European journal of pharmacology最新文献

{"title":"HSP70: From molecular chaperone to integrative hub in castration-resistant prostate cancer therapeutic resistance","authors":"Qiuyu Liu,&nbsp;Tianwen Huang,&nbsp;Lu Li,&nbsp;Zhongxiu Liang,&nbsp;Yonghong Liu,&nbsp;Jian Xiao,&nbsp;Xueni Wang","doi":"10.1016/j.ejphar.2026.179102","DOIUrl":"10.1016/j.ejphar.2026.179102","url":null,"abstract":"<div><div>The emergence of castration-resistant prostate cancer (CRPC), driven by ‘undruggable’ targets such as androgen receptor splice variant 7 (AR-V7), represents a fundamental barrier to curative therapeutic outcomes. This review proposes a conceptual framework reconceptualizing heat shock protein 70 (HSP70) as a potential integrative hub that may coordinate multiple resistance mechanisms. We synthesize available evidence to explore the hypothesis that HSP70 lies at the nexus of these pathways. We delineate how HSP70 has been reported to be associated with a multidimensional network: stabilizing oncoproteins (AR/AR-V7), potentially contributing to lineage plasticity via Plexin D1 (PLXND1), modulating ferroptosis through the AR-membrane-associated O-acyltransferase domain protein 2 (MBOAT2) axis, and engaging in synthetic vulnerability with heat shock protein 60 (HSP60). Consequently, therapeutic strategies are undergoing a paradigm shift from broad-spectrum inhibition to precision modalities targeting specific HSP70 interactions and functions. We provide a framework for leveraging this hub to overcome CRPC resistance.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179102"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148351337","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":"Vitamin D3 facilitates mucosal healing and modulates macrophage polarization in DSS-induced colitis, accompanied by restoration of epithelial Hippo–YAP signaling","authors":"Hongliang Gao,&nbsp;Ziying Hu,&nbsp;Longxiang Zhang,&nbsp;Keke Zhao,&nbsp;Yersen Asai,&nbsp;Yuan Li,&nbsp;Jing Wang,&nbsp;Zhiqiang Zhang,&nbsp;Guoli Du","doi":"10.1016/j.ejphar.2026.179134","DOIUrl":"10.1016/j.ejphar.2026.179134","url":null,"abstract":"<div><div>Damage to the epithelial barrier and dysregulated immune responses are core features of ulcerative colitis (UC). Although vitamin D3 (VD3) is widely recognized for immunomodulatory actions, how it contributes to mucosal repair remains incompletely defined. We used a dextran sulfate sodium (DSS)-induced acute colitis model to assess epithelial regeneration, macrophage polarization, and Hippo–Yes-associated protein (YAP) signaling. Mice received 3% DSS in drinking water and were treated with VD3 or vehicle, after which clinical indices, epithelial injury/repair, immune phenotypes, and inflammatory mediators were evaluated. VD3 markedly alleviated colitis severity and partially preserved mucosal architecture. VD3 showed dual protective effects: it reduced epithelial apoptosis and increased the expression of Ki67, zonula occludens-1 (ZO-1), and Claudin-1, indicating enhanced epithelial restitution; in parallel, it shifted macrophage polarization toward an anti-inflammatory M2-like profile and lowered pro-inflammatory mediator levels. At the signaling level, VD3 attenuated DSS-associated Hippo pathway activation and was accompanied by partial normalization of Yes-associated protein 1 (YAP1) phosphorylation status and YAP-related readouts. Collectively, VD3 improved DSS-induced colitis with coordinated enhancement of epithelial repair and immune-resolution features, accompanied by partial restoration of Hippo–YAP signaling, supporting its relevance to mucosal healing.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179134"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419886","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":"Senegenin mitigates neuroinflammation, pyroptosis, and apoptosis in cerebral ischemia via inhibiting STING and downstream inflammatory pathway","authors":"Chandan Chauhan,&nbsp;Ravinder K. Kaundal","doi":"10.1016/j.ejphar.2026.179147","DOIUrl":"10.1016/j.ejphar.2026.179147","url":null,"abstract":"<div><div>Ischemic stroke continues to be a major cause of mortality and persistent disability, with neuroinflammation at the central stage of cell death signaling. The stimulator of interferon genes (STING) pathway is emerging as a central driver of microglial activation and inflammatory damage. However, therapeutic strategies targeting this pathway are limited. We investigated the neuroprotective effects of senegenin, a bioactive natural compound, in a rat middle cerebral artery occlusion/reperfusion (MCAO/R) model and N9 microglia subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Behavioral, histological, and biochemical analyses were performed to assess neurological outcomes, infarct volume, microglial activation, and neuroinflammatory response. Mechanistic studies evaluated the effects of senegenin on STING-TBK1-IRF3 signaling, NFκB-dependent NLRP3 inflammasome activation, pyroptosis, and apoptosis. Molecular docking, dynamics simulations, and pharmacological validation with the STING agonist DMXAA were used to confirm direct STING inhibition. Senegenin treatment significantly improved neurological outcomes, decreased infarct volume, and preserved cortical and hippocampal neurons. It attenuated oxidative stress, reduced DNA damage, and inhibited microglial activation. Mechanistically, senegenin suppressed STING activation and downstream phosphorylation of TBK1 and IRF3, blocked NF-κB/NLRP3-mediated pyroptosis, and inhibited apoptotic death by modulating Bcl2 and BAX expression. Molecular docking predicted stable binding of senegenin to STING, and DMXAA experiments confirmed direct inhibition of STING signaling as the mechanistic basis of its neuroprotective effects. This study demonstrates that senegenin confers potent neuroprotection in ischemic stroke by attenuating regulated cell death pathways through direct inhibition of STING, highlighting its ability as a promising therapeutic candidate for STING-targeted interventions in ischemic stroke and related neuroinflammatory disorders.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179147"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148445203","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":"Selective pulmonary vasorelaxant effects of an N2,N4-diaminoquinazoline PDE5 inhibitor involving endothelial signaling and ion channel modulation","authors":"Usana Chatturong,&nbsp;Tipparat Meebangsue,&nbsp;Guntur Guntur,&nbsp;M. Paul Gleeson,&nbsp;Krongkarn Chootip","doi":"10.1016/j.ejphar.2026.179154","DOIUrl":"10.1016/j.ejphar.2026.179154","url":null,"abstract":"<div><div>Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary vascular resistance and right ventricular overload. Phosphodiesterase type-5 (PDE5) inhibitors are standard therapy but are limited by systemic vasodilation and side effects. <em>N</em>^<em>2</em>,<em>N</em>^<em>4</em>-diaminoquinazoline and <em>N</em>^<em>2</em>,<em>N</em>^<em>6</em>-diaminopurine derivatives have been identified as selective PDE5 inhibitors, however, achieving pulmonary vascular selectivity remains challenging. This study therefore evaluated the vasorelaxant effects of seven potent derivatives developed from the initial lead compound <strong>A</strong> with novel bioisosteric modifications. Their mechanisms of action were investigated in isolated rat pulmonary arteries and aorta. All compounds induced concentration-dependent vasorelaxation, with <em>N</em>⁴-benzyl-<em>N</em>²-(4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)quinazoline-2,4-diamine (compound <strong>6</strong>) demonstrating greater vasorelaxation in pulmonary arteries versus aorta (SI = 9.9 <em>vs</em> 5.6 for <strong>A</strong> and 2.1 for Sildenafil). In endothelium-intact vessels, inhibition of eNOS, cyclooxygenase, or EDHF attenuated vasorelaxation-induced by <strong>6</strong>, whereas in endothelium-denuded vessels, blocking guanylate cyclase or K_V channels reduced vasorelaxation, with K_Ca channels contributing in a modulatory manner. Importantly, <strong>6</strong> reduced extracellular Ca²⁺ influx through both voltage- and receptor-operated Ca²⁺ channels and reduced sarcoplasmic reticulum Ca²⁺ release, without affecting SNP-induced vasorelaxation. From molecular docking and pharmacophoric analysis, we postulate that the observed effects on Ca²⁺ influx may be associated with the introduction of a basic center into the original lead molecule <strong>A</strong>. This modified pharmacophore shares structural similarities with other heteroaromatic ion channel blockers that are capable of binding to VOCC and ROCC related targets. These findings demonstrate that <strong>6</strong> induces preferential pulmonary artery vasorelaxation under <em>ex vivo</em> conditions through multi-target mechanisms, supporting its potential as a therapeutic candidate for PAH.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179154"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469664","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":"Valerenic acid attenuates chronic stress-exacerbated metabolic dysfunction-associated steatotic liver disease via the estrogen receptor α-GDF15 axis","authors":"Xingli Wu,&nbsp;Yuzi Jiang,&nbsp;Junmin Wang,&nbsp;Simin Gu,&nbsp;Yanping Wang,&nbsp;Ning Li,&nbsp;Chunmei Qian,&nbsp;Hongming Nie,&nbsp;Yiyuan Zheng,&nbsp;Yong Li","doi":"10.1016/j.ejphar.2026.179106","DOIUrl":"10.1016/j.ejphar.2026.179106","url":null,"abstract":"<div><div>The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been rising annually. Meanwhile, with intensifying societal pressure, there has been a parallel surge in the prevalence of psychological disorders. The coexistence of these conditions creates a complex comorbidity, leading to heightened metabolic and cardiovascular risks, and posing challenges to traditional therapeutic approaches. Valerenic acid, a natural compound derived from the roots of <em>Valeriana officinalis</em>, exhibits sedative, anxiolytic, anti-inflammatory, and antioxidant effects, which may offer a promising therapeutic intervention for MASLD complicated by stress. The present study aims to experimentally evaluate the therapeutic effects of valerenic acid as well as to explore its pharmacological mechanisms, thereby providing evidence for its clinical application. Both male and female C57BL/6J mice were utilized in this study. A Western diet was employed to induce MASLD, while moderate, intermittent, and prolonged restraint stress was applied to simulate chronic stress, whereas valerenic acid was orally gavaged to assess its therapeutic efficacy. The outcomes revealed that, in both sexes, the initial phase of restraint stress induced concurrent reductions in food intake and body weight; however, following an adaptation period, persistent chronic stress paradoxically resulted in escalation of both food consumption and weight gain. Intervention with valerenic acid effectively attenuated stress-induced fluctuations in feeding behavior and body weight. Furthermore, estrogen receptor α was identified as a key target of valerenic acid, which regulated the pivotal immunometabolic mediator growth differentiation factor 15, thereby suppressing appetite while ameliorating hepatic inflammatory pathology.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179106"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367599","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":"CD47/SIRPα axis in cancer immunotherapy: Mechanisms, regulation, and therapeutic strategies","authors":"Yinghan Li,&nbsp;Hongxu Yu,&nbsp;Juanjuan Shi,&nbsp;Yongzhong Hou,&nbsp;Qian Gou","doi":"10.1016/j.ejphar.2026.179122","DOIUrl":"10.1016/j.ejphar.2026.179122","url":null,"abstract":"<div><div>The CD47/SIRPα axis functions as a critical “don't eat me” signaling pathway that enables tumor immune evasion by inhibiting macrophage-mediated phagocytosis. Although therapeutic blockade of this pathway holds significant promise for cancer immunotherapy, achieving an optimal balance between antitumor efficacy and on-target hematotoxicity, particularly anemia, remains a major clinical challenge. This comprehensive review synthesizes recent advances in our understanding of CD47 biology, including transcriptional and post-translational regulation, crosstalk with other signaling pathways, and innovative therapeutic strategies for safely targeting this innate immune checkpoint. We highlight emerging evidence that CD47 functions beyond its canonical role as a phagocytosis checkpoint, including its roles in regulating the tumor microenvironment and T-cell dysfunction. Finally, we discuss the development of next-generation CD47-targeting agents, including tumor-selective bispecific antibodies, peptide inhibitors, and combination regimens designed to maximize therapeutic efficacy while minimizing systemic toxicity.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179122"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410915","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":"Research advances of colchicine in anti-inflammatory treatment for coronary artery disease","authors":"Mengyu Han,&nbsp;Yugang Yan,&nbsp;Cuimei Guo,&nbsp;Xinxin Bian,&nbsp;Fengyi Shan,&nbsp;Yuntao Cheng,&nbsp;Xueying Chen","doi":"10.1016/j.ejphar.2026.179128","DOIUrl":"10.1016/j.ejphar.2026.179128","url":null,"abstract":"<div><div>Atherosclerosis is a chronic inflammatory disease, and anti-inflammatory therapy has become a key strategy for preventing and treating coronary artery disease (CAD). Colchicine, a cost-effective anti-inflammatory drug, can intervene in the atherosclerotic process through multiple mechanisms, such as inhibiting neutrophils and the nucleotide-binding domain, leucine-rich repeat family, pyrin domain-containing protein 3 (NLRP3) inflammasome. Numerous clinical trials have demonstrated that colchicine significantly improves cardiovascular outcomes in CAD patients, reducing the incidence of major adverse cardiovascular events (MACE) such as revascularization and stroke. Current clinical guidelines recommend low-dose colchicine for secondary prevention in chronic CAD. However, trials like CLEAR SYNERGY may yield negative results due to limitations such as design heterogeneity. Although the application value of low-dose colchicine in patients with chronic CAD has been fully established, more comprehensive research is still warranted to clarify its clinical benefits, personalized dosing regimens, and long-term safety profile in other populations. This article reviews the mechanism of action and pharmacological properties of colchicine, provides a detailed analysis of numerous clinical trials and meta-analyses examining its use in different types of CAD, and integrates safety data and guidelines to establish a solid foundation for clinical management. Furthermore, it explores its potential application value in special high-risk populations such as those with diabetes and Clonal Hematopoiesis (CH), offering direction for future precision treatment in this field.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179128"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148411017","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":"Low-molecular-weight fucoidan inhibits HMGB1-induced thromboinflammation by modulating HMGB1-TLR4 axis","authors":"Muhammad Awais,&nbsp;Siwen Fang,&nbsp;Xue Chen,&nbsp;Kang Liu,&nbsp;Haidong Chen,&nbsp;Qi-sheng Ling,&nbsp;Shaoyun Zhou,&nbsp;Tianxia Hou,&nbsp;Xinke Fang,&nbsp;Ming Liu,&nbsp;Chuanbin Shen","doi":"10.1016/j.ejphar.2026.179138","DOIUrl":"10.1016/j.ejphar.2026.179138","url":null,"abstract":"<div><div>Thromboinflammation is the pathological hallmark of diverse cardiovascular and inflammatory disorders. Platelets are the key effector cells linking thrombosis and inflammation and are known to express Toll-like receptors (TLRs) including TLR4. High mobility group box 1 protein (HMGB1) initiates a thromboinflammatory cascade by functioning as a primary ligand for platelet TLR4. Despite its central role in thromboinflammatory responses, HMGB1-TLR4 axis remains an unmet clinical need. In this study, we explored therapeutic potential of Low-molecular-weight Fucoidan (LMF) in modulating HMGB1-TLR4-driven thromboinflammation. It was found that LMF interacted with HMGB1 and interrupted HMGB1-dependent TLR4-mediated pro-inflammatory signaling. By targeting HMGB1, LMF profoundly suppressed early TLR4-driven platelet outside-in signaling events, encompassing intracellular calcium mobilization, Akt-upregulation and subsequent αIIbβ3 activation. This early signaling interception was manifested as functional deficit including impaired activation, reduced platelet aggregation and thrombus consolidation under shear conditions. Importantly, LMF disrupted HMGB1-driven platelet-leukocyte crosstalk as evident through reduced formation of neutrophil-extracellular traps. Further, LMF administration conferred cerebrovascular protection in mice by limiting HMGB1-driven thrombus growth, accompanied by marked reduction in cerebral infarction and systemic inflammation as reflected by decreased circulating IL-6 concentration. These findings demonstrate that LMF restrains HMGB1-dependent TLR4-driven thrombosis and vascular inflammation and could be a promising therapeutic intervention for thromboinflammatory disorders.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179138"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419806","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":"Aspirin enhances the anti-tumour activity of lapatinib in HER2-positive breast cancer","authors":"Hanbin Luo,&nbsp;Panpan Yuan,&nbsp;Kaili Guo,&nbsp;Junxi Chen,&nbsp;Junqing Xu,&nbsp;Yu Jiang,&nbsp;Chuan Wang,&nbsp;Jiping Liu,&nbsp;Bin Wang,&nbsp;Xingmei Zhu","doi":"10.1016/j.ejphar.2026.179132","DOIUrl":"10.1016/j.ejphar.2026.179132","url":null,"abstract":"<div><div>Resistance to human epidermal growth factor receptor 2 (HER2)-directed therapies remains a challenge in HER2-positive breast cancer. We evaluated whether aspirin could enhance the activity of lapatinib, a HER2/EGFR tyrosine kinase inhibitor, in HER2-positive breast cancer models. In BT-474 and SK-BR-3 cells, aspirin plus lapatinib inhibited cell viability, clonogenic growth and DNA synthesis more effectively than either agent alone, with combination index values supporting a synergistic interaction under the tested fixed-aspirin combination conditions. Cyclooxygenase-2 inhibition or PTGS2 knockdown did not fully recapitulate this potentiation, suggesting that cyclooxygenase-2 suppression alone is insufficient to explain the interaction. The combination was associated with increased AMP-activated protein kinase and acetyl-CoA carboxylase phosphorylation and reduced HER2 expression and phosphorylation of phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin pathway components. Compound C partially attenuated growth inhibition and pathway suppression, consistent with possible, non-exclusive involvement of AMPK, whereas rapamycin partially reproduced the growth-inhibitory pattern, suggesting a possible contribution of mTOR pathway attenuation without establishing it as the primary mediator. In BT-474 xenografts, co-administration significantly suppressed tumour growth and tumour weight, reduced Ki-67 positivity and increased cleaved caspase-3 expression. No marked systemic toxicity signals were detected based on body weight, major-organ histology and serum liver and renal function markers, although mild gastrointestinal histological changes occurred in aspirin-treated mice. Because the principal in vitro assays used millimolar aspirin concentrations and the in vivo dose exceeded conventional low-dose antiplatelet exposure, these findings should be interpreted as preclinical proof-of-concept evidence requiring further PK/PD-guided validation under clinically feasible conditions.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179132"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419867","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":"Trichostatin A improves impaired autophagic flux associated with ERK/FoxO3a signaling to alleviate acute pancreatitis","authors":"Xiangli Ma,&nbsp;Yurong Zhang,&nbsp;Zhenzhen Huang,&nbsp;Yujie Lin,&nbsp;Ling Zhang,&nbsp;Xu Fu,&nbsp;Peiwu Li","doi":"10.1016/j.ejphar.2026.179140","DOIUrl":"10.1016/j.ejphar.2026.179140","url":null,"abstract":"<div><div>Acute pancreatitis (AP) is an inflammatory disease with increasing incidence and limited therapeutic options. Impaired autophagic flux is recognized as a key pathological event in AP, while its upstream regulatory mechanisms remain incompletely understood. FoxO3a, a transcription factor involved in autophagy regulation, is negatively regulated by ERK-mediated phosphorylation. This study investigated whether Trichostatin A (TSA), a histone deacetylase inhibitor, protects against AP through modulation of the ERK/FoxO3a axis.</div><div>Network pharmacology, protein–protein interaction analysis, and enrichment analyses identified the ERK/FoxO3a pathway as a potential target of TSA. In AR42J cells, TSA was combined with the autophagy inhibitor 3-MA or the ERK activator PMA to validate the underlying mechanisms. Autophagic flux, inflammatory cytokines, mitochondrial function, and related protein expression were assessed, and a rat model of AP was used for in vivo validation.</div><div>TSA improved impaired autophagic flux and alleviated AP-associated injury. ERK phosphorylation was significantly increased under AP conditions, while FoxO3a expression showed a modest increase, suggesting possible regulatory adaptation and functional suppression under stress conditions. TSA treatment was associated with reduced ERK phosphorylation and modulation of FoxO3a-associated signaling, and was accompanied by improvement of impaired autophagic flux. These effects were partially reversed by PMA. Consistently, TSA reduced serum amylase, TNF-α, and IL-6 levels and improved pancreatic histopathology.</div><div>In conclusion, TSA alleviates AP-associated injury by improving impaired autophagic flux, which may be associated with inhibition of ERK phosphorylation and modulation of FoxO3a-related signaling. These findings highlight the ERK/FoxO3a axis as a potential regulatory pathway involved in AP pathology and a possible therapeutic target.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179140"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419872","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}