Kai Xiong , Haihai Liang , Lifang Lv , Yunyan Gu
Background
Immune checkpoint inhibitor (ICI) has revolutionized cancer treatment but can trigger severe immune-related adverse events (irAEs). Among these, cardiovascular irAEs (CV-irAEs) are rare yet associated with particularly high morbidity and mortality. This study aims to characterize the clinical features and underlying molecular mechanisms of CV-irAEs using pharmacovigilance and single-cell RNA sequencing data.
Methods
CV-irAEs are identified in the FDA Adverse Event Reporting System (FAERS) database through disproportionality analysis using reporting odds ratios. Onset times are compared across clinical variables using non-parametric tests. Factors associated with fatal outcomes are evaluated by Fisher's exact test, whereas logistic regression is employed to identify predictors of CV-irAEs occurrence. Finally, single-cell RNA sequencing explores sex differences in myocarditis irAEs.
Results
Twenty-six cardiovascular toxicity events are identified as CV-irAEs. Over 55 % of patients with CV-irAEs are diagnoses with lung or skin cancer. Additionally, CV-irAEs have a 43.91% fatality rate, and 51.82% of patients experience CV-irAEs within one month of ICI therapy initiation. Notably, patients over 75 years of age and those receiving anti-PD-1 monotherapy or combination therapy with anti-CTLA-4 are more susceptible to developing CV-irAEs. Furthermore, males experience more severe CV-irAEs. Accordingly, single-cell analysis reveals enhanced MIF and CD99 signaling between dendritic cells and effector memory T cells in male myocarditis irAEs patients, potentially explaining their greater susceptibility to severe CV-irAEs compared to females.
Conclusions
We identify key clinical risk factors and a male-specific immune signature in CV-irAEs, providing a foundation for personalized risk assessment and further mechanistic studies.
{"title":"Unraveling sex-related cardiovascular toxicity of immune checkpoint inhibitors by pharmacovigilance and single-cell transcriptomic analysis","authors":"Shaocong Sang , Huiming Han , Mingyue Liu , Nan Zhang , Yanrui Cui , Kaidong Liu , Kai Xiong , Haihai Liang , Lifang Lv , Yunyan Gu","doi":"10.1016/j.ejphar.2026.178569","DOIUrl":"10.1016/j.ejphar.2026.178569","url":null,"abstract":"<div><h3>Background</h3><div>Immune checkpoint inhibitor (ICI) has revolutionized cancer treatment but can trigger severe immune-related adverse events (irAEs). Among these, cardiovascular irAEs (CV-irAEs) are rare yet associated with particularly high morbidity and mortality. This study aims to characterize the clinical features and underlying molecular mechanisms of CV-irAEs using pharmacovigilance and single-cell RNA sequencing data.</div></div><div><h3>Methods</h3><div>CV-irAEs are identified in the FDA Adverse Event Reporting System (FAERS) database through disproportionality analysis using reporting odds ratios. Onset times are compared across clinical variables using non-parametric tests. Factors associated with fatal outcomes are evaluated by Fisher's exact test, whereas logistic regression is employed to identify predictors of CV-irAEs occurrence. Finally, single-cell RNA sequencing explores sex differences in myocarditis irAEs.</div></div><div><h3>Results</h3><div>Twenty-six cardiovascular toxicity events are identified as CV-irAEs. Over 55 % of patients with CV-irAEs are diagnoses with lung or skin cancer. Additionally, CV-irAEs have a 43.91% fatality rate, and 51.82% of patients experience CV-irAEs within one month of ICI therapy initiation. Notably, patients over 75 years of age and those receiving anti-PD-1 monotherapy or combination therapy with anti-CTLA-4 are more susceptible to developing CV-irAEs. Furthermore, males experience more severe CV-irAEs. Accordingly, single-cell analysis reveals enhanced MIF and CD99 signaling between dendritic cells and effector memory T cells in male myocarditis irAEs patients, potentially explaining their greater susceptibility to severe CV-irAEs compared to females.</div></div><div><h3>Conclusions</h3><div>We identify key clinical risk factors and a male-specific immune signature in CV-irAEs, providing a foundation for personalized risk assessment and further mechanistic studies.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178569"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997529","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}
Pub Date : 2026-02-15Epub Date: 2026-01-17DOI: 10.1016/j.ejphar.2026.178570
Stephanie Pain , Núria Nadal-Gratacós , Morgane De Macedo , Virginie Lardeux , Sandra Mata , Pol Puigseslloses , Fu-Hua Wang , Liselott Källsten , David Pubill , Xavier Berzosa , Jan Kehr , Jorge Camarasa , Elena Escubedo , Raul López-Arnau , Nathalie Thiriet , Marcello Solinas
Synthetic cathinones constitute a major class of New Psychoactive Substances (NPS) with significant abuse potential. Within this class, 3F-N-ethylbuphedrone (3F-NEB or 2-(ethylamino)-1-(3-fluorophenyl)butan-1-one), a novel N-ethyl buphedrone derivative, has recently emerged in recreational drug markets. However, its pharmacological properties and abuse liability remain uncharacterized.
The present study aimed to evaluate the neurochemical mechanisms and behavioral effects of 3F-NEB to assess its potential for abuse and addiction. To this end, we conducted in vitro monoamine uptake inhibition assays and in mice we performed locomotor activity and conditioned place preference tests. In rats, we conducted in vivo microdialysis in the nucleus accumbens, intravenous self-administration, and assessed neuroadaptive changes by ΔFosB immunohistochemistry following chronic self-administration.
Our results demonstrate that 3F-NEB acts as a potent dopamine transporter (DAT) inhibitor, with more than 100-fold selectivity over the serotonin transporter (SERT). Acute administration (3 mg/kg) rapidly increased extracellular dopamine levels in the nucleus accumbens of rats. At the behavioral level, 3F-NEB induced dose-dependent locomotor increases (10–30 mg/kg), with anxiety-like effects at the highest doses, and conditioned place preference at all tested doses (3–30 mg/kg) in mice. 3F-NEB was readily self-administered by rats under both fixed-ratio and progressive-ratio schedules. Furthermore, chronic self-administration significantly increased ΔFosB expression in dorsomedial and dorsolateral striatum, mirroring patterns observed with methamphetamine.
Taken together, these results demonstrate that 3F-NEB exhibits potent dopaminergic activity and high abuse liability through selective dopamine transporter inhibition. The compound's robust reinforcing properties and induction of addiction-related molecular adaptations suggest significant public health risks warranting immediate regulatory control.
{"title":"Neurochemical and behavioral evidence of high abuse liability of 3F-NEB, a novel synthetic cathinone","authors":"Stephanie Pain , Núria Nadal-Gratacós , Morgane De Macedo , Virginie Lardeux , Sandra Mata , Pol Puigseslloses , Fu-Hua Wang , Liselott Källsten , David Pubill , Xavier Berzosa , Jan Kehr , Jorge Camarasa , Elena Escubedo , Raul López-Arnau , Nathalie Thiriet , Marcello Solinas","doi":"10.1016/j.ejphar.2026.178570","DOIUrl":"10.1016/j.ejphar.2026.178570","url":null,"abstract":"<div><div>Synthetic cathinones constitute a major class of New Psychoactive Substances (NPS) with significant abuse potential. Within this class, 3F-N-ethylbuphedrone (3F-NEB or 2-(ethylamino)-1-(3-fluorophenyl)butan-1-one), a novel N-ethyl buphedrone derivative, has recently emerged in recreational drug markets. However, its pharmacological properties and abuse liability remain uncharacterized.</div><div>The present study aimed to evaluate the neurochemical mechanisms and behavioral effects of 3F-NEB to assess its potential for abuse and addiction. To this end, we conducted <em>in vitro</em> monoamine uptake inhibition assays and in mice we performed locomotor activity and conditioned place preference tests. In rats, we conducted in vivo microdialysis in the nucleus accumbens, intravenous self-administration, and assessed neuroadaptive changes by ΔFosB immunohistochemistry following chronic self-administration.</div><div>Our results demonstrate that 3F-NEB acts as a potent dopamine transporter (DAT) inhibitor, with more than 100-fold selectivity over the serotonin transporter (SERT). Acute administration (3 mg/kg) rapidly increased extracellular dopamine levels in the nucleus accumbens of rats. At the behavioral level, 3F-NEB induced dose-dependent locomotor increases (10–30 mg/kg), with anxiety-like effects at the highest doses, and conditioned place preference at all tested doses (3–30 mg/kg) in mice. 3F-NEB was readily self-administered by rats under both fixed-ratio and progressive-ratio schedules. Furthermore, chronic self-administration significantly increased ΔFosB expression in dorsomedial and dorsolateral striatum, mirroring patterns observed with methamphetamine.</div><div>Taken together, these results demonstrate that 3F-NEB exhibits potent dopaminergic activity and high abuse liability through selective dopamine transporter inhibition. The compound's robust reinforcing properties and induction of addiction-related molecular adaptations suggest significant public health risks warranting immediate regulatory control.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178570"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003328","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}
Pub Date : 2026-02-15Epub Date: 2026-01-14DOI: 10.1016/j.ejphar.2026.178550
Mohammad J. Eslamizade , Ali Dabbagh , Fariba Karimzadeh , Mahyar Janahmadi , Fatemeh Saffarzadeh
Over the last decade, experimental and clinical evidence has shaped the excitation/inhibition imbalance doctrine, which serves as our contemporary understanding of the mechanisms underlying various epilepsies. In addition, emerging findings have highlighted the peculiar role of γ-aminobutyric acid (GABA), the brain's main inhibitory neurotransmitter, as an underappreciated factor in hyperexcitation disorders such as epilepsy. Intriguingly, the unique neuroanatomy and synaptic physiology of thalamocortical (TC) circuits have made this axis a distinctive field of study. In this review, we focus on the current literature that explores the detailed structure of the GABAergic system in TC circuits under both normal conditions and absence seizures. Augmented excitability of TC neurons as well as cortical somatosensory neurons due to differential activity of various GABAergic neurons and synapses contributes to hyperoscillatory circuits in absence seizures. Furthermore, subtle yet significant differential expression of GABA receptor subunits in the thalamus and somatosensory cortex plays crucial roles in the pathophysiology of absence seizures. Convincing evidence also underscores the pivotal importance of the lower expression of GABA transporters, particularly in astrocytes, which increases synaptic concentration of GABA and promotes persistent tonic inhibition in the thalamus. This, in turn, creates a priming membrane potential that facilitates activation of transient (T)-type calcium channels, thereby increasing the excitability of TC neurons. In summary, this review accentuates hyperinhibition as a leading pathophysiology of absence seizures. Thus, there is a pressing need to develop targeted pharmacologic interventions or precision medicine approaches to treat absence seizures and potentially other TC related disorders.
{"title":"GABAergic dynamics in thalamocortical circuits: Insights into absence seizures and hyperinhibition","authors":"Mohammad J. Eslamizade , Ali Dabbagh , Fariba Karimzadeh , Mahyar Janahmadi , Fatemeh Saffarzadeh","doi":"10.1016/j.ejphar.2026.178550","DOIUrl":"10.1016/j.ejphar.2026.178550","url":null,"abstract":"<div><div>Over the last decade, experimental and clinical evidence has shaped the excitation/inhibition imbalance doctrine, which serves as our contemporary understanding of the mechanisms underlying various epilepsies. In addition, emerging findings have highlighted the peculiar role of γ-aminobutyric acid (GABA), the brain's main inhibitory neurotransmitter, as an underappreciated factor in hyperexcitation disorders such as epilepsy. Intriguingly, the unique neuroanatomy and synaptic physiology of thalamocortical (TC) circuits have made this axis a distinctive field of study. In this review, we focus on the current literature that explores the detailed structure of the GABAergic system in TC circuits under both normal conditions and absence seizures. Augmented excitability of TC neurons as well as cortical somatosensory neurons due to differential activity of various GABAergic neurons and synapses contributes to hyperoscillatory circuits in absence seizures. Furthermore, subtle yet significant differential expression of GABA receptor subunits in the thalamus and somatosensory cortex plays crucial roles in the pathophysiology of absence seizures. Convincing evidence also underscores the pivotal importance of the lower expression of GABA transporters, particularly in astrocytes, which increases synaptic concentration of GABA and promotes persistent tonic inhibition in the thalamus. This, in turn, creates a priming membrane potential that facilitates activation of transient (T)-type calcium channels, thereby increasing the excitability of TC neurons. In summary, this review accentuates hyperinhibition as a leading pathophysiology of absence seizures. Thus, there is a pressing need to develop targeted pharmacologic interventions or precision medicine approaches to treat absence seizures and potentially other TC related disorders.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178550"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976391","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}
Pub Date : 2026-02-15Epub Date: 2026-01-16DOI: 10.1016/j.ejphar.2026.178563
Huajie Li , Huangming Zhuang , Panghu Zhou
Background
Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by disruption of articular cartilage homeostasis, with ferroptosis of chondrocytes playing a crucial role. Cerium oxide nanoparticles (CeONPs), a class of inorganic nanozymes, exhibit potent antioxidant and anti-inflammatory properties. However, their effects on OA chondrocytes remain poorly understood.
Methods: mPEG2k-DSPE was employed to facilitate the transfer of CeONPs into the aqueous phase, resulting in PEG-CeONPs. Primary chondrocytes were isolated and subjected to erastin treatment to induce ferroptosis. The impact of PEG-CeONPs on oxidative stress, Fe2+ concentrations, mitochondrial dysfunction, ferroptosis-associated proteins, and OA-related catabolic phenotypes was evaluated. Additionally, the involvement of NRF2 in ferroptosis and its chondroprotective effects were investigated using NRF2-siRNA. An experimental OA model was established in rats through anterior cruciate ligament transection.
Results
Our study demonstrated that PEG-CeONPs attenuated erastin-induced cytotoxicity and reduced oxidative stress in chondrocytes. Moreover, PEG-CeONPs inhibited erastin-induced ferroptosis and promoted collagen matrix synthesis and secretion. The protective effects of PEG-CeONPs were mediated by the NRF2 pathway, as NRF2 silencing via siRNA significantly diminished the anti-ferroptosis and chondroprotective effects of PEG-CeONPs in vitro. These findings were further validated in OA rat models, where PEG-CeONPs treatment led to a reduction in ferroptosis-related gene expression and significantly alleviated cartilage degradation.
Conclusions
This study elucidates the previously unexplored relationship between PEG-CeONPs and ferroptosis in OA chondrocytes. PEG-CeONPs demonstrate anti-ferroptosis and chondroprotective effects by activating the NRF2 pathway, suggesting their potential as therapeutic agents for OA.
{"title":"PEGylated cerium oxide nanoparticles alleviate osteoarthritis progression by inhibiting chondrocyte ferroptosis and maintaining cartilage homeostasis","authors":"Huajie Li , Huangming Zhuang , Panghu Zhou","doi":"10.1016/j.ejphar.2026.178563","DOIUrl":"10.1016/j.ejphar.2026.178563","url":null,"abstract":"<div><h3>Background</h3><div>Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by disruption of articular cartilage homeostasis, with ferroptosis of chondrocytes playing a crucial role. Cerium oxide nanoparticles (CeONPs), a class of inorganic nanozymes, exhibit potent antioxidant and anti-inflammatory properties. However, their effects on OA chondrocytes remain poorly understood.</div><div>Methods: mPEG<sub>2k</sub>-DSPE was employed to facilitate the transfer of CeONPs into the aqueous phase, resulting in PEG-CeONPs. Primary chondrocytes were isolated and subjected to erastin treatment to induce ferroptosis. The impact of PEG-CeONPs on oxidative stress, Fe<sup>2+</sup> concentrations, mitochondrial dysfunction, ferroptosis-associated proteins, and OA-related catabolic phenotypes was evaluated. Additionally, the involvement of NRF2 in ferroptosis and its chondroprotective effects were investigated using NRF2-siRNA. An experimental OA model was established in rats through anterior cruciate ligament transection.</div></div><div><h3>Results</h3><div>Our study demonstrated that PEG-CeONPs attenuated erastin-induced cytotoxicity and reduced oxidative stress in chondrocytes. Moreover, PEG-CeONPs inhibited erastin-induced ferroptosis and promoted collagen matrix synthesis and secretion. The protective effects of PEG-CeONPs were mediated by the NRF2 pathway, as NRF2 silencing via siRNA significantly diminished the anti-ferroptosis and chondroprotective effects of PEG-CeONPs <em>in vitro</em>. These findings were further validated in OA rat models, where PEG-CeONPs treatment led to a reduction in ferroptosis-related gene expression and significantly alleviated cartilage degradation.</div></div><div><h3>Conclusions</h3><div>This study elucidates the previously unexplored relationship between PEG-CeONPs and ferroptosis in OA chondrocytes. PEG-CeONPs demonstrate anti-ferroptosis and chondroprotective effects by activating the NRF2 pathway, suggesting their potential as therapeutic agents for OA.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178563"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976246","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}
Pub Date : 2026-02-15Epub Date: 2026-01-20DOI: 10.1016/j.ejphar.2026.178580
Wenyu Hui , Weiwei Cui , Jie Li , Mengyuan Cheng , Yangyang Liu , Yunru Peng , Yongfang Ding
Objective
Cardiorenal syndrome (CRS), a spectrum of disorders involving intertwined cardiac and renal dysfunction, poses a significant challenge to mechanistic research due to a lack of accurate in vivo models. This study investigated the role of endoplasmic reticulum (ER) stress in mediating endothelial-to-mesenchymal transition (EndMT) and epithelial-to-mesenchymal transition (EMT) in a mouse model of cardiorenal comorbidity. Moreover, we investigated the therapeutic potential of 4-phenylbutyrate (4-PBA), an ER stress inhibitor, in attenuating cardiorenal comorbidity.
Methods
We employed a doxorubicin (Dox)-induced mouse model of cardiorenal comorbidity to investigate the role of ER stress in mediating EndMT and EMT. Six weeks post-Dox treatment, echocardiography, urinalysis, and blood tests were performed, complemented by immunofluorescence and Western blot analyses of cardiac and renal tissues. 4-PBA was intraperitoneally administered to evaluate the effect of ER stress inhibition on cardiorenal comorbidity.
Results
Dox administration significantly impaired cardiac and renal function, accompanied by pronounced fibrosis and upregulation of EndMT, EMT and ER stress markers. 4-PBA treatment attenuated cardiac injury, restored function, and ameliorated renal lesions. Consistent with in vivo results, Dox activated ER stress in HUVEC and HK-2 cells, promoting mesenchymal transformation. Critically, 4-PBA suppressed EndMT and EMT in vitro, supporting ER stress involvement in these processes.
Conclusions
Our findings demonstrate that Dox induces concurrent cardiorenal dysfunction, primarily through ER stress-mediated EndMT and EMT transitions. Importantly, pharmacological inhibition of ER stress with 4-PBA attenuated these pathological changes, suggesting its potential as a therapeutic strategy for cardiorenal syndrome.
{"title":"4-Phenylbutyrate attenuates doxorubicin-induced cardiorenal comorbidity by suppressing ER stress-mediated epithelial-mesenchymal transition and endothelial-mesenchymal transition","authors":"Wenyu Hui , Weiwei Cui , Jie Li , Mengyuan Cheng , Yangyang Liu , Yunru Peng , Yongfang Ding","doi":"10.1016/j.ejphar.2026.178580","DOIUrl":"10.1016/j.ejphar.2026.178580","url":null,"abstract":"<div><h3>Objective</h3><div>Cardiorenal syndrome (CRS), a spectrum of disorders involving intertwined cardiac and renal dysfunction, poses a significant challenge to mechanistic research due to a lack of accurate <em>in vivo</em> models. This study investigated the role of endoplasmic reticulum (ER) stress in mediating endothelial-to-mesenchymal transition (EndMT) and epithelial-to-mesenchymal transition (EMT) in a mouse model of cardiorenal comorbidity. Moreover, we investigated the therapeutic potential of 4-phenylbutyrate (4-PBA), an ER stress inhibitor, in attenuating cardiorenal comorbidity.</div></div><div><h3>Methods</h3><div>We employed a doxorubicin (Dox)-induced mouse model of cardiorenal comorbidity to investigate the role of ER stress in mediating EndMT and EMT. Six weeks post-Dox treatment, echocardiography, urinalysis, and blood tests were performed, complemented by immunofluorescence and Western blot analyses of cardiac and renal tissues. 4-PBA was intraperitoneally administered to evaluate the effect of ER stress inhibition on cardiorenal comorbidity.</div></div><div><h3>Results</h3><div>Dox administration significantly impaired cardiac and renal function, accompanied by pronounced fibrosis and upregulation of EndMT, EMT and ER stress markers. 4-PBA treatment attenuated cardiac injury, restored function, and ameliorated renal lesions. Consistent with <em>in vivo</em> results, Dox activated ER stress in HUVEC and HK-2 cells, promoting mesenchymal transformation. Critically, 4-PBA suppressed EndMT and EMT <em>in vitro</em>, supporting ER stress involvement in these processes.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that Dox induces concurrent cardiorenal dysfunction, primarily through ER stress-mediated EndMT and EMT transitions. Importantly, pharmacological inhibition of ER stress with 4-PBA attenuated these pathological changes, suggesting its potential as a therapeutic strategy for cardiorenal syndrome.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178580"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024875","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}
Pub Date : 2026-02-15Epub Date: 2026-01-10DOI: 10.1016/j.ejphar.2026.178539
Hailin Zhang , Hongzhuang Wang , Kai Kang , Shuaijie Chen , Yong Chu , Weiqiang Liu , Wenxiang Zhao , Zhongxing Zhou , Ruming Shen , Xiaoyan Lin , Jinxiu Lin , Dajun Chai
Background
Myocardial infarction (MI) remains a leading cause of cardiovascular mortality. While ketone bodies show cardioprotective potential, their role in regulating cardiomyocyte autophagy post-MI is unclear.
Methods
A rat MI model was established and treated with 1,3-butanediol (1,3-BD, 10 mg/100 g/day), a ketone precursor. Cardiac structure and function were assessed alongside autophagy and apoptosis levels. In vitro, hypoxia-induced cardiomyocytes were treated with β-hydroxybutyrate (β-HB) and phosphatidylinositol 3-kinase (PI3K) inhibitor. Mechanisms were explored via transcriptomics/metabolomics and validated by immunoblotting.
Results
1,3-BD treatment for 4 weeks significantly elevated serum β-HB, improved cardiac structure and function,and reduced cardiomyocyte apoptosis in MI rats, a finding corroborated in vitro where β-HB attenuated hypoxia-induced apoptosis in primary neonatal rat cardiomyocytes. The number of autophagic vesicles and LC3 fluorescence intensity in the infarct border zone decreased in the MI group compared with the control group, whereas 1,3-BD significantly increased autophagy levels in cardiomyocytes. In vitro, both β-HB and the PI3K inhibitor increased autophagy. However, the combination did not have an additional effect on regulating autophagy. Multi-omics analysis revealed 1,3-BD enriched the autophagy and PI3K-Akt-FOXO3 pathways. MI activated PI3K-Akt signaling and suppressed FOXO3, downregulating autophagy proteins (Atg7, Atg13, Beclin1, ULK1, LC3II/LC3I). 1,3-BD intervention reversed these changes.
Conclusion
1,3-BD improves post-MI cardiac remodeling by inhibiting cardiomyocyte apoptosis and enhancing autophagy, the latter mediated via suppression of the PI3K/Akt/FOXO3 pathway. Ketone supplementation represents a promising strategy against ischemic cardiomyopathy.
{"title":"1,3-Butanediol enhances autophagy via PI3K/Akt/FOXO3 pathway to ameliorate cardiac remodeling post-myocardial infarction","authors":"Hailin Zhang , Hongzhuang Wang , Kai Kang , Shuaijie Chen , Yong Chu , Weiqiang Liu , Wenxiang Zhao , Zhongxing Zhou , Ruming Shen , Xiaoyan Lin , Jinxiu Lin , Dajun Chai","doi":"10.1016/j.ejphar.2026.178539","DOIUrl":"10.1016/j.ejphar.2026.178539","url":null,"abstract":"<div><h3>Background</h3><div>Myocardial infarction (MI) remains a leading cause of cardiovascular mortality. While ketone bodies show cardioprotective potential, their role in regulating cardiomyocyte autophagy post-MI is unclear.</div></div><div><h3>Methods</h3><div>A rat MI model was established and treated with 1,3-butanediol (1,3-BD, 10 mg/100 g/day), a ketone precursor. Cardiac structure and function were assessed alongside autophagy and apoptosis levels. In vitro, hypoxia-induced cardiomyocytes were treated with β-hydroxybutyrate (β-HB) and phosphatidylinositol 3-kinase (PI3K) inhibitor. Mechanisms were explored via transcriptomics/metabolomics and validated by immunoblotting.</div></div><div><h3>Results</h3><div>1,3-BD treatment for 4 weeks significantly elevated serum β-HB, improved cardiac structure and function,and reduced cardiomyocyte apoptosis in MI rats, a finding corroborated <em>in vitro</em> where β-HB attenuated hypoxia-induced apoptosis in primary neonatal rat cardiomyocytes. The number of autophagic vesicles and LC3 fluorescence intensity in the infarct border zone decreased in the MI group compared with the control group, whereas 1,3-BD significantly increased autophagy levels in cardiomyocytes. In vitro, both β-HB and the PI3K inhibitor increased autophagy. However, the combination did not have an additional effect on regulating autophagy. Multi-omics analysis revealed 1,3-BD enriched the autophagy and PI3K-Akt-FOXO3 pathways. MI activated PI3K-Akt signaling and suppressed FOXO3, downregulating autophagy proteins (Atg7, Atg13, Beclin1, ULK1, LC3II/LC3I). 1,3-BD intervention reversed these changes.</div></div><div><h3>Conclusion</h3><div>1,3-BD improves post-MI cardiac remodeling by inhibiting cardiomyocyte apoptosis and enhancing autophagy, the latter mediated via suppression of the PI3K/Akt/FOXO3 pathway. Ketone supplementation represents a promising strategy against ischemic cardiomyopathy.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1015 ","pages":"Article 178539"},"PeriodicalIF":4.7,"publicationDate":"2026-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951314","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}
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