European journal of pharmacology最新文献

{"title":"Okanin alleviates osteoarthritis by suppressing oxidative stress and pyroptosis via Nrf2/HO-1 activation","authors":"Di Guo,&nbsp;Tao Xia,&nbsp;Dawei Han,&nbsp;Shuai He,&nbsp;Huifeng Xi","doi":"10.1016/j.ejphar.2026.179111","DOIUrl":"10.1016/j.ejphar.2026.179111","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a chronic joint disorder characterized by degenerative cartilage and chondrocyte dysfunction. Oxidative stress and NLRP3 inflammasome-mediated pyroptosis play pivotal roles in OA progression. This study investigated the protective effects and mechanisms of Okanin, a natural flavonoid, in a mouse model of knee osteoarthritis. We found that Okanin effectively activated the Nrf2/HO-1 signaling pathway, significantly enhanced the antioxidant capacity of chondrocytes and scavenged excess ROS. Concurrently, Okanin inhibited the assembly and activation of the NLRP3 inflammasome, thereby suppressing the caspase-1/GSDMD-dependent pyroptosis pathway. In vivo experiments demonstrated that Okanin treatment improved articular cartilage morphology, reduced proteoglycan loss, and decreased OARSI scores in a destabilization of the medial meniscus (DMM) murine model. Mechanistically, Nrf2 was identified as a key target of Okanin through siRNA knockdown. This study is the first to reveal that Okanin exerts dual chondroprotective effects against oxidative stress and pyroptosis via the Nrf2/HO-1 axis, suggesting a novel strategy for OA treatment.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179111"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148375023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Allicin alleviates myocardial PANoptosis during ischemia-reperfusion by inhibiting TLR4 activation","authors":"Shichao Liang,&nbsp;Jiajie Yin,&nbsp;Yijie Gao,&nbsp;Fangyuan Luo,&nbsp;Song Wu,&nbsp;Danni Wu,&nbsp;Lin Zhao,&nbsp;Tong Gao,&nbsp;Mengru Liu,&nbsp;Hong Jiang,&nbsp;Baofu Wang,&nbsp;Xianlun Li","doi":"10.1016/j.ejphar.2026.179159","DOIUrl":"10.1016/j.ejphar.2026.179159","url":null,"abstract":"<div><h3>Background</h3><div>PANoptosis is a newly identified form of programmed cell death characterized by necroptosis, pyroptosis, and apoptosis. However, the mechanism of myocardial PANoptosis in myocardial ischemia-reperfusion (MI/R) remains unclear. Allicin is a promising drug for MI/R treatment, and the targets for myocardial PANoptosis remain to be explored.</div></div><div><h3>Purpose</h3><div>This study aims to clarify the mechanism of myocardial PANoptosis during MI/R and therapeutic targets of allicin.</div></div><div><h3>Methods</h3><div>Sprague-Dawley rats were used to establish MI/R models. Allicin (3.6 mg/kg) was injected via the tail vein 5 min before reperfusion. Myocardial damage (cardiac function, structure, cTnT, CK-MB and apoptosis), PANoptosome components (RIPK1/3, caspase-8, ASC and NLRP3), PANoptosis indicators (MLKL, GSDMD, IL-1β/18 and caspase-3) were assessed to evaluate the cardioprotective effects of allicin. Subsequently, the potential signaling pathway related to PANoptosis and therapeutic targets of allicin were screened through transcriptomic analysis, and TLR4 signaling was selected for verification. Then, H9C2 cells were used to establish an oxygen-glucose deprivation/reperfusion (OGD/R) model. The TLR4 inhibitor TAK-242, agonist RS09, and allicin were used to clarify the pathological role of TLR4 in myocardial PANoptosis and the therapeutic target of allicin by measuring the indicators of myocardial damage, PANoptosis and TLR4 expression.</div></div><div><h3>Results</h3><div><em>In vivo</em> experiments revealed that allicin alleviated MI/R injury and reduced both myocardial PANoptosome components and PANoptosis. Based on transcriptomic analysis and published studies, the TLR4 signaling pathway was selected to verify the pathological role in PANoptosis and the therapeutic effects of allicin. <em>In vitro</em> experiments demonstrated that TLR4 activation further aggravated OGD/R-induced PANoptosis and increased TLR4 expression. Conversely, both allicin and the TLR4 inhibitor suppressed myocardial PANoptosis and TLR4 expression.</div></div><div><h3>Conclusion</h3><div>Allicin can reduce myocardial PANoptosis and ameliorate MI/R injury by inhibiting TLR4 activation. These findings provide a new target and strategy for the treatment of MI/R injury.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179159"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469611","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":"Inhibition of MST1/2 attenuates the anti-hepatocarcinogenesis effect of Salvianolic acid B via the ERK/MAPK signaling pathway","authors":"Miaomiao Li,&nbsp;Jiacheng Xu,&nbsp;Lele Zhu,&nbsp;Xiaoyu Yang,&nbsp;Huimin Ren,&nbsp;Jiemei Jiang,&nbsp;Lili Li,&nbsp;Yan Yang,&nbsp;Yongfang Gong","doi":"10.1016/j.ejphar.2026.179156","DOIUrl":"10.1016/j.ejphar.2026.179156","url":null,"abstract":"<div><div>Salvianolic acid B (Sal B), extracted from <em>Salvia miltiorrhiza</em>, has a commendable effect on liver-related disease. The Hippo/YAP and MAPK pathways were reported to exert synergistic effect on hepatocarcinogenesis. Our group has demonstrated that Sal B could restrain the MAPK pathway and postpone the hepatic fibrosis process. Also, Sal B exhibits anti-tumor activity by regulating the Hippo/YAP signaling. Simultaneously, the inhibition of the MAPK pathway could diminish the YAP expression in HepG2 cells; thus, we investigated the impact of <em>MST1/2</em> gene double knockout (DKO) on the MAPK signaling pathway during hepatocarcinogenesis. Furthermore, the role of ERK/MAPK pathway in the interference of Hippo/YAP signaling associated with the anti-hepatocarcinogenic actions of Sal B was explored. DEN/CCl₄/C₂H₅OH-induced liver fibrosis and cancer in <em>MST1/2</em> DKO mice and TGF-β1/XMU-MP-1 (MST1/2 inhibitor)-stimulated or YAP-shRNAs/pEGFP lentiviral transfected hepatic stellate cells or hepatoma cells were employed in this study. <em>In vivo</em>, our results demonstrated that <em>MST1/2</em> DKO attenuated Sal B's curative histopathological and serological outcomes, and its mechanism of action involves the activation of the MAPK signaling pathway, notably the ERK/MAPK. <em>In vitro</em>, studies showed that MST1/2 inhibitor promoted the activation of MAPK pathway resulting in weakened the inhibitory effect of Sal B. Meanwhile, reduced YAP boosted Sal B's suppressive roles on proliferation, migration, and apoptosis accompanied by suppression of pERK and pJNK, and activation of pp38. The ERK1/2 inhibitor further validated the role of YAP/TAZ in the moderating effect of Sal B's anti-carcinogenesis. This study revealed <em>MST1/2</em> as a pivotal target for Sal B through which it prevents hepatocarcinogenesis <em>via</em> the ERK/MAPK signaling pathway.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179156"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469654","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":"Sirtuin 1 deacetylates NCOA4 to suppress ferritinophagy-mediated ferroptosis and ameliorate acute pancreatitis","authors":"Zhao-Jian Shen,&nbsp;Zi-Yu Han,&nbsp;Lu Fu,&nbsp;Shi-Ya Ma,&nbsp;Zhong-Hua Lu,&nbsp;Yun Sun,&nbsp;Wei-Li Yu","doi":"10.1016/j.ejphar.2026.179167","DOIUrl":"10.1016/j.ejphar.2026.179167","url":null,"abstract":"<div><h3>Background</h3><div>Acute pancreatitis (AP) is a severe inflammatory disease lacking mechanism-based therapy. Ferroptosis driven by Nuclear receptor coactivator (NCOA4)-mediated ferritinophagy contributes to acinar cell injury, but how NCOA4 is regulated post-translationally in AP remains unknown. We examined whether Sirtuin 1 (SIRT1) deacetylates NCOA4 to suppress ferritinophagy-dependent ferroptosis.</div></div><div><h3>Methods</h3><div>Serum SIRT1, NCOA4 and inflammatory cytokines were measured in AP patients and healthy controls. <em>In vivo</em>, AP was induced in rats by L-arginine, with or without resveratrol (SIRT1 activator) or EX527 (SIRT1 inhibitor). <em>In vitro</em>, AR42J cells were transfected with SIRT1/NCOA4 plasmids or siRNAs before caerulein treatment. Ferroptosis markers, protein interactions, and clinical correlations were assessed.</div></div><div><h3>Results</h3><div>In AP patients, serum SIRT1 correlated negatively with disease severity and NCOA4, while NCOA4 correlated positively with disease severity and inflammatory cytokines. In AP rat model, SIRT1 activation via resveratrol lowered NCOA4, increased Ferritin heavy chain 1 (FTH1), reduced lipid peroxidation and pancreatic injury, whereas SIRT1 inhibition had opposite effects. In <em>in vitro</em> AP model, SIRT1 overexpression produced similar protection. NCOA4 overexpression induced ferritinophagy (LC3 II accumulation, FTH1 decline) and ferroptosis. Co-expressing NCOA4 together with SIRT1 counteracted the protection afforded by SIRT1 alone. Co-immunoprecipitation confirmed a direct SIRT1-NCOA4 interaction. SIRT1 overexpression decreased NCOA4 acetylation and expression. SIRT1 knockdown increased both.</div></div><div><h3>Conclusions</h3><div>Serum SIRT1 and NCOA4 may serve as predictive markers for AP severity. SIRT1 deacetylates NCOA4, down-regulates it, and thereby suppresses ferritinophagy-dependent ferroptosis, protecting against AP. Resveratrol exerts a protective effect against AP by inhibiting ferroptosis dependent on ferritinophagy through activating SIRT1 to deacetylate NCOA4.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179167"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148548254","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":"Impact of co-morbidities on preconditioning signalling cascades in cardiovascular diseases: strategies for intervention","authors":"Lamiaa A. Ahmed,&nbsp;Khaled F. Al-Massri,&nbsp;Shireen A. Hedya,&nbsp;Tarek M. Abdelghany","doi":"10.1016/j.ejphar.2026.179118","DOIUrl":"10.1016/j.ejphar.2026.179118","url":null,"abstract":"<div><div>Preconditioning has emerged as a promising approach in the management of ischaemic heart diseases. Ischaemic and pharmacological preconditioning have shown their ability to reduce myocardial infarct size and preserve cardiac function in various experimental and clinical settings. The underlying protective mechanisms of preconditioning involve the activation of signalling cascades that promote cell survival, inhibit cell damage and improve cellular energetics. However, the presence of cardiovascular co-morbidities such as ageing, diabetes, hyperlipidaemia, hypertension and chronic kidney disease is known to impair preconditioning stimuli and limit their effectiveness upon translation to clinical practice. This review discusses the impact of these co-morbidities on preconditioning signalling cascades and strategies to overcome this impairment by targeting comorbidity-specific pathways; using various preconditioning triggers, employing combined therapies and amplifying preconditioning stimuli. Additionally, bridging the gap between experimental and clinical studies through well-designed clinical trials is crucial for guaranteeing the feasibility and efficacy of preconditioning interventions in cardiovascular patients with diverse comorbidities.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179118"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic effect and mechanism of pirfenidone in bladder fibrosis after spinal cord injury","authors":"Xiaoling Huang,&nbsp;Jiajie Zhang,&nbsp;Yanping Hou,&nbsp;Fei Yuan,&nbsp;Pengtao Liu,&nbsp;Susu Guo,&nbsp;Kaiping Bai,&nbsp;Jie Sun","doi":"10.1016/j.ejphar.2026.178930","DOIUrl":"10.1016/j.ejphar.2026.178930","url":null,"abstract":"<div><div>Pirfenidone (PFD), a broad-spectrum anti-fibrotic agent, shows therapeutic potential in various fibrotic diseases. However, its effect on neurogenic bladder fibrosis following spinal cord injury (SCI) and its association with ferroptosis remain unclear. This study aimed to investigate the therapeutic efficacy of PFD against bladder fibrosis after SCI and to preliminarily analyze its potential link with ferroptosis using a rat SCI model and a Transforming Growth Factor-β1 (TGF-β1)-induced fibrotic model in Simian Virus 40-Transformed Human Urothelial Cells (SV-HUC-1). In SCI rats, PFD treatment significantly improved urodynamic parameters, while markedly reducing collagen deposition, inflammatory infiltration, and the progression of epithelial–mesenchymal transition (EMT) in bladder tissue. In the cellular model, PFD effectively attenuated TGF-β1-induced fibrotic responses. Mechanistically, network pharmacology analysis predicted that PFD could modulate the TGF-β1 signaling and lipid peroxidation pathways. In vivo experiments confirmed that PFD reversed the dysregulation of key ferroptosis-related molecules, and in vitro studies demonstrated that PFD antagonized Erastin-induced ferroptosis, an effect comparable to the ferroptosis inhibitor Ferrostatin-1 (Fer-1). However, in the TGF-β1-induced fibrotic model, inhibition of ferroptosis alone only partially ameliorated the fibrotic phenotype, and its effect was weaker than that of PFD. This study demonstrates that PFD can effectively alleviate bladder fibrosis after SCI, and its therapeutic effect may be associated with the ferroptosis pathway. These findings suggest that PFD likely exerts its anti-fibrotic action through multi-pathway synergy, with ferroptosis inhibition representing an important contributing pathway supported by the current data, providing a new theoretical basis for treating neurogenic bladder fibrosis.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 178930"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223991","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":"Baicalin downregulates Thromboxane A2 receptor via SIRT1/NRF2 and NLRP3 pathways to attenuate Cyclosporine A-induced hypertension","authors":"Teng Gao,&nbsp;Quanbin Li,&nbsp;Jialiang Chen,&nbsp;Qian Li,&nbsp;Xiaoxuan Fan,&nbsp;Luping Yang,&nbsp;Jiping Liu,&nbsp;Bin Wang,&nbsp;Chuan Wang","doi":"10.1016/j.ejphar.2026.179105","DOIUrl":"10.1016/j.ejphar.2026.179105","url":null,"abstract":"<div><div>Cyclosporine A, an immunosuppressant, is clinically limited by its hypertensive and nephrotoxic effects. Baicalin, a bioactive flavonoid derived from <em>Scutellaria baicalensis</em>, effectively alleviates CsA-induced hypertension by downregulating the thromboxane A₂ (TP) receptor via the SIRT1/NRF2 and NLRP3 pathways. Ex vivo, in vivo, and in vascular smooth muscle cells (VSMCs), baicalin markedly reversed CsA-induced vasoconstriction, elevated blood pressure, upregulation of TP receptor, KEAP-1, NLRP3, Caspase-1, IL-1β, and ASC, as well as downregulation of SIRT1, NRF2, HO-1, and NQO-1. Importantly, siRNA-mediated knockdown of SIRT1 or NLRP3 abolished baicalin's protective effects. CETSA and ITDRF-CETSA demonstrated that baicalin directly binds to and stabilizes SIRT1 and NLRP3. Molecular docking further confirmed strong binding affinity of baicalin to both TP receptor and SIRT1. Immunofluorescence revealed that baicalin significantly inhibited CsA-induced NLRP3/ASC speck formation. Collectively, baicalin may improve CsA-induced hypertension by downregulating the TP receptor through the SIRT1/NRF2 and NLRP3 pathways.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179105"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367565","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":"Arbutin as a therapeutic candidate for autism: Current evidence and mechanistic insights into PI3K/Akt/mTOR and Nrf2 pathways","authors":"Abhishek,&nbsp;Shamsher Singh","doi":"10.1016/j.ejphar.2026.179103","DOIUrl":"10.1016/j.ejphar.2026.179103","url":null,"abstract":"<div><div>Arbutin is a natural glycoside that protects neurons and is useful in a variety of neurological conditions. There is a need to further explore its scientific properties as arbutin regulates mitochondrial function, control apoptotic proteins, lowers oxidative stress, enhance behavioral and cognitive outcomes and thus may be considered a potential target for Parkinson's, Alzheimer's, neuroinflammation, epilepsy and Huntington's disease. Arbutin via PI3K/Akt/mTOR and Nrf2 signaling pathways, helps to balance redox equilibrium, mitochondrial integrity and neuronal survival, plays a major role in mediating these effects. Autism Spectrum Disorder (ASD) is closely associated with dysfunction of these pathways, which cause oxidative 2 stress, synaptic deficits and neuroinflammation. While reducing NF-κB mediated pro-inflammatory cytokines including TNF-α, IL-1β and IL-6, arbutin increases Akt phosphorylation and Nrf2 nuclear translocation, activating antioxidant enzymes like SOD, GSH, HO-1 and NQO1. These coordinated molecular processes may help preserve neuronal homeostasis, inhibit apoptosis and decrease ROS induced neuronal damage. Arbutin may enhance synaptic plasticity and potentially modulate the pathogenic pathways underlying ASD and other neurodevelopmental disorders by concurrently regulating oxidative stress, mitochondrial dysfunction and neuroinflammation. Taken together these finding suggest arbutin may act as a promising therapeutic candidate capable of restoring neuronal homeostasis and translating mechanistic understanding into potential therapeutic applications. Arbutin is a promising phytochemical with potential relevance for autism and associated neurological diseases due to its combined molecular actions. However, direct experiment and clinical evidence supporting the role of arbutin in ASD remains limited.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179103"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367575","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 “Neuroprotection by post-stroke administration of the slow-releasing hydrogen sulfide (H2S) donor AP39: Long-term functional, MRI, and molecular evidence in a rodent stroke model” [European J. Pharmacol. 1008 (2025) 178331]","authors":"Bartosz Pomierny,&nbsp;Weronika Krzyżanowska,&nbsp;Alicja Skórkowska,&nbsp;Jakub Jurczyk,&nbsp;Katarzyna Przejczowska-Pomierny,&nbsp;Małgorzata Szafarz,&nbsp;Monika Marcinkowska,&nbsp;Zuzanna Guzda,&nbsp;Patrycja Rachwał,&nbsp;Eugene Kim,&nbsp;Michel Mesquita,&nbsp;Roberta Torregrossa,&nbsp;Matthew Whiteman,&nbsp;Lucyna Pomierny-Chamioło,&nbsp;Joanna Pera,&nbsp;Bogusława Budziszewska","doi":"10.1016/j.ejphar.2026.179077","DOIUrl":"10.1016/j.ejphar.2026.179077","url":null,"abstract":"","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 179077"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148249840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sinomenine alleviates ulcerative colitis by targeting FXR to regulate arachidonic acid metabolism and Th17/Treg homeostasis","authors":"Mengting Li,&nbsp;Danyang Chen,&nbsp;Yu Shao,&nbsp;Zimeng Wang,&nbsp;Yanan Peng,&nbsp;Qiu Zhao,&nbsp;Lan Liu","doi":"10.1016/j.ejphar.2026.178976","DOIUrl":"10.1016/j.ejphar.2026.178976","url":null,"abstract":"<div><div>Sinomenine (SIN), a bioactive alkaloid with anti-inflammatory activity, has shown therapeutic potential in ulcerative colitis (UC), but its precise molecular targets remain unclear. This study investigated the key targets and mechanisms underlying SIN-mediated protection in UC. In a dextran sulfate sodium (DSS)-induced colitis mouse model, SIN dose-dependently alleviated colitis symptoms, restored colon length, improved histopathology injury, and enhanced intestinal barrier integrity by increasing ZO-1 and claudin-1 expression. Integrated bioinformatics analyses, including differential expression analysis, WGCNA, network pharmacology, and machine-learning algorithms, identified farnesoid X receptor (FXR) as a core therapeutic target of SIN. Molecular docking predicted stable SIN-FXR binding, and cellular thermal shift assay further supported engagement of SIN with FXR. FXR expression was reduced in UC tissues and DSS-induced colitis mice but was restored after SIN treatment. Functional enrichment and single-cell RNA sequencing analyses linked FXR to lipid metabolism, immune regulation, and the Th17/Treg balance. Mechanistically, SIN suppressed arachidonic acid metabolism, reduced pro-inflammatory cytokines, increased anti-inflammatory cytokines, decreased Th17 cells, and promoted Treg accumulation. Co-administration of SIN with the FXR agonist fexaramine further potentiated its protective effects, whereas the FXR antagonist glycine-β-muricholic acid markedly reversed SIN-mediated improvements in intestinal inflammation, barrier integrity, arachidonic acid metabolism, and Th17/Treg homeostasis. Collectively, these findings demonstrate that SIN ameliorates experimental colitis, at least in part, by targeting FXR to modulate lipid metabolism and restoring Th17/Treg balance. This study provides a mechanistic basis for the therapeutic application of SIN, either alone or in combination with FXR agonists, in UC treatment.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1030 ","pages":"Article 178976"},"PeriodicalIF":5.7,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216996","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}