International immunopharmacology最新文献

{"title":"Type I and II pili mediate Streptococcus pneumoniae invasion into human blood-brain barrier-derived cells through extracellular matrix protein receptors and different endocytosis pathways","authors":"Sui-Ning Chen ,&nbsp;Yu-Jin Wang ,&nbsp;Meng-Jie Li ,&nbsp;Yi-Qiong Xing ,&nbsp;Meng-Yi Guo ,&nbsp;Jie Yan ,&nbsp;Ai-Hua Sun","doi":"10.1016/j.intimp.2025.114918","DOIUrl":"10.1016/j.intimp.2025.114918","url":null,"abstract":"<div><div><em>Backgroud: Streptococcus pneumoniae</em> is the most common pathogen of bacterial meningitis, but mechanisms of this pathogen invading blood-brain barrier (BBB) remain unknown.</div><div><em>Methods:</em> Invasion of <em>S. pneumoniae</em> strains and microbeads coated with recombinant pilin, rRrgA-B or rPitB, into human BBB-derived brain microvascular endothelial cells (HBMECs), brain vascular pericytes (HBVPs), and astrocytes (HAs) by laser scanning confocal microscopy (LSCM). Fibronectin (FN), laminin (LN), and collagen-1/3/4 (COL-1/3/4) in the extracellular matrix (ECM) were detected by LSCM and flow cytometry. rRrgA-B and rPitB binding to the ECM proteins were identified using surface plasmon resonance. Pneumococcal endocytosis pathways, Ca²⁺ level, microfilament (MF) and microtubule (MT) polymerization in the cells were determined by LSCM-based inhibition assay.</div><div><em>Results:</em> Type I/II pili-positive <em>S. pneumoniae</em> SP007 displayed natably stronger invasiveness into the cells than pilus-free <em>S. pneumoniae</em> ATCC49619. rRrgA-B-/rPitB-coated microbeads also exhibited invasion ability. HBMECs express FN, LN, and COL1, while HBVPs and HAs express all the ECM proteins. rRrgA-B and rPitB displayed a rapid binding to all the ECM proteins with K_D values ranging from 3.25 × 10⁻⁷ to 9.58 × 10⁻⁸ M. Intracellular free Ca²⁺ increase and MF-dependent cytoskeleton rearrangement occurred during invasion of the pneumococcal strains and rRrgA-B-/rPitB-coated microbeads. Invasion of the strains and rRrgA-B-/rPitB-coated microbeads into these cells involved integrin (ITG), focal adhesion kinase (FAK), Rho-associated coiled-coil forming kinase (ROCK) or phosphatidylinositol-3-kinase (PI3K), clathrin (CLN)-, caveolae (CAV)- or macropinocytosis (MPC)-dependent endocytosis.</div><div><em>Conclusion:</em> Type I and II pili play important roles to mediate <em>S. pneumoniae</em> invasion into BBB-direived cells through FN/LN/COL1-ITG-FAK/ROCK-Ca²⁺-MF-CLN/CAV/MPC- or FN/LN/COL1/3/4-ITG-FAK/PI3K-Ca²⁺-MF-CLN/CAV-dependent endocytosis pathways to cause meningitis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114918"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170443","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":"Acetylation of FABP3 alleviates radioimmunotherapy-induced cardiomyocyte senescence by modulating long-chain polyunsaturated fatty acid metabolism","authors":"Yuxi Luo ,&nbsp;Ying Yu ,&nbsp;Fujuan Zeng ,&nbsp;Yali Yi ,&nbsp;Zhiqin Lu ,&nbsp;Bilin Lin ,&nbsp;Leifeng Chen ,&nbsp;Zhimin Zeng ,&nbsp;Daya Luo ,&nbsp;Anwen Liu","doi":"10.1016/j.intimp.2025.114912","DOIUrl":"10.1016/j.intimp.2025.114912","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;The combination of thoracic radiotherapy and immunotherapy (radioimmunotherapy) has shown significant antitumor efficacy but is associated with increased cardiotoxicity, the mechanisms of which remain poorly understood.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;A total of 72 male C57BL/6 J mice were employed to establish the radioimmunotherapy-induced cardiac injury model, with 18 mice allocated to each of four groups, including the IR group (single-dose 16 Gy cardiac irradiation), ICI group (PD-1 inhibitor 200 μg every 3 days), iRT group (16 Gy cardiac irradiation combined with PD-1 inhibitor), and Control group (IgG). Cardiac function and myocardial senescence were assessed at 28 days, 3 months, and 5 months post-intervention. Additionally, myocardial tissue transcriptomics, non-targeted metabolomics, and acetylated proteomics were performed at 28 days post-intervention, integrated with molecular experiments to investigate the mechanisms of cardiomyocyte senescence. H9C2 cardiomyocytes with FABP3 K45 acetylation-mimetic (K45Q), empty vector (EV), and non-acetylatable (K45R) mutant were used for functional validation.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Combined radioimmunotherapy significantly exacerbated cardiac dysfunction and cardiomyocyte senescence in murine models, manifested with elevated serum levels of cardiac injury biomarkers of cTnI and NT-proBNP, reduced LVEF and LVFS, aggravated myocardial histopathological changes characterized by enhanced inflammatory infiltration, interstitial edema, and myocardium structure disorder in iRT group compared to the other three groups. Concomitantly, compared with other groups, the senescence-associated markers (p16, p21, and SASP factors) in the myocardial tissues of the iRT group were markedly upregulated from 28 days to 5 months. By integrating transcriptomic and non-targeted metabolomics analyses, as well as molecular experiments, we revealed that radioimmunotherapy resulted in dysregulated myocardial metabolism by suppressing ATP production, promoting lipid droplet accumulation, mitochondrial dysfunction, and fatty acid metabolism alterations, particularly involving long-chain polyunsaturated fatty acid (PUFAs) metabolism. Acetylome profiling identified a significant increase in FABP3 K45 acetylation (log&lt;sub&gt;2&lt;/sub&gt;FC = 8.73, &lt;em&gt;P&lt;/em&gt; &lt; 0.05) in iRT vs. Control group, with acute-phase elevation (28 days, &lt;em&gt;P&lt;/em&gt; &lt; 0.001) and chronic-phase reduction (3 months, &lt;em&gt;P&lt;/em&gt; &lt; 0.001). Functional validation in H9C2 cardiomyocytes demonstrated that, compared to EV and K45R groups, FABP3 K45Q attenuated cellular senescence, enhanced mitochondrial oxidative phosphorylation, fatty acid metabolism, and ATP production, while attenuated ROS generation, lipid droplet accumulation, and glycolysis. Metabolomic analysis also revealed the acetylation of FABP3 K45 was significantly associated with the synthesis or accumulation of PUFAs, such as arachidonic acid and linolei","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114912"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170550","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":"Targeting SPP1+ macrophages via the SPP1-CD44 axis reveals a key mechanism of immune suppression and tumor progression in ovarian cancer","authors":"Lisha Hou ,&nbsp;Mei Jiang ,&nbsp;Yue Li ,&nbsp;Jin Cheng ,&nbsp;Fei Liu ,&nbsp;Xiaoyang Han ,&nbsp;Jiahao Guo ,&nbsp;Lei Feng ,&nbsp;Zhefeng Li ,&nbsp;Junjie Yi ,&nbsp;Xiaoting Zhao ,&nbsp;Yan Gao ,&nbsp;Wentao Yue","doi":"10.1016/j.intimp.2025.114906","DOIUrl":"10.1016/j.intimp.2025.114906","url":null,"abstract":"<div><div>Tumor-associated macrophages (TAMs) play a pivotal role in immune suppression, tumor progression, and metastasis within the tumor microenvironment (TME) of ovarian cancer. While TAMs are known to promote T-cell dysfunction, the precise molecular mechanisms governing this process remain poorly understood. Here, we performed an integrated analysis of six high-grade serous ovarian cancer (HGSOC) single-cell sequencing datasets to investigate the molecular and functional diversity of TAMs in HGSOC. We identified an SPP1⁺ TAM subpopulation enriched in HGSOC and strongly associated with poor prognosis. These macrophages promoted T-cell exhaustion <em>via</em> the SPP1-CD44 axis, which emerged as the principal mediator of immune suppression. Functional assays demonstrated that SPP1 secreted by TAMs drove T-cell exhaustion, weakening anti-tumor immunity. Blocking either SPP1 or CD44 effectively reversed T-cell exhaustion, restored CD8⁺ T-cell functionality, and suppressed tumor growth <em>in vivo</em>. Furthermore, molecular docking and dynamics simulations identified nilotinib as a potential SPP1 inhibitor, exhibiting strong binding affinity and stability. <em>In vitro</em> assays confirmed that nilotinib reduced PD-1 expression in Jurkat cells induced by M2-type macrophages, underscoring its therapeutic potential in reversing T-cell exhaustion in ovarian cancer. The research demonstrates that SPP1⁺ TAMs drive immune suppression and T-cell exhaustion in ovarian cancer <em>via</em> the SPP1-CD44 axis, highlighting this pathway as a promising therapeutic target for reprogramming the immune microenvironment and improving patient outcomes.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114906"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170442","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":"Mefunidone treats pulmonary fibrosis by targeting SDH to regulate fibro-promoting macrophages","authors":"Xiangyu Zhang ,&nbsp;Yijun He ,&nbsp;Lingzhi Long ,&nbsp;Guoliang Jiang ,&nbsp;Tingting Yao ,&nbsp;Xiaoyun Cheng ,&nbsp;Zhangzhe Peng ,&nbsp;Gaoyun Hu ,&nbsp;Lijian Tao ,&nbsp;Jie Meng","doi":"10.1016/j.intimp.2025.114971","DOIUrl":"10.1016/j.intimp.2025.114971","url":null,"abstract":"<div><h3>Background and objective</h3><div>Pulmonary fibrosis, a pathological process where the extracellular matrix overly deposits in lung tissue because of various pathogenic factors, leads to lung structure damage and function decline. Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and high mortality, lacking effective drug treatments. Mefunidone (MFD), a new small-molecule compound, showed therapeutic effects on it in previous studies, but its specific molecular target is unknown. This study aims to clarify MFD's target and its potential mechanism. By exploring this, we hope to offer new insights and potential solutions for treating IPF and improving patients' outcomes.</div></div><div><h3>Methods</h3><div>Mice with pulmonary fibrosis induced by bleomycin (BLM) were used as experimental models. MFD was administered by gavage. The changes in inflammation and fibrosis were evaluated through histopathological examinations. Subsequently, single-cell sequencing technology was used to explore how MFD affects the phenotype of pro-fibrotic macrophages, and verification was carried out <em>in vitro</em> to prove that MFD treats pulmonary fibrosis by influencing the phenotype of pro-fibrotic macrophages.</div></div><div><h3>Result</h3><div>MFD can inhibit the generation of succinate by binding and inhibiting the activity of succinate dehydrogenase (SDH). MFD can also inhibit the transformation of MMP12⁺CCL2⁺ profibrotic macrophages in the BLM pulmonary fibrosis model. Treatment with succinate can induce the transformation of macrophages into MMP12⁺CCL2⁺ profibrotic macrophages, and this induction depends on the succinate-specific receptor GPR91.</div></div><div><h3>Conclusion</h3><div>Our research results have revealed for the first time that MFD can treat pulmonary fibrosis by targeting SDH and regulating the transformation of MMP12⁺CCL2⁺ profibrotic macrophages.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114971"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170445","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":"Mycobacterium tuberculosis stimulates cuproptosis by regulating Lnc-Gm5532 to target FDX1 for bacteria intracellular survival","authors":"Zhaoqian Gong ,&nbsp;Jiaxue Zhang ,&nbsp;Jialin Yu ,&nbsp;Li Liu ,&nbsp;Xiaoping Wang ,&nbsp;Qiumeng Ma ,&nbsp;Guangcun Deng ,&nbsp;Xiaoling Wu","doi":"10.1016/j.intimp.2025.114967","DOIUrl":"10.1016/j.intimp.2025.114967","url":null,"abstract":"<div><div>Cuproptosis is a novel cell death modality but its regulatory role in tuberculosis remains obscure. This study is committed to explore the specific mechanism of cuproptosis induced by <em>Mycobacterium tuberculosis</em> (M.tb) infection. We confirmed that M.tb induced cuproptosis contributes to its intracellular survival. Then microarray analysis was employed to screen M.tb-infected DE mRNAs and LncRNAs which may be potential regulators of cuproptosis. We focus on a key cuproptosis gene FDX1, and 7 LncRNAs that can target FDX1. Among them, LncRNA-Gm5532 upregulated the expression of FDX1 by sponging miR-7232-5p, which further promoted the expression of cuproptosis-associated proteins, increased intracellular copper ions, worsened lipid acylation-DLAT aggregation, and resulting in cuproptosis. Meanwhile, LncRNA-Gm5532 boosts the survival of M.tb in macrophages. Collectively, LncRNA-Gm5532 exacterbates M.tb-induced cuproptosis by targeting FDX1 and promotes immune escape of M.tb. The study will provide new insights into the regulation of tuberculosis pathogenesis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114967"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144178378","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":"Cysteine-S-sulfate promotes arteriosclerosis obliterans by inducing TH17 differentiation and promoting pyroptosis","authors":"Yujie Jiang ,&nbsp;Xia Feng ,&nbsp;Yuan Yin ,&nbsp;Chao Ma ,&nbsp;Jie Deng ,&nbsp;Hao Yin ,&nbsp;Jian Chen ,&nbsp;Yicheng Xu ,&nbsp;Tianhua Yan ,&nbsp;Yeming Cao ,&nbsp;Yongbing Cao ,&nbsp;Qun Lu ,&nbsp;Chenglin Jia","doi":"10.1016/j.intimp.2025.114951","DOIUrl":"10.1016/j.intimp.2025.114951","url":null,"abstract":"<div><div>Arteriosclerotic obliterans (ASO) is a peripheral vascular disease with a high rate of amputation, the mechanism of which remains unclear and markers for early diagnosis are seriously lacking. Therefore, we first used untargeted metabolomics analysis to reveal significant differences in metabolites between the ASO cohort and the healthy volunteer cohort. Combined with targeted analysis, it was confirmed that cysteine-S-sulfate could be identified as a potential biomarker for ASO, with good diagnostic performance. In addition, we analyzed the distribution of helper T cells (T_H1, T_H2, T_H9, T_H17 and T_H22), and the results showed that T_H17 was highly expressed in the ASO cohort, and IL-17 was also elevated. Through in vitro experiments, we found that cysteine-S-sulfate can promote IL-17 secretion and induce HUVCEs pyroptosis. To further clarify the pathogenicity of cysteine-S-sulfate, we used an acute lower limb ischemia model and gave a high methionine diet to simulate the high cysteine-S-sulfate state in vivo. What was shocking was that the high methionine diet group mice had lower blood flow than the control group, as well as higher levels of cysteine-S-sulfate, higher levels of T_H17, and higher levels of pyroptosis. This also confirms that cysteine-S-sulfate promotes the differentiation of T_H17, the secretion of cytokines, and the occurrence of pyroptosis, promoting the progression of ASO. This study is valuable in providing a diagnostic marker for ASO and elucidating its pathogenesis. This suggests that blocking IL-17 may be a new strategy to treat ASO, offering clinicians a therapeutic possibility.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114951"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144178456","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":"Unveiling the therapeutic potential of anthocyanins in reserpine-induced fibromyalgia: A multi-dimensional study on behavioral, molecular, and pathological changes","authors":"Heba Mostafa ,&nbsp;Lamia A.A. Barakat ,&nbsp;Ghada S. El-Tanbouly ,&nbsp;Rania M. Khalil","doi":"10.1016/j.intimp.2025.114965","DOIUrl":"10.1016/j.intimp.2025.114965","url":null,"abstract":"<div><div>Fibromyalgia (FM) is a chronic syndrome, associated with unidentified musculoskeletal pain, depression, neuropathic pain, memory impairment, and chronic fatigue. As a natural therapy with minimal risk, the multi-therapeutic benefits of Anthocyanins (ANs) are unfolded. This study evaluates efficacy of two doses of ANs, compared to a common treatment for FM; Neurontin (Neu), against reserpine (Res)-induced FM-associated biochemical, molecular and behavioral alterations in rats. Fibromyalgia is induced by Res (1 mg/kg, sc) for three consecutive days, followed by ANs (100, 200 mg/kg, <em>po</em>), and Neu (30 mg/kg, <em>po</em>) for 28 d. Behavior tests were performed from day 26 to 31. The expression of miR-145-5p, and miR-451a in peripheral blood mononuclear cells, brain serotonin levels, and serum levels of H₂O₂ were measured. Meanwhile, spinal neurons histology, and immunohistochemistry for TNF-α, and caspase 3 were evaluated. Dose-dependently, ANs followed by Neu exhibited a marked improvement in behavior tests compared to Res group. ANs alleviated pain in hot plate test, ameliorated depression, improved motor coordination in Rota-Rod, locomotor activity in open field tests, and enhanced spatial learning and memory in Morris Water Maze test. Additionally, ANs 200 exerted the most remarkable increase in miR-145-5p, and miR-451a expressions, serotonin levels with the same significant decrease in H₂O₂ level. ANs 200, and Neu showed weak nuclear translocation of TNF-α and caspase 3 and demonstrated few spinal neuron degenerations over ANs 100.</div><div>Exceptionally, as a natural alternative to conventional FM therapy, ANs, dose-dependently proved its remarkable neuro/psycho-protective actions joined with its antioxidant, anti-inflammatory and antiapoptotic impacts.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114965"},"PeriodicalIF":4.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170446","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":"Exosome-derived SLC12A2-DT promotes macrophage M2 polarization-mediated hepatocellular carcinoma progression","authors":"Jingyi Zhou ,&nbsp;Wencong Ma ,&nbsp;Runkai Zhou ,&nbsp;Di Ma ,&nbsp;Chuan Liu ,&nbsp;Fan Wang ,&nbsp;Lin Yuan ,&nbsp;Ling Xu ,&nbsp;Chen Wang ,&nbsp;Qi Li","doi":"10.1016/j.intimp.2025.114955","DOIUrl":"10.1016/j.intimp.2025.114955","url":null,"abstract":"<div><h3>Background</h3><div>Previous scholarly research highlights the indispensable roles of tumor-associated macrophages (TAMs) and exosomes in the progression of hepatocellular carcinoma (HCC). However, the nuanced molecular mechanisms by which tumor-derived exosomal lncRNAs interact with TAMs to modulate macrophage polarization and HCC proliferation remain largely obscure.</div></div><div><h3>Method</h3><div>Clinical specimens were subjected to sequencing and bioinformatics analysis, revealing the previously unreported SLC12A2-DT. The presence of exosomes was assessed via transmission electron microscopy and differential ultracentrifugation. In vivo and in vitro coculture experiments were employed to elucidate the functions of exosomal SLC12A2-DT. RNA pull-down assays, dual-luciferase reporter assays, and mass spectrometry were utilized to delineate the mechanisms by which exosomal SLC12A2-DT regulates the interaction between HCC cells and M2 macrophages.</div></div><div><h3>Results</h3><div>Our study revealed the aberrant upregulation of SLC12A2-DT expression in HCC, particularly in advanced stages, and its association with poor prognosis in HCC patients. Notably, SLC12A2-DT-induced M2 macrophage polarization significantly induced lung metastasis in a murine HCC model. We subsequently confirmed that HCC cell-derived exosomal SLC12A2-DT induced M2 macrophage polarization by specifically binding to GSK3β/β-catenin and downregulating the degradation of ubiquitinated β-catenin, leading to Wnt signaling pathway activation. Furthermore, we revealed that KLF4 transcriptionally repressed SLC12A2-DT expression in HCC cells.</div></div><div><h3>Conclusion</h3><div>These findings suggest that tumor-derived exosomal SLC12A2-DT facilitates HCC progression by modulating the interplay between HCC cells and TAMs through the Wnt/GSK3β/β-catenin signaling pathway.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114955"},"PeriodicalIF":4.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144169731","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":"BAP1 exacerbates inflammatory bowel disease by promoting ferroptosis via SLC7A11 suppression","authors":"Xing Chen ,&nbsp;Yang Yang ,&nbsp;Bingjie Han ,&nbsp;Zheng Zhou ,&nbsp;Congying Xu ,&nbsp;Mengke Gu ,&nbsp;Zhen Huang ,&nbsp;Hui Liu ,&nbsp;Kaidi Ren ,&nbsp;Yi Luan","doi":"10.1016/j.intimp.2025.114957","DOIUrl":"10.1016/j.intimp.2025.114957","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to elucidate the role of BAP1 in inflammatory bowel disease (IBD) and elucidate the underlying mechanism.</div></div><div><h3>Methods</h3><div>A colitis model was established in C57BL/6 mice with dextran sulfate sodium (DSS) and in the HT-29 cell line. Ferroptosis-related gene expression was analyzed via RNA sequencing, qRT–PCR, and Western blotting. Ferroptosis was induced by Fin56, and oxidative stress markers, iron levels, and cystine uptake were assessed. BAP1 knockdown and overexpression experiments were conducted in vivo and in vitro to determine its impact on SLC7A11 expression, ferroptosis, and intestinal inflammation.</div></div><div><h3>Results</h3><div>BAP1 was significantly upregulated in DSS-induced colitis and correlated with increased ferroptosis markers. Knockdown of BAP1 alleviated colitis symptoms, reduced inflammatory cytokine levels, and decreased bacterial translocation. In vitro, BAP1 promoted ferroptosis by increasing oxidative stress and iron accumulation while inhibiting SLC7A11 expression. The C91A mutation of BAP1 failed to suppress SLC7A11, suggesting that BAP1-mediated ferroptosis is dependent on its deubiquitinase activity. Furthermore, BAP1 overexpression inhibited cystine uptake by repressing SLC7A11, whereas SLC7A11 overexpression rescued cystine uptake and mitigated ferroptosis.</div></div><div><h3>Conclusion</h3><div>Our findings reveal that BAP1 exacerbates IBD by promoting ferroptosis through the inhibition of SLC7A11. Knockdown of BAP1 alleviates colitis by suppressing ferroptosis, highlighting a potential therapeutic strategy for IBD. Targeting the BAP1–SLC7A11 axis may provide novel insights into the treatment of ferroptosis-related intestinal diseases.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114957"},"PeriodicalIF":4.8,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170441","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":"Unleashing the cardioprotective potential of berberine against doxorubicin cardiotoxicity: Innovative exploitation of the peculiar antipyroptotic/antioxidant/anti-inflammatory capacity via modulation of inflammasome/caspase-1/interleukin pathway in rats","authors":"Omaima A. Ahmedy ,&nbsp;Heba H. Salem ,&nbsp;Yasmin S. Mohamed ,&nbsp;Doaa A. Zaky","doi":"10.1016/j.intimp.2025.114964","DOIUrl":"10.1016/j.intimp.2025.114964","url":null,"abstract":"<div><div>The anticancer use of doxorubicin (DXR) is limited by its irreversible cardiotoxicity. Berberine (BRB) alkaloid is endowed with peculiar anti-inflammatory/antioxidant/antipyroptotic characteristics. Pyroptosis, the lytic/inflammatory form of programmed cell death, has been implicated in DXR-provoked cardiomyopathy. This study aimed at examining the protective role of BRB in DXR-induced cardiotoxicity using male Wistar rats, randomly assigned into 5 groups (<em>n</em> = 10 per group). BRB was solely tested apart from the model group (BRB CTRL; 100 mg/kg/d, 10d, p.o., DXR model; 22.5 mg/kg, single i.p. injection), while the last 2 groups were pretreated with BRB (50, 100 mg/kg/d, 10d, p.o.). DXR upregulated serum troponin-I, creatine kinase, and total lactate dehydrogenase (<em>p</em> &lt; 0.0001) that were partially restored by the low (<em>p</em> = 0.0053/0.0006/0.0037, respectively) and high doses (p &lt; 0.0001). Overexpression of the pyroptotic markers, namely, NADPH oxidase-4, dynamin-related protein-1, NOD-like receptor pyrin-like protein-3, and gasdermin-D, with simultaneous downregulation of nuclear factor erythroid-2-related factor-2, was also observed in DXR-challenged rats (<strong><em>p</em></strong> &lt; 0.0001). Moreover, DXR incited oxidative stress manifested by elevated thiobarbituric acid reactive substances and diminished cardiac glutathione contents and superoxide dismutase activity (<strong><em>p</em></strong> &lt; 0.0001). Contemporaneously, enhancement of the cardiac inflammatory markers' levels, viz, toll-like receptor-4, nuclear factor-κBp65, caspase-1/3, interleukin-18/1β was demonstrated (<strong><em>p</em></strong> &lt; 0.0001). This biochemical deterioration was coupled with detrimental hemodynamic/histopathological alterations. Of interest, BRB reversed these effects by properly handling the released immunogenic cell death-associated molecular patterns via the synchronous suppression of the oxidative/inflammatory burden and mitochondrial fission that together interrupted the inflammasome priming, prohibiting the resultant demise. The reported findings pinpoint BRB as a promising agent for managing DXR-induced cardiotoxicity.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114964"},"PeriodicalIF":4.8,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144146335","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}