International immunopharmacology最新文献

{"title":"Inhibiting ubiquitin-specific protease 38 safeguards against diabetic nephropathy by limiting tubular epithelial cell ferroptotic death through the suppression of IREB2-mediated iron overload","authors":"Shan Gao,&nbsp;Chunping Dong,&nbsp;Hui Li,&nbsp;Jing Li,&nbsp;Ailiyasi Abula","doi":"10.1016/j.intimp.2026.116307","DOIUrl":"10.1016/j.intimp.2026.116307","url":null,"abstract":"<div><div>Kidney tubular cell death caused by elevated blood sugar levels plays a significant role in the progression of diabetic nephropathy (DN). Recent studies have highlighted ferroptosis, a form of regulated cell death, as a critical mechanism underlying tubular cell death in DN. Ubiquitin-specific protease 38 (USP38) has been identified as a key modulator of the ferroptosis process; however, its role in renal tubular cell ferroptosis and DN progression remains unexplored. This study aimed to investigate whether USP38 adjusts ferroptosis in renal tubular cells and its impact on DN progression, elucidating the underlying mechanisms involved. USP38 levels were markedly increased in HK-2 cells stimulated with high glucose (HG) and in the kidneys of diabetic mice. Knockdown of USP38 mitigated HG-induced damage and fibrosis while inhibiting ferroptosis in HK-2 cells; conversely, overexpression of USP38 exacerbated these effects. Further investigations revealed that USP38 modulated the expression of iron metabolism-related proteins, including responsive element binding protein 2 (IREB2), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), and transferrin receptor protein 1 (TfR1). Mechanistically, USP38 was found to directly interact with IREB2 and regulate both its ubiquitination and stability. Moreover, overexpression of IREB2 significantly reversed the inhibitory effect of USP38 silencing on ferroptosis. In vivo experiments demonstrated that USP38 knockdown alleviated renal damage, fibrosis, and inflammation while suppressing iron overload and ferroptosis in DN mice. In conclusion, USP38 mediates renal tubular cell ferroptosis under HG conditions through IREB2-mediated iron overload. Targeting USP38 to prevent tubular epithelial cell ferroptosis may effectively mitigate DN progression, providing a novel regulatory mechanism and potential therapeutic target for this disease.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116307"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125016","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":"Neogambogic acid promotes M-MDSC differentiation into M1 macrophages to inhibit peritoneal metastasis of colorectal cancer","authors":"Jinjin Liu ,&nbsp;Zhao Wu ,&nbsp;Jing Xun ,&nbsp;Xiaolin Jiang ,&nbsp;Bin Liu ,&nbsp;Huichao Yang ,&nbsp;Yingdi Han ,&nbsp;Zhibo Hu ,&nbsp;Qi Gao ,&nbsp;Ai’min Zhang ,&nbsp;Shimin Yang ,&nbsp;Xiangyang Yu ,&nbsp;Qi Zhang","doi":"10.1016/j.intimp.2026.116255","DOIUrl":"10.1016/j.intimp.2026.116255","url":null,"abstract":"<div><h3>Background</h3><div>The immunosuppressive microenvironment severely constrains the efficacy of immunotherapy for colorectal cancer with peritoneal metastasis (CPM), urgently demanding strategies to reprogram it. Here, we aim to evaluate natural compound neogambogic acid (NGA) for its potential to modulate CPM progression and reshape the tumor immune microenvironment.</div></div><div><h3>Methods</h3><div>CPM mouse models were established via intraperitoneal injection of murine colorectal cancer cells, and then treated with NGA. Tumor burden and ascites, and immune microenvironment were assessed. Flow cytometry and RT-qPCR were performed to determine the impact of NGA on the differentiation of monocytic myeloid-derived suppressor cells (M-MDSCs) into M1 macrophages. Network pharmacology was used to screen the potential targets of NGA, and molecular docking, cellular thermal shift assay (CTESA) and drug affinity responsive target stability (DARTS) assays were employed to validate the interaction between NGA and STAT3. Finally, the synergistic effect of NGA combined with anti-PD-1/anti-CD47 blockade on inhibiting CPM progression was evaluated.</div></div><div><h3>Results</h3><div>NGA significantly reduced tumor burden, suppressed ascites formation, and reshaped immunosuppressive microenvironment by decreasing M-MDSCs, increasing tumor-infiltrating CD4⁺/CD8⁺T cells and M1 macrophage frequency. Notably, NGA promoted the differentiation of M-MDSCs toward M1 macrophages. Mechanically, NGA directly bound to STAT3 and inhibited its phosphorylation (pSTAT3). Therapeutically, NGA synergized with anti-PD-1/anti-CD47 combination therapy, leading to a marked reduction in tumor burden in CPM models.</div></div><div><h3>Conclusion</h3><div>NGA, a multi-targeted agent that prominently targets STAT3, enhances the immunotherapy efficacy in CPM by reshaping the immunosuppressive microenvironment through M-MDSC-to-M1 macrophage conversion. These findings provide a promising preclinical basis for NGA-based combinatorial strategies in advanced colorectal cancer.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116255"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146037434","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":"Dihydromyricetin improves DSS-induced colitis and behavioral disorders by regulating the microbiota-gut-brain axis balance and inhibiting the activation of NLRP3 inflammasome","authors":"Guyi Cong ,&nbsp;Di Ao ,&nbsp;Xuelian Mei ,&nbsp;Rui Zhao ,&nbsp;Rui Guo ,&nbsp;Xiquan Ke ,&nbsp;Zhenzeng Ma ,&nbsp;Lin Gu ,&nbsp;Hailun Zheng","doi":"10.1016/j.intimp.2026.116237","DOIUrl":"10.1016/j.intimp.2026.116237","url":null,"abstract":"<div><div>Patients with inflammatory bowel disease (IBD) commonly exhibit psychiatric symptoms, such as anxiety and depression. However, studies on drugs addressing the concurrent amelioration of these symptoms in this patient population are rare. Previous studies have suggested that dihydromyricetin (DHM) may show therapeutic potential for IBD. This study investigated the therapeutic effects of DHM on dextran sulfate sodium (DSS)-induced colitis and associated behavioral disorders in mice. The findings of the experiments indicated that DHM could ameliorate colitis symptoms, including changes in body weight, colon length, disease activity index (DAI) scores, and histopathological damage. Furthermore, DHM improved the behavioral impairments observed in colitis mouse model, as evidenced by results from the open field test, elevated plus maze test, and tail suspension test, along with hippocampal histopathological assessments. Molecular analysis revealed that DHM notably suppressed the activation of NLRP3 inflammasome and IL-1β in both the colon and the hippocampus. DHM enhanced the intestinal barrier, elevated brain-derived neurotrophic factor (BDNF) levels in the hippocampus and serum, and concurrently reduced microglia activation. DHM lowered the levels of IL-1β, tumor necrosis factor-α (TNF-α), and lipopolysaccharide (LPS) in the serum. 16S rDNA sequencing results indicated that DHM could modulate DSS-induced gut microbiota dysbiosis, enriching various beneficial metabolic and neuromodulatory pathways. Metabolomic analysis demonstrated that DHM notably elevated acetic acid, propionic acid, and butyric acid levels in intestinal feces. Network pharmacology analysis identified the central intersecting genes of DHM, ulcerative colitis (UC), and neuroinflammation. Differential gene expression analysis underscored IL-1 β as a pivotal target for the co-occurrence of UC and psychiatric conditions. These findings imply that DHM may ameliorate DSS-induced colitis and concomitant behavioral disturbances in mice, underscoring its potential as a natural therapeutic agent for IBD accompanied by psychiatric comorbidities.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116237"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015884","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":"ResiDUBs: A deubiquitinating enzyme-based prognostic model identifies UBXN1 driving sorafenib resistance in liver cancer","authors":"Manqi Li ,&nbsp;Yuxin Xie ,&nbsp;Jinrui Wei ,&nbsp;Lichuan Wu","doi":"10.1016/j.intimp.2026.116290","DOIUrl":"10.1016/j.intimp.2026.116290","url":null,"abstract":"<div><div>Deubiquitinating enzymes (DUBs) are a class of biological macromolecules with molecular weights ranging from 30 to 150 kDa that play extensive roles in tumor initiation and progression. However, their implications in sorafenib resistance in liver cancer remain incompletely understood. In this study, we identified sorafenib resistance-associated DUBs through weighted gene co-expression network analysis and differential expression profiling. Subsequently, we developed a DUB-based predictive model for liver cancer resistance, designated ResiDUBs, using multivariate Cox regression analysis. This model was employed to assess drug resistance and prognostic outcomes. The ResiDUBs model—constructed based on five DUBs (OTUB1, USP32, USP48, USP49, and UBXN1)—stratified patients into high- and low-risk groups. Patients in the high-risk group exhibited significantly greater sorafenib resistance, poorer prognosis, and hyperactivation of the PI3K/AKT signaling pathway. Multi omics analyses, including single-cell RNA sequencing, spatial transcriptomics, and bulk RNA sequencing, consistently identified UBXN1 as the most prominent resistance-associated gene within the ResiDUBs signature. UBXN1 expression was markedly upregulated in treatment-resistant tumors. Knockdown of UBXN1 sensitizes liver cancer cells to sorafenib and inhibits PI3K/AKT pathway activity. Conversely, overexpression of UBXN1 increases cellular resistance to sorafenib, activates the PI3K/AKT pathway, and induces macrophage polarization toward the M2 phenotype. In vivo experiments further demonstrate that UBXN1 knockdown enhances the sensitivity of liver cancer cells to sorafenib and significantly reduces PI3K/AKT pathway activity. Our findings suggest that targeting UBXN1 may represent a promising therapeutic strategy to overcome sorafenib resistance in liver cancer.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116290"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076140","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":"A novel mouse model of arthritis with enthesitis and heterotopic ossification","authors":"Shanshan Kang ,&nbsp;Shuqiong Zhang ,&nbsp;Xingyi Wang ,&nbsp;Jianyong Chen ,&nbsp;Qinyi Cai ,&nbsp;Lvlv Ye ,&nbsp;Huilin Hu ,&nbsp;Ling Lin ,&nbsp;Peng Cao ,&nbsp;Yang Sun ,&nbsp;Fenli Shao","doi":"10.1016/j.intimp.2026.116273","DOIUrl":"10.1016/j.intimp.2026.116273","url":null,"abstract":"<div><div>Ankylosing spondylitis (AS), enthesitis-related arthritis, and psoriatic arthritis are autoimmune bone diseases that share the characteristic pathological features of enthesitis and heterotopic ossification. This sets them apart from bone-eroding inflammatory joint diseases such as rheumatoid arthritis. The lack of effective animal models severely hampers the research on their pathogenesis and treatment. Here, we report that a peptide derived from amino acids 91–115 in the G1 domain of the chondroitin sulfate proteoglycan versican potently increases the incidence of type II collagen-induced arthritis in BALB/c mice from less than 20% to over 95%. This novel model, designated the C2V7 model, exhibited key features of these types of arthritis, including enthesitis, arthritis, and extensive ectopic ossification. The joint inflammation level in the C2V7 model was comparable to that in the curdlan-induced SKG model established in BALB/c-ZAP70^W163C mice. Moreover, co-administration of the versican peptide with type II collagen exacerbated arthritis in this SKG strain. Notably, the C2V7 model showed a significantly higher proportion of IL-17 A⁺CD3⁺ T cells than the SKG model. Therapeutic blockade of IL-17 A in the C2V7 model markedly reduced both inflammatory infiltration and ectopic bone formation. Owing to its rapid onset, robustness, cost-effectiveness, and defined antigenic trigger, the C2V7 model is well-suited for probing the pathogenesis of these types of arthritis. The pronounced IL-17 A response further establishes it as a rigorous platform for evaluating related therapeutics.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116273"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076253","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":"Periplogenin alleviates osteoarthritis by suppressing NF-κB-mediated inflammation and apoptosis in chondrocytes","authors":"Zhonghua Zhou ,&nbsp;Jinxu Li ,&nbsp;Qiong Wang ,&nbsp;Shengling Zhang ,&nbsp;Yang Li ,&nbsp;Shaobin Jin ,&nbsp;Zhe Wang ,&nbsp;Junfei Chen ,&nbsp;Weiwei Yang ,&nbsp;Tianyi Liu ,&nbsp;Xinyu Wang ,&nbsp;Cheng Qiu ,&nbsp;Fan Zhang ,&nbsp;Yawen Wang","doi":"10.1016/j.intimp.2026.116296","DOIUrl":"10.1016/j.intimp.2026.116296","url":null,"abstract":"<div><div>Osteoarthritis (OA), a prevalent chronic degenerative disorder among middle-aged and elderly populations, is closely linked to inflammatory responses and subsequent extracellular matrix degradation. This condition causes significant patient suffering and imposes substantial socioeconomic burdens. Current therapies primarily focus on symptomatic relief (pain reduction and functional improvement), lacking targeted approaches addressing OA's underlying pathophysiological processes, while drug-related adverse effects remain problematic. Periplogenin, a natural compound with documented anti-inflammatory and anti-tumor properties, has garnered increasing attention; however, its potential role in OA pathogenesis is unexplored. This study first investigated periplogenin's effects on primary murine chondrocytes. Utilizing multiple experimental approaches, we demonstrated that periplogenin effectively attenuates TNF-α-induced inflammation, apoptosis, and consequent metabolic imbalance in chondrocytes. Furthermore, in a murine OA model, periplogenin administration conferred protective effects <em>in vivo</em>, mitigating OA progression. RNA sequencing analysis suggested suppression of the NF-κB signaling pathway as the potential mechanism, which was subsequently validated through both cellular and animal-level experiments. Collectively, our findings establish that periplogenin alleviates OA by inhibiting the NF-κB pathway, thereby reducing inflammation and chondrocyte apoptosis. This study identifies periplogenin as a promising candidate and provides a novel therapeutic strategy for targeted OA intervention.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116296"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076249","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":"USP18 orchestrates malignant progression in nasopharyngeal carcinoma through UBR5-driven attenuation of p53 signaling","authors":"Qiang Yi ,&nbsp;Daiyu Wang ,&nbsp;Kui Zhong ,&nbsp;Zheng Chen ,&nbsp;Jiangyue An ,&nbsp;Xinting Ouyang ,&nbsp;Weijian Zhu ,&nbsp;Yu Xin ,&nbsp;Jinghua Zhong","doi":"10.1016/j.intimp.2026.116316","DOIUrl":"10.1016/j.intimp.2026.116316","url":null,"abstract":"<div><h3>Background</h3><div>Ubiquitin-specific protease 18 (USP18) is a deubiquitinating enzyme initially recognized for its regulatory role in interferon signaling and antiviral immunity. In recent years, aberrant overexpression of USP18 has been increasingly reported across various malignancies, where it is implicated in tumor proliferation and immune evasion. However, its expression profile and mechanistic function in nasopharyngeal carcinoma (NPC) remain largely uncharacterized.</div></div><div><h3>Methods</h3><div>This study systematically assessed USP18 expression and its clinical relevance in NPC by integrating analyses of public databases with evaluation of clinical tissue specimens. Functional characterization was performed using NPC cell lines engineered for USP18 overexpression or silencing, followed by assays measuring cell proliferation, migration, invasion, apoptosis, and cell cycle dynamics. In vivo validation was conducted via subcutaneous xenograft models in nude mice. Mechanistic insights were further obtained through transcriptomic profiling (RNA-seq) and proteomic analysis of USP18-interacting proteins, leading to the identification of downstream targets and signaling pathways. Rescue experiments were employed to delineate the regulatory network orchestrated by USP18 in NPC.</div></div><div><h3>Results</h3><div>USP18 was markedly upregulated in NPC tissues and its elevated expression correlated with poor clinical prognosis. Gain- and loss-of-function experiments demonstrated that USP18 significantly enhanced NPC cell proliferation, migration, and invasion, while concurrently suppressing apoptosis. Mechanistically, USP18 was found to interact with the E3 ubiquitin ligase UBR5, thereby attenuating activation of the canonical tumor suppressor pathway p53, resulting in downregulation of its downstream effectors involved in apoptosis and cell cycle arrest. Co-immunoprecipitation assays further validated the physical interaction between USP18 and UBR5, suggesting that USP18 may regulate p53 signaling through UBR5-mediated mechanisms.</div></div><div><h3>Conclusions</h3><div>This study unveils a previously unrecognized oncogenic mechanism wherein USP18 promotes malignant progression of nasopharyngeal carcinoma via UBR5-dependent suppression of the p53 signaling pathway. These findings highlight USP18 as a promising candidate biomarker and potential therapeutic target in NPC.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116316"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146113132","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 “adjuvant bacillus Calmette-Gu'erin (BCG) immunotherapy versus BCG combined with disitamab vedotin in BCG-naïve high-risk non-muscle invasive bladder cancer with HER2 expression: A real-world study”","authors":"Haonan Jin","doi":"10.1016/j.intimp.2026.116312","DOIUrl":"10.1016/j.intimp.2026.116312","url":null,"abstract":"","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116312"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118779","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":"Melatonin inhibits ferroptosis by activating CREB-GPX4/ferritin axis in cigarette smoke-induced chronic obstructive pulmonary disease","authors":"Jia-Ying Kang ,&nbsp;Meng-Meng Xu ,&nbsp;Ting-Ting Chen ,&nbsp;Ming-Yu Wang ,&nbsp;Qiu-Yan Wang ,&nbsp;Yuan-Yuan Tan ,&nbsp;Yuan-Yuan Wei ,&nbsp;Guang-He Fei","doi":"10.1016/j.intimp.2026.116314","DOIUrl":"10.1016/j.intimp.2026.116314","url":null,"abstract":"<div><div>Chronic obstructive pulmonary disease (COPD) is a global public-health concern due to its currently high morbidity and mortality. Cigarette smoke (CS) exposure, the primary inducer of COPD, can provoke ferroptosis in lung epithelial cells. Melatonin, a neurohormone, has potential anti-inflammatory and anti-oxidative capacities. In this study, we investigated the protective effects of melatonin on CS exposure-induced COPD mice, and its underlying mechanisms of actions. The results showed that CS exposure caused obvious lipid peroxidation and the accumulation of ferrous (Fe²⁺) with the decreased expression of melatonin receptor (MT), thus triggered ferroptosis of lung epithelial cells in vitro and in vivo. In vitro, melatonin upregulated xCT, GPX4 and ferritin (FTH1/FTL) expression, reversed the CSE-induced ferroptosis depending on activated MT with the elevated phosphorylation of cAMP response element-binding protein (CREB^ser133). CREB knockdown (KD) caused melatonin failure to upregulate GPX4 and FTH1/FTL expression, thus did not inhibit CSE-induced ferroptosis of airway epithelial cells. Moreover, after suppressing the transcriptional regulation of p-CREB, melatonin again failed to promote GPX4 and FTH1/FTL expression and inhibit CSE-induced ferroptosis. The mechanistic dissection showed that melatonin led to the nuclear translocation of p-CREB which in turn bound to the promoter regions of <em>GPX4</em> and <em>FTH1/FTL</em> genes, promoted their expression. In CS-induced COPD mice, melatonin alleviated pulmonary inflammation, emphysema and airway remodeling, improved lung function via activating the CREB-GPX4/ferritin signaling axis and inhibiting ferroptosis of pulmonary epithelial cells. Taken together, our findings indicates that melatonin inhibits CS-induced ferroptosis via activating CREB-GPX4/ferritin axis depending on activated MT. These findings can help lead to promising protective strategies for COPD.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116314"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146124973","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":"A novel DYRK1A inhibitor alleviates lipopolysaccharide-induced acute lung injury via suppressing inflammatory pathway","authors":"Xi Zeng ,&nbsp;Lingyu Cui ,&nbsp;Yetong li ,&nbsp;Xinhui Ye ,&nbsp;Xiaoxuan Song ,&nbsp;Han Wen ,&nbsp;Chengkang Wang ,&nbsp;Panpan Fan ,&nbsp;Zixian Shen ,&nbsp;Hui Huang ,&nbsp;Junjie Lin ,&nbsp;Tianqi Zhang ,&nbsp;Aihemaitijiang Abuduhalike ,&nbsp;Huanhua Chen ,&nbsp;Zihua Xu ,&nbsp;Qingchun Zhao","doi":"10.1016/j.intimp.2026.116300","DOIUrl":"10.1016/j.intimp.2026.116300","url":null,"abstract":"<div><h3>Background</h3><div>Acute lung injury (ALI) is a highly fatal inflammatory disease, lacking of safe and effective therapeutic drugs. Anti-inflammatory treatment is an effective strategy of ALI.</div></div><div><h3>Purpose</h3><div>This study aimed to identify compound <strong>24</strong>, a novel dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) inhibitor, as an anti-inflammatory agent for ALI.</div></div><div><h3>Methods</h3><div>We established the LPS-induced RAW 264.7 cell inflammation model and the mouse ALI model. ELISA and real time-PCR (RT-PCR) were used to detect the levels of inflammatory factors in supernatant and lung. Reactive oxygen species (ROS) production was measured by flow cytometry using DCFH-DA. HE was used to determine the pathological damage of lung. Immunohistochemistry was applied to detect inflammatory biomarkers in lung. The infiltration of inflammatory cells in bronchoalveolar lavage fluid (BALF) was determine by flow cytometry. Molecular docking, cellular thermal shift assay (CETSA), and western blot (WB) were conducted to measure the drug-target interaction and inflammatory signaling.</div></div><div><h3>Results</h3><div>Pretreatment with compound <strong>24</strong> significantly reduced the levels of inflammatory mediators including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), nitric oxide (NO), and ROS in vitro, and alleviated the release of inflammatory factors, infiltration of inflammatory cells, and tissue damage in the lung. Mechanistic studies indicated that compound <strong>24</strong> might exert its anti-inflammatory effect by targeting DYRK1A and inhibiting the TLR4/NF-κB signaling pathway.</div></div><div><h3>Conclusions</h3><div>In summary, compound <strong>24</strong> exerted anti-inflammation effect with potential value for further development into a therapeutic drug for ALI treatment.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"173 ","pages":"Article 116300"},"PeriodicalIF":4.7,"publicationDate":"2026-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125057","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}