International immunopharmacology最新文献

{"title":"Corrigendum to \"Engineered macrophages in breast cancer: bridging targeted therapy and advanced drug delivery\" [Int. Immunopharmacol. 163 (2025) 115237].","authors":"Da Qian, Yuxiao Mu, Zirong Jiang, Haotian Liu, Liquan Zhu, Zhuotao Yang, Chaoshen Wu, Chaoqi He, Xuli Meng","doi":"10.1016/j.intimp.2025.115279","DOIUrl":"https://doi.org/10.1016/j.intimp.2025.115279","url":null,"abstract":"","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":" ","pages":"115279"},"PeriodicalIF":4.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717894","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":"Calreticulin-driven immunogenic cell death promotes osteoclast differentiation and osteoarthritis progression via the LRP1/Rac1 signaling","authors":"Qi Ma ,&nbsp;Zhibin Lan ,&nbsp;Yang Yang ,&nbsp;Rui Sun ,&nbsp;Di Xue ,&nbsp;Xue Lin ,&nbsp;Yajing Su ,&nbsp;Long Ma ,&nbsp;Zhijun Hu ,&nbsp;Gang Wu ,&nbsp;Xiaoxin He ,&nbsp;Kuanmin Tian ,&nbsp;Qunhua Jin","doi":"10.1016/j.intimp.2025.115277","DOIUrl":"10.1016/j.intimp.2025.115277","url":null,"abstract":"<div><div>Aberrant osteoclast activation in subchondral bone is a hallmark of osteoarthritis (OA). This study identifies calreticulin (CALR), a key immunogenic cell death (ICD) marker, as a critical regulator of osteoclast differentiation and OA pathogenesis. Proteomic analysis revealed elevated CALR expression in subchondral bone from OA patients, which was further validated in human specimens and a destabilization of the medial meniscus (DMM)-induced murine OA model. In vitro, CALR upregulation during osteoclast differentiation activated the low-density lipoprotein receptor-related protein 1 (LRP1)/Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling pathway, promoting osteoclastogenesis and bone resorption. These effects were suppressed by the apoptosis inhibitor zVAD-fmk or CALR knockdown. CALR-deficient mice exhibited attenuated subchondral bone damage and delayed OA progression post-DMM. Mechanistically, CALR governs osteoclast function via LRP1/Rac1-mediated nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) activation and secretion of bone-resorbing factors (matrix metalloproteinase-9 (MMP-9), cathepsin K (CTSK)). Our study establishes CALR as a novel therapeutic target for OA, bridging ICD to osteoclast-driven subchondral bone resorption and microarchitectural disruption.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"163 ","pages":"Article 115277"},"PeriodicalIF":4.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703801","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":"S100A9 inhibition ameliorates HFpEF by modulating mitochondrial fission and oxidative stress","authors":"Moran Wang ,&nbsp;Bowen Ren ,&nbsp;Xiaofan Wu ,&nbsp;Junyi Guo ,&nbsp;Yu Cao ,&nbsp;Lintong Men ,&nbsp;Wei Shi ,&nbsp;Cuntai Zhang ,&nbsp;Li Lin ,&nbsp;Jiagao Lv ,&nbsp;Sheng Li ,&nbsp;Shengqi Huo","doi":"10.1016/j.intimp.2025.115280","DOIUrl":"10.1016/j.intimp.2025.115280","url":null,"abstract":"<div><div>Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction and myocardial stiffness, with limited treatment options due to the unclear molecular mechanisms underlying the disease. In this study, we investigate the role of S100A9, an inflammatory mediator, in regulating mitochondrial dynamics in HFpEF. Using “two-hit” (high-fat diet and L-NAME) and db/db mouse models, we show that S100A9 is significantly elevated in both cardiac tissue and serum, correlating with impaired diastolic function, cardiac hypertrophy, and increased oxidative stress. Inhibition of S100A9 with Paquinimod (PAQ) improved diastolic function, reduced cardiac hypertrophy, and decreased S100A9-positive macrophage infiltration, while preventing M1 macrophage polarization. In vitro, S100A9 secreted by palmitic acid-stimulated RAW 264.7 macrophages promoted mitochondrial fission in AC16 cardiomyocytes by increasing p-Drp1 and Fis1 expression, similar to the effects observed with recombinant S100A9. Excessive mitochondrial fission, regulated by S100A9, is a key factor in HFpEF progression. Transcriptomic analysis revealed significant upregulation of pyruvate dehydrogenase kinase 4 (PDK4) in HFpEF mice. Mechanistically, S100A9 induced PDK4 expression via SPI1-mediated transcription, exacerbating oxidative stress and mitochondrial fragmentation. PAQ treatment or silencing PDK4/SPI1 in AC16 cells reversed these effects, restoring ATP levels and stabilizing mitochondrial membrane potential. Cardiomyocyte-specific PDK4 knockdown in vivo further ameliorated HFpEF progression without affecting systolic function. These findings highlight S100A9 inhibition as a promising therapeutic strategy for HFpEF by targeting mitochondrial dysfunction through the S100A9/SPI1/PDK4 axis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"163 ","pages":"Article 115280"},"PeriodicalIF":4.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703806","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":"In vivo modulation of the tumor microenvironment: anti-tumor effects of combination therapy of fucoidan and small molecule immune checkpoint inhibitor BMS-202","authors":"Dalia H.H. Amer ,&nbsp;Mai F. Tolba ,&nbsp;Maha R.A. Abdollah","doi":"10.1016/j.intimp.2025.115271","DOIUrl":"10.1016/j.intimp.2025.115271","url":null,"abstract":"<div><div>Cancer immunotherapy has gained significant momentum, particularly in counteracting the immunosuppressive tumor microenvironment (TME). This study investigates the therapeutic potential of a combination therapy of fucoidan, a marine-derived polysaccharide with anti-cancer and immunomodulatory properties, and BMS-202, a small molecule immune checkpoint inhibitor targeting programmed cell death 1 (PD-1) and its ligand PDL-1, in a murine model of Ehrlich solid-phase carcinoma. Tumor bearing mice received saline (control), BMS-202, fucoidan or their combination (at half the monotherapy doses). Both monotherapies significantly reduced tumor volumes. Histological analysis of excised tumors from the control group revealed large areas of viable tumor cells, whereas the combination therapy induced central tumor necrosis, with abundant pyknotic and fragmented tumor cells. The area percentage of tumor necrosis increased by 6.3-, 4.1- and 1.4-fold in the combination group versus control, fucoidan, and BMS-202, respectively (<em>p</em> &lt; 0.05). Immunohistochemistry (IHC) was used to assess Ki-67 and cleaved caspase-3, ELISA measured IL-6 and TGF-β while Western blotting evaluated p-ERK1/2, p-Akt, and p-p38 MAPK. The combination therapy significantly increased cleaved caspase-3 by 8.3 folds and reduced Ki-67, IL-6, TGF-β, p-ERK1/2, p-Akt, and p-p38 MAPK levels by 67 %, 98.9 %, 75.8 %, 69 %, 85 %, and 87.5 %, respectively, relative to the control (<em>p</em> &lt; 0.05). Additionally, immune profiling of the tumor tissue using IHC revealed an increased CD8+/FOXP3+ ratio and a reduced CD4+/CD8+ ratio, suggesting an immunomodulatory effect. In conclusion, fucoidan demonstrated the potential to enhance the anti-tumor efficacy of BMS-202 via modulation of the immune TME and downregulating key oncogenic pathways, warranting further investigation into its role in combination with immunotherapy.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"163 ","pages":"Article 115271"},"PeriodicalIF":4.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703805","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":"ZEB2: a multifunctional regulator of neural injury repair","authors":"Saiqun Nie,&nbsp;Li Fang,&nbsp;Bingbin Wang,&nbsp;Ran Chen,&nbsp;Tao Wei,&nbsp;Yanren Zhang,&nbsp;Hao Ji,&nbsp;Yanqing Wu","doi":"10.1016/j.intimp.2025.115266","DOIUrl":"10.1016/j.intimp.2025.115266","url":null,"abstract":"<div><div>Nerve injury is a pathological condition characterized by damage or necrosis of nerve cells in injured areas due to trauma, infection, ischemia, genetic factor or other factors. Neural injury repair is precisely regulated by the complex regulatory network of body. Zinc finger E-box-binding protein 2 (ZEB2), known as a critical transcription factor, not only serves as a key participant in embryonic neural development, but also exerts a vital regulatory role in neural injury repair. This paper summarizes the structure, function, and regulatory network of ZEB2 and then elucidates its pivotal roles in glial scar formation, remyelination, and epithelial-to-mesenchymal transition (EMT) for neural injury repair. Furthermore, it provides a comprehensive summary of advances about ZEB2's regulatory role in peripheral nerve injury, spinal cord injury, hemorrhagic brain injury, and Mowat-Wilson syndrome. This paper deepens the theoretical significance of ZEB2 in regulating neural injury repair and aims to offer a new perspective for therapeutic strategies in neural injury repair.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"163 ","pages":"Article 115266"},"PeriodicalIF":4.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703804","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":"Leveraging readily available clinical data with machine learning to predict first-line immunotherapy outcomes in non-small cell lung cancer","authors":"Fang Liu ,&nbsp;Rong Huang ,&nbsp;Qin Wang ,&nbsp;Ruitao Wang ,&nbsp;Jia Lu ,&nbsp;Yanying Zhang ,&nbsp;Xuejiao Ma ,&nbsp;Xiaoyu Liu ,&nbsp;Xudong Kong ,&nbsp;Pengmei Li ,&nbsp;Liqun Jia ,&nbsp;Yanni Lou","doi":"10.1016/j.intimp.2025.115259","DOIUrl":"10.1016/j.intimp.2025.115259","url":null,"abstract":"<div><h3>Background</h3><div>Immune checkpoint inhibitors (ICIs) are essential first-line treatments for recurrent or metastatic non-small cell lung cancer (NSCLC). However, predicting their effectiveness and the occurrence of immunotherapy-related adverse events (irAEs) remains challenging.</div></div><div><h3>Methods</h3><div>This retrospective study involved NSCLC patients who received first-line ICI therapy at China-Japan Friendship Hospital in Beijing, China, between October 29, 2018, and July 10, 2024. We employed five machine learning models to predict treatment responses to ICIs and the occurrence of irAEs.</div></div><div><h3>Results</h3><div>A total of 397 NSCLC patients who received first-line ICIs were included in the analysis, with 277 patients in the train-validation cohort and 120 in the test cohort. The neural network and gradient boosting models were the most effective for predicting treatment responses, achieving AUC values of 0.87 and 0.84, respectively. For predicting irAEs, random forest and gradient boosting emerged as the top performers, with AUC values of 0.84 and 0.80. Feature importance analysis identified key predictors such as red blood cell (RBC) counts and metastatic sites for treatment response, while metastatic sites and sex were significant for irAE prediction. In the validation cohort, the neural network demonstrated strong performance in predicting treatment response (AUC of 0.84, recall of 0.8406, and F1 score of 0.8007), while the random forest model excelled in predicting irAEs (AUC of 0.82, accuracy of 0.7417, precision of 0.7500, recall of 0.8261, and F1 score of 0.7862).</div></div><div><h3>Conclusion</h3><div>These findings highlight the potential for enhancing personalized treatment strategies for NSCLC patients undergoing first-line ICI therapy.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"163 ","pages":"Article 115259"},"PeriodicalIF":4.8,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703803","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":"Hepatic ischemia-reperfusion and mitochondrial quality control: potential therapeutic targets","authors":"Junqi Wang ,&nbsp;Wenkai Fu ,&nbsp;Nan Lu ,&nbsp;Zhijiang Guo ,&nbsp;Ong Sang Bing ,&nbsp;Hongshuo Shi ,&nbsp;Hao Zhou ,&nbsp;Xing Chang ,&nbsp;Miao Meng","doi":"10.1016/j.intimp.2025.115267","DOIUrl":"10.1016/j.intimp.2025.115267","url":null,"abstract":"<div><h3>Background</h3><div>Hepatic ischemia-reperfusion injury (HIRI) represents a significant challenge in liver surgical procedures. This complex pathology arises from the interplay of inflammation, oxidative damage, and regulated cell death cascades. Compromised mitochondrial function critically contributes to HIRI progression. Consequently, maintaining cellular equilibrium necessitates effective mitochondrial quality control (MQC), a fundamental axis encompassing mitochondrial autophagy, dynamic remodeling, biogenesis, and the mitochondrial unfolded protein response (UPRmt).</div></div><div><h3>Key Mechanisms</h3><div>Mitophagy: Selectively removes damaged mitochondria via PINK1/Parkin (ubiquitin-dependent) and BNIP3/FUNDC1 (ubiquitin-independent) pathways. Impaired mitophagy during ischemia-reperfusion exacerbates mitochondrial damage, while enhancing it (e.g., via PEG35, Sirtuin activators) mitigates injury.</div><div>Mitochondrial Dynamics: The stability of the mitochondrial network is critically dependent on the equilibrium between fusion, regulated by Mfn1, Mfn2, and Opa1, and fission, mediated by Drp1. HIRI disrupts this equilibrium, promoting fragmentation and apoptosis. Pharmacological agents (e.g., DEX, exogenous irisin) restore dynamics by modulating Drp1 and fusion proteins.</div><div>Biogenesis: The PGC-1α/NRF-1/TFAM axis drives mitochondrial renewal. HIRI suppresses biogenesis, but interventions (e.g., ADSC-exo, genipin) enhance ATP production and mitochondrial DNA replication.</div></div><div><h3>Therapeutic Interventions</h3><div>Pharmacological strategies targeting MQC components demonstrate efficacy:</div><div>Mitophagy: PEG35 enhances ALDH2-mediated LC3 conversion; quercetin regulates SIRT1/TMBIM6.</div><div>Dynamics: COX-2 inhibitors and SIRT3 deacetylate Opa1 to promote fusion.</div><div>Biogenesis: Irisin and NRF2 activators upregulate PGC-1α/TFAM, restoring mitochondrial mass.</div></div><div><h3>Conclusion</h3><div>MQC mechanisms are pivotal in HIRI pathogenesis. Targeting mitophagy, dynamics, and biogenesis offers promising therapeutic avenues to attenuate inflammation, oxidative stress, and cell death. Translational research on MQC modulators (e.g., PEG35, Sirt1 activators) may yield novel treatments.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"163 ","pages":"Article 115267"},"PeriodicalIF":4.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144694721","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":"Comment on: Oleoylethanolamide exerts neuroprotection following ischemic stroke through microglial PPARα signal","authors":"Keping Jiao ,&nbsp;Huiqin Zhang ,&nbsp;Yanyan Wang ,&nbsp;Jian Liu","doi":"10.1016/j.intimp.2025.115228","DOIUrl":"10.1016/j.intimp.2025.115228","url":null,"abstract":"","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"163 ","pages":"Article 115228"},"PeriodicalIF":4.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144694722","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":"Dendritic cell-based vaccine prepared with recombinant Lactococcus lactis eukaryotic-prokaryotic dual expressing OVA enhances antitumor efficacy by both direct and cross-presentation","authors":"Tingting Zhang ,&nbsp;Shuai Huang ,&nbsp;Peng Liu ,&nbsp;Xiaoqiu Su ,&nbsp;Jiahe Zou ,&nbsp;Yulin Wu ,&nbsp;Yijie Li ,&nbsp;Yuekang Xu ,&nbsp;Jinyao Li","doi":"10.1016/j.intimp.2025.115263","DOIUrl":"10.1016/j.intimp.2025.115263","url":null,"abstract":"<div><div>Probiotic <em>Lactococcus lactis</em> (<em>L.L</em>) can act as an antigen delivery carrier to cross-present (XPT) exogenous antigens in dendritic cells (DCs). To optimize antigen XPT in a DC-based vaccine for improved antitumor efficacy, we produced recombinant <em>L.L</em> strains expressing the model antigen OVA <em>via</em> distinct methods: prokaryotic expression alone, eukaryotic expression alone, or dual prokaryotic-eukaryotic expression (designated <em>pOVA-L.L</em>, <em>eOVA-L.L</em>, and <em>dOVA-L.L</em>, respectively). These strains were used to deliver antigens into DCs. Although all three recombinant OVA-<em>L.L</em> strains significantly enhanced DCs' ability to promote OT-I cell proliferation (with <em>dOVA-L.L</em>-treated DCs (<em>dOVA-L.L</em>-DCs) showing the strongest effect), only <em>dOVA-L.L</em>-DCs demonstrated significantly more potent antitumor efficacy in the B16-OVA tumor mouse model, consistent with the <em>in vitro</em> data. Further investigation into the mechanisms underlying the enhanced antigen XPT and anti-tumor efficacy of <em>dOVA-L.L</em>-DCs revealed that <em>pOVA-L.L</em> and <em>dOVA-L.L</em> resided both inside and outside lysosomes, whereas <em>eOVA-L.L</em> was located exclusively outside lysosomes. Consequently, <em>dOVA-L.L</em>-DCs could XPT higher amounts of MHC I-OVA peptide complex on their surface. Furthermore, these DCs could also directly present lysosome-derived OVA peptide-MHC II complexes to stimulate antigen-specific CD4⁺ T cell responses <em>in vivo</em>. Collectively, these mechanisms induced more persistent cellular immune responses than either of the other two recombinant <em>L.L</em>-DCs. In conclusion, we developed an enhanced antigen delivery system using probiotic food-grade bacteria. This system promotes the prolonged expression of exogenous antigens and significantly enhances the XPT capacity of DC vaccines for tumor immunotherapy.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"163 ","pages":"Article 115263"},"PeriodicalIF":4.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685535","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":"Knockdown of Nr4a3 mitigates acute pancreatitis-induced injury by modulating Btg2 to reduce oxidative stress, mitochondrial damage, and apoptosis","authors":"Zhongcheng Zhu ,&nbsp;Xiaolin Dou ,&nbsp;Qizhen Chen ,&nbsp;Yebin Lu","doi":"10.1016/j.intimp.2025.115269","DOIUrl":"10.1016/j.intimp.2025.115269","url":null,"abstract":"<div><div>Acute pancreatitis (AP) has a high mortality, involving oxidative stress and mitochondrial damage. Nuclear receptor subfamily 4 group A member 3 (Nr4a3) and BTG anti-proliferation factor 2 (Btg2) have a close connection with mitochondrial damage. Here, we found that Nr4a3 expression was upregulated in pancreatic tissues of AP mice induced by cerulein. To elucidate Nr4a3's role, we injected adeno-associated virus 9 (AAV9) carrying Nr4a3-targeting short hairpin RNA into the pancreatic duct. This intervention reduced pancreatic edema, inflammatory infiltration, and acinar cell necrosis by suppressing pancreatic enzyme activation. Moreover, Nr4a3 knockdown improved mitochondrial function in pancreatic acinar cells, evidenced by increased mitochondrial membrane potential, enhanced ATP production, and decreased superoxide levels. It also inhibited cell apoptosis by suppressing the activation of the caspase pathway. In vitro, Nr4a3 knockdown in CCK-treated pancreatic acinar cells decreased oxidative stress, mitigated mitochondrial damage, and suppressed apoptosis, while Nr4a3 overexpression exacerbated cell injury. Further investigation identified Btg2 as a downstream target of Nr4a3. Btg2 expression was elevated in pancreatic acinar cells of AP mice, and siRNA-mediated Btg2 knockdown alleviated CCK-induced cell injury. Mechanistically, Nr4a3 promoted Btg2 transcription, thereby promoting mitochondrial damage in pancreatic acinar cells and leading to cell apoptosis. Btg2 overexpression reversed the protective effects of Nr4a3 knockdown. Overall, our findings demonstrate that downregulation of Nr4a3 exerts anti-AP effects by regulating Btg2, providing potential therapeutic targets for AP.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"163 ","pages":"Article 115269"},"PeriodicalIF":4.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685536","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}