Biochemical pharmacology最新文献

{"title":"IRF8 and RUNX1 cooperatively regulate the senescence and damage of urine-derived renal progenitor cells by upregulating LINC01806","authors":"Jie Ma ,&nbsp;Wei Yang ,&nbsp;Fu-Ming Chen ,&nbsp;Qian He ,&nbsp;Hua-Lin Ma ,&nbsp;Cong-Hui Li ,&nbsp;Min-Li Liang ,&nbsp;Jia-Qi Zhong ,&nbsp;Xin-Zhou Zhang ,&nbsp;Fu-Rong Li","doi":"10.1016/j.bcp.2025.117068","DOIUrl":"10.1016/j.bcp.2025.117068","url":null,"abstract":"<div><div>Urine-derived renal progenitor cells (UdRPCs) from healthy individuals have been identified as having the potential to repair kidney damage. However, it remains uncertain whether UdRPCs retain their functionality in chronic kidney disease (CKD) patients. In this study, UdRPCs were isolated from healthy individuals and CKD patients. Notably, senescent cells were observed in the UdRPCs of CKD patients, which increase with the severity of CKD, hindering the repair of renal tissue damage and exacerbating the progression of CKD. This senescence phenotype is characterized by decreased proliferation, increased expression of kidney injury marker 1 (KIM-1), and an enhanced senescence-associated secretory phenotype (SASP). Transcriptomics analysis revealed a significant correlation between long intergenic non-coding RNA 01806 (LINC01806) and UdRPCs damage and senescence. LINC01806 activation modulates the expression of KIM-1 and senescence-related factors (p53, p21 and p16), promotes SASP secretion by stimulating the MAPK pathway, thereby inducing damage and senescence in UdRPCs. Mechanistically, the IRF8-RUNX1 complex binds to the promoter of LINC01806, promoting its expression in the nucleus. Our findings clarify the pathogenesis of CKD from a new perspective, and more importantly, provide new targets for drug screening and potential therapeutic interventions.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"240 ","pages":"Article 117068"},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144490315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Colchicine as a therapeutic possibility for the treatment of pulmonary arterial hypertension (PAH) in a rat model","authors":"K. Ordog ,&nbsp;O. Horvath ,&nbsp;Sz. Toth ,&nbsp;L. Deres ,&nbsp;S. Pusalavidyasagar ,&nbsp;K. Kovacs ,&nbsp;Sz. Soós ,&nbsp;F. Gallyas ,&nbsp;K. Toth ,&nbsp;R. Halmosi ,&nbsp;L. Czopf","doi":"10.1016/j.bcp.2025.117058","DOIUrl":"10.1016/j.bcp.2025.117058","url":null,"abstract":"<div><div>The right ventricular failure is the most important cause of death in pulmonary arterial hypertension (PAH). Colchicine, a naturally occurring tricyclic alkaloid, protects against inflammatory diseases by favorable modulation of pro-inflammatory cytokine production. In our present work, we aimed to clarify the effects of colchicine treatment in PAH, specifically on right ventricular cardiac myocytes. We examined the effects of colchicine treatment on the pulmonary vasculature and on the right ventricular cardiomyocytes. Pulmonary arterial hypertension was induced in Wistar Kyoto rats by monocrotaline (MCT). Wistar Kyoto (WKY) rats were then treated with colchicine or placebo for two-weeks. Colchicine treatment successfully prevented the development of right ventricular failure in an MCT-induced PAH model. The echocardiographic parameters characterizing right ventricular function improved. The signaling pathways associated with cardiac remodeling showed favorable alterations attributed to colchicine treatment. Consequently, the interstitial collagen deposition was reduced, and the energy supply of right ventricular myocytes was preserved. Colchicine treatment inhibited pulmonary vascular remodeling and reduced the amount of α-smooth muscle actin (α-SMA) and collagen in pulmonary vessel walls. Our results suggest that even a short-term and low-dose colchicine treatment could protect against PAH-induced right ventricular failure. Therefore, colchicine may be a promising therapeutic option in the treatment of PAH.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"239 ","pages":"Article 117058"},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144490606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stabilization of DNA G-quadruplexes on the 5′-flanking region of CYP3A4 promotes transcription","authors":"Seiya Takemoto ,&nbsp;Itsuki Yokoseki ,&nbsp;Seigo Shuto ,&nbsp;Masataka Nakano ,&nbsp;Tatsuki Fukami ,&nbsp;Miki Nakajima","doi":"10.1016/j.bcp.2025.117055","DOIUrl":"10.1016/j.bcp.2025.117055","url":null,"abstract":"<div><div>G-quadruplexes (G4s) are higher-order nucleic acid structures in genomic DNA that stack two or more G-quartets formed by Hoogsteen base pairing between four guanines. These structures play a critical regulatory role in transcription. We noticed potential G4-forming sequences in the 5′-flanking region of the gene encoding cytochrome P450 3A4 (CYP3A4), an enzyme that contributes most significantly to drug metabolism in humans. In the present study, we investigated the effects of these G4s on CYP3A4 expression. Using a qPCR stop assay and a chromatin immunoprecipitation (ChIP) assay with a G4-specific antibody, we found that three guanine-rich sequences in this region could indeed form a G4 structure. Treatment with the G4 stabilizer pyridostatin increased CYP3A4 expression in HepG2 cells. Formaldehyde-assisted isolation of regulatory elements and ChIP assays demonstrated that pyridostatin-mediated G4 stabilization relaxed the chromatin structure, enhancing the binding of the pregnane X receptor (PXR) to response elements of <em>CYP3A4</em>. Screening of an FDA-approved drug library using a qPCR stop assay identified digoxin as a G4 stabilizer of <em>CYP3A4</em>, which induces CYP3A4 expression, even though it is not a PXR ligand. These findings demonstrate that G4s on <em>CYP3A4</em> can enhance transcription by relaxing the chromatin structure. Drugs currently in clinical use and new chemical entities capable of modulating G4 formation may cause drug-drug interactions with CYP3A4 substrates through a novel mechanism that alters CYP3A4 expression.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"240 ","pages":"Article 117055"},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WISP3 upregulates SDCBP expression to promote the progression of non-small cell lung cancer via the TGF-β signaling pathway","authors":"Xiaoshen Zhang ,&nbsp;Tao Jiang ,&nbsp;Lingyun Ye ,&nbsp;Jianguo Sun ,&nbsp;Lei Wang ,&nbsp;Juanjuan Li ,&nbsp;Fengying Wu ,&nbsp;Shengxiang Ren ,&nbsp;Guanghui Gao","doi":"10.1016/j.bcp.2025.117082","DOIUrl":"10.1016/j.bcp.2025.117082","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, posing a major health burden. Our prior work indicated fibronectin promotes NSCLC angiogenesis and progression by upregulating Wnt-inducible signaling pathway protein 3 (WISP3) and activating Wnt signaling. This study aims to explore WISP3<strong>′</strong>s role and mechanisms in NSCLC progression. Cells were transfected with a reconstructed plasmid to study gene overexpression/silencing effects. Functional assays were conducted, including tube formation, sphere formation, immunohistochemistry, western blotting, Transwell, and MTT. Mass spectrometry and bioinformatics analysis were used to identify differentially expressed proteins and their associated signaling pathways in NSCLC cells. Additionally, the xenograft tumor model of NSCLC was constructed. High expression of WISP3 in NSCLC is associated with poor prognosis, as it enhances angiogenic and tumorigenic potential in NSCLC cells, further verified in our constructed xenograft tumor experiment. In terms of mechanisms, the activation of the TGF-β signaling pathway, indicated by p-smad2/3 activation, is implicated in the progression of NSCLC promoted by WISP3. Additionally, overexpression of WISP3 leads to increased syntenin binding protein (SDCBP) expression <em>in vitro</em> and <em>in vivo</em>, and WISP3 binding to SDCBP enhances angiogenic and tumorigenic potential in NSCLC, which can be counteracted by silencing SDCBP, indicating their crucial role in NSCLC progression. We offer new insights into WISP3<strong>′</strong>s role in promoting NSCLC progression, showing it upregulates SDCBP and is involved in TGF-β signaling. The findings contribute to a better understanding of NSCLC biology and suggest potential therapeutic targets for the disease.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"240 ","pages":"Article 117082"},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144502791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory T cells and their role in inflammatory bowel disease: molecular targets, therapeutic strategies and translational advances.","authors":"Chaelin Lee, Ye Won Park, Min Ho Park, Yong Jun Lee, Inmoo Rhee","doi":"10.1016/j.bcp.2025.117087","DOIUrl":"10.1016/j.bcp.2025.117087","url":null,"abstract":"<p><p>Regulatory T cells (T_regs) are essential for immune tolerance and for controlling pathological inflammation, particularly in mucosal tissues such as the gastrointestinal tract. Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is increasingly associated with T_reg dysfunction. This dysfunction is marked by loss of lineage stability, impaired suppressive function, and a disrupted balance with pro-inflammatory T helper type 17 (Th17) cells. Advances in molecular immunology have identified key pathways that control T_reg differentiation, epigenetic maintenance, and metabolic signaling. These include interleukin-2/signal transducer and activator of transcription 5 (IL-2/STAT5), forkhead box P3/conserved non-coding DNA sequences 2 (FOXP3/CNS2), mechanistic target of rapamycin (mTOR), and retinoic acid-related orphan receptor gamma t (RORγt) pathways, several of which are genetically linked to IBD susceptibility and offer viable targets for therapeutic development. This structural and biochemical mechanisms contribute to T_reg instability in IBD and evaluates pharmacological strategies aimed at restoring immune balance. Therapeutic strategies include small molecules, antibody therapies, and cell-based approaches that support T_reg expansion, stabilize lineage identity, or enhance suppressive function. We emphasize interventions supported by genetic and translational evidence, positioning T_reg modulation as a promising direction for precision therapy in IBD. The review also discusses ongoing clinical trials and future opportunities involving omics-driven patient stratification, targeted delivery platforms, and chimeric antigen receptor (CAR)-T_reg technologies to improve treatment outcomes.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117087"},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the anticancer potential of ergosterol and ergosta-5,22,25-triene-3-ol against colorectal cancer: Insights from experimental models and molecular mechanisms","authors":"Yogain Taank,&nbsp;Navneet Agnihotri","doi":"10.1016/j.bcp.2025.117061","DOIUrl":"10.1016/j.bcp.2025.117061","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is the third most frequently diagnosed cancer and second leading cause of cancer associated mortality globally. Aberrant cholesterol metabolism due to altered expression and activity of Liver X Receptors (LXRs) contribute significantly to the development of CRC. Previously, we had identified ergosterol (ERG) and ergosta-5,22,25-triene-3-ol (ERG2) as LXR agonists with selective cytotoxicity towards colon cancer cells. The present study was designed to further understand their anticancer potential and mechanism of action. In HCT116 cell, both ERG and ERG2 increased the cell population in the late stage apoptosis via increasing the expression of Bax, CD95, and decreasing the expression of Bcl-2. They also suppressed cell survival and proliferation by reducing the protein expression of cyclin D1, Ras, and MEK1/2, and inhibiting the phosphorylation of PI3K. Erg and Erg2 also suppressed cell invasion and metastasis, which was evident from the decrease in cell migration of HCT116, SW620 cells and protein expression of MMP2 and MMP9. The present study also assessed the chemopreventive potential of ergosterol by using the DMH + DSS induced experimental model of CRC. In line with the findings of the <em>in vitro</em> experiments, ergosterol administration significantly reduced tumor burden, volume, and Ki-67 expression in DMH + DSS + ERG group animals, along with a marked decrease in cancer-like features in the colonic mucosa. It also induced apoptosis and inhibited β-catenin and PI3K/Akt signaling, while upregulating cholesterol efflux genes. Taken together, the findings of the current study are suggestive of the immense anticancer potential of ergosterol mediated through its pleiotropic mode of action.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"240 ","pages":"Article 117061"},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of action of ubiquitin-specific proteases, particularly ubiquitin-specific proteases 7, 8, and 25, in depression treatment","authors":"Yue-Yue Zhang ,&nbsp;Wei Guan ,&nbsp;Yang Miao","doi":"10.1016/j.bcp.2025.117085","DOIUrl":"10.1016/j.bcp.2025.117085","url":null,"abstract":"<div><div>Depression is one of the most common and debilitating mental disorders and one of the main causes of disability worldwide. Despite the progress made in the treatment of depression, approximately 20 %–40 % of patients with a major depressive episode do not show a clinical response to current antidepressant treatments. Approximately 85 % of patients with major depressive disorder (MDD) experience a high relapse rate after recovering from an acute episode of major depression. Over the past decade, protein ubiquitination and deubiquitination have attracted considerable interest. An increasing number of studies have shown that ubiquitin-specific proteases (USPs) play essential roles in the pathogenesis of depression. USP is part of the ubiquitin–proteasome system (UPS), a critical non-lysosomal pathway specific for protein degradation, and plays a significant role in presynaptic and postsynaptic proteins crucial for regulating neurotransmission and synaptic plasticity. However, its potential contribution to the pathophysiology of depression has not yet been addressed in detail. Therefore, this review explores the potential of targeting USP as a novel approach to antidepressant treatment, focusing on the targets and mechanisms of USP in the regulation of depression. By providing insights into USP in preclinical research, this review aims to contribute to developing new therapeutic methods for enhancing the efficacy of antidepressant treatments.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"239 ","pages":"Article 117085"},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144490605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferulic acid promotes thrombopoiesis via TLR4/JAK2/STAT3 signaling: A novel therapeutic strategy for thrombocytopenia","authors":"Rui Liao ,&nbsp;Miao Huang ,&nbsp;Zhixuan Liu ,&nbsp;Xinle Wang ,&nbsp;Xiaolin Gan ,&nbsp;Lu Hao ,&nbsp;Peilian Jiang ,&nbsp;Jiesi Luo ,&nbsp;Qianqian Huang ,&nbsp;Qibing Mei ,&nbsp;Anguo Wu ,&nbsp;Long Wang ,&nbsp;Jianming Wu","doi":"10.1016/j.bcp.2025.117088","DOIUrl":"10.1016/j.bcp.2025.117088","url":null,"abstract":"<div><div>Thrombocytopenia, a common hematological disorder, is associated with increased mortality in various diseases. However, the existing clinical treatments are often accompanied by various adverse effects and may even disrupt platelet homeostasis, highlighting the urgent need to develop novel therapeutic agents. Here, we developed a drug screening model based on virtual screening utilizing known monomeric components of <em>Sanguisorba officinalis</em> L. (SOL) and identified ferulic acid (FA) as a promising candidate for thrombocytopenia intervention. <em>In vitro</em> study using Meg-01 and K562 cell lines demonstrated that FA enhanced<!--> <!-->the megakaryocyte (MK) maturation. <em>In vivo</em>, thrombopoietic effects were evaluated in Tg (itga2b:eGFP) transgenic zebrafish, revealing significant modulation of platelet production. Furthermore, in a thrombocytopenia mouse model, FA treatment increased<!--> <!-->megakaryocyte progenitors (MKPs) and MKs numbers in the bone marrow and spleen, inhibited oxidative stress and apoptosis in the bone marrow, and stimulated new platelet production in peripheral blood, thereby accelerating platelet count and function. Importantly, FA did not disrupt the platelet homeostasis in normal mice. Mechanistically, FA was identified as a direct activator of Toll-like receptor 4 (TLR4), which in turn activated the JAK2/STAT3 signaling pathway, thereby promoting MK differentiation and thrombopoiesis. These findings present FA as a potential novel therapeutic strategy for thrombocytopenia and provide a basis for its clinical development as an alternative or adjunctive therapy.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"239 ","pages":"Article 117088"},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144501143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isatin ameliorates ovarian inflammation and apoptosis caused by hormonal imbalances in PCOS mice","authors":"Xiaoran Li ,&nbsp;Taowen Ye ,&nbsp;Wanqing Zhu ,&nbsp;Jiale Gu ,&nbsp;Zihan Zheng ,&nbsp;Chengniu Wang ,&nbsp;Xiaoli Zhang ,&nbsp;Haiying Geng ,&nbsp;Wenbiao Zhou ,&nbsp;Xiaofang Tan ,&nbsp;Yumin Ma ,&nbsp;Haibo Zhang ,&nbsp;Xiaorong Wang","doi":"10.1016/j.bcp.2025.117083","DOIUrl":"10.1016/j.bcp.2025.117083","url":null,"abstract":"<div><div>Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine disorder in women of childbearing age. Isatin (ISA) is a bioactive compound naturally found in mammalian body fluids and tissues, known for its potent antioxidant, anti-inflammatory, and anticancer properties. We used letrozole to induce a PCOS mouse model and evaluated the reproductive benefits of ISA. The mice were initially grouped according to the concentration of ISA administered at 25, 50, and 100 mg/kg. Subsequently, research results indicated that the optimal concentration was determined to be 100 mg/kg, while a positive control group was established using 150 mg/kg of metformin. The results demonstrated that PCOS mice exhibited obesity, disrupted estrous cycles, polycystic ovaries, insulin resistance, disruption of cytoskeletal structure, mitochondrial damage and decreased fertility. Additionally, the elevated androgen levels in PCOS mice also led to ovarian inflammation, oxidative stress, and apoptosis. However, ISA effectively reversed these damages. High-throughput sequencing revealed that ISA significantly downregulated the expression of genes related to androgen production, including STAR, CYP11A1 and CYP17A1. ISA can also reduce the expression of pro-inflammatory factors and inhibit the activation of the NF-κB pathway, thereby alleviating ovarian inflammation. Post-treatment with ISA resulted in reduced levels of ROS and MDA, and inhibited apoptosis in the ovarian tissue of PCOS mice by modulating apoptosis related proteins, such as BAX, P53, BCL-2, and Caspase-3. In summary, a protective effect of ISA on the ovaries in the letrozole-induced PCOS mouse model was demonstrated by regulating hormone secretion, alleviating inflammation and oxidative stress, and subsequently inhibiting ovarian cell apoptosis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"239 ","pages":"Article 117083"},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144481408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel aryl hydrocarbon receptor agonists as potential anti-inflammatory therapeutics: Identification and validation through drug repurposing","authors":"Janine Haupt ,&nbsp;Oliver Keminer ,&nbsp;Christina Neser ,&nbsp;Björn Windshügel ,&nbsp;Vivien Wiltzsch ,&nbsp;Johannes R. Schmidt ,&nbsp;Palina Pliushcheuskaya ,&nbsp;Georg Künze ,&nbsp;Ulrike Scholz ,&nbsp;Claudia Müller ,&nbsp;Gustavo Henrique Oliveira da Rocha ,&nbsp;Melina K. Biermann ,&nbsp;Daniela Zdzieblo ,&nbsp;Marco Metzger ,&nbsp;Ingolf Schiefke ,&nbsp;Markus F. Neurath ,&nbsp;Britta Siegmund ,&nbsp;Carsten Claussen ,&nbsp;Ulrike Köhl ,&nbsp;Gerd Geisslinger ,&nbsp;Jörg Lehmann","doi":"10.1016/j.bcp.2025.117066","DOIUrl":"10.1016/j.bcp.2025.117066","url":null,"abstract":"<div><div>The aryl hydrocarbon receptor (AhR) was shown to be an important regulator of inflammatory processes at epithelial barriers, and is thus considered a therapeutic target for several chronic inflammatory diseases, such as inflammatory bowel disease. We aimed to identify and validate new AhR agonists that sustainably attenuate intestinal inflammation. Using a high-throughput luciferase reporter gene assay, 90 AhR ligands were identified out of 7448 approved and investigational drugs. Out of these, 15 AhR ligands were selected based on substance class, half maximal effective concentration, known toxicity and pharmacokinetic/pharmacodynamic profiles, and preclinical/clinical evaluation status for other indications. While Febuxostat, Nitazoxanide, Rabeprazole, 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester, 3-Indolepropionic acid, and Indirubin, were already known as AhR agonists, Nabumetone, Teriflunomide, Timapiprant/OC000459, and Caffeic acid phenylethyl ester have not yet been directly described in this context. Six compounds (Daidzein/Equol, as well as compounds no. 19, 22, 49, and 64, not yet disclosed due to pending patent applications) were newly described as AhR agonists. Hit compounds were studied in silico for their molecular interactions with AhR and in vitro for potential immunotoxicity and their ability to induce interleukin (IL)-10 and/or to suppress IL-1β in murine macrophages without significant cytochrome P450 1A1 induction in Caco-2 cells. Five compounds that met these criteria were functionally tested using organoid-based Transwell®-like models derived from gut biopsies. Five candidates restored the epithelial barrier, as evidenced by increased transepithelial electrical resistance and induction of the tight junction proteins claudin-1/-2 and occludin, while exhibiting anti-inflammatory effects, i.e., decreased expression of toll-like receptor 4. Out of these, one compound was selected for future in vivo preclinical studies.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"240 ","pages":"Article 117066"},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}