International immunopharmacology最新文献

{"title":"Tubular STING drives renal fibrosis via extracellular vesicle–mediated activation of the SMO/GLI-1 pathway","authors":"Dongxue Xu ,&nbsp;Xiaoyu Zhang ,&nbsp;Jinmeng Suo ,&nbsp;Yinye Huang ,&nbsp;Yiming Li ,&nbsp;Zhiyong Peng","doi":"10.1016/j.intimp.2026.116350","DOIUrl":"10.1016/j.intimp.2026.116350","url":null,"abstract":"<div><div>The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a major clinical challenge, with its molecular drivers still not fully defined. Here, we identify a previously unrecognized mechanism in which renal tubular cells secrete extracellular vesicles (EVs) enriched in activated STING during early AKI. Using STING-deficient mice, we demonstrate that loss of STING markedly reduces tubular senescence, maladaptive repair, and subsequent fibrosis following injury. Mechanistically, we show that EVs selectively package and transfer activated STING to interstitial fibroblasts, where EV-STING robustly stimulates the Smoothened (SMO) and the downstream effector glioma-associated oncogene 1 (GLI-1) signaling pathway, promoting fibroblast activation and fibrotic progression. Pharmacologic inhibition of EV secretion (GW4869) or blockade of the SMO–GLI-1 pathway (CPN) significantly attenuates kidney injury, underscoring the functional relevance of this STING–SMO–GLI-1 axis. Our findings reveal that STING exerts its pro-fibrotic effects primarily through EV-mediated intercellular trafficking rather than direct intracellular signaling. This study defines a critical tubular cell–STING–EV–fibroblast communication loop that drives the AKI-to-CKD transition and highlights therapeutic opportunities targeting EV-STING release or SMO–GLI-1 signaling to prevent chronic kidney disease.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116350"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179441","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":"Covalently targeting HSP90 with a natural small-molecule costunolide to inhibit necroptosis and ulcerative colitis","authors":"Shan Yang ,&nbsp;Yunsen Zhang ,&nbsp;Yuying Shi ,&nbsp;Ting Liu ,&nbsp;Jingjing Tian ,&nbsp;Shuai Tan ,&nbsp;Xianli Meng ,&nbsp;Wuzheng Luo ,&nbsp;Xiaofei Shen","doi":"10.1016/j.intimp.2026.116348","DOIUrl":"10.1016/j.intimp.2026.116348","url":null,"abstract":"<div><h3>Background</h3><div>Necroptosis exacerbates ulcerative colitis (UC) by disrupting intestinal barriers and promoting necroinflammation. Heat shock protein 90 (HSP90) regulates receptor-interacting protein kinase 1/3 (RIPK1/3) activity through its chaperone function, thereby participating in necroptosis and emerging as a potential therapeutic target for its inhibition in UC therapy. Costunolide (CTL), a principal sesquiterpene lactone from <em>Aucklandia lappa</em>, has poorly defined mechanisms in UC treatment. This study aimed to elucidate CTL's role in necroptosis inhibition and UC therapy by targeting HSP90.</div></div><div><h3>Methods</h3><div>Multiple cellular models were employed to assess CTL's inhibitory effects on necroptosis and necroinflammation. Subsequently, western blotting and co-immunoprecipitation (Co-IP) were used to analyze the impact of CTL on necroptosis signaling. Functional targets and binding sites of CTL were identified through drug affinity responsive target stability (DARTS), mass spectrometry, and cellular thermal shift assay (CETSA). Molecular dynamics simulation and tryptophan quenching were then conducted to elucidate CTL-mediated allosteric regulatory mechanisms. In vivo, dextran sulfate sodium (DSS)-induced colitis mice were used to evaluate the therapeutic efficacy of CTL.</div></div><div><h3>Results</h3><div>CTL is identified as a novel necroptosis inhibitor that suppresses RIPK1/3-mixed lineage kinase domain-like protein (MLKL) signaling and mitigates necroinflammation in vitro. Mechanistically, CTL covalently binds to the conserved cysteine (Cys) 572/564 in the middle domain of HSP90, inhibiting its dimerization and chaperone function via an allosteric effect without significantly compromising ATPase activity or triggering substantial heat shock response. This covalent interaction further disrupts HSP90-RIPK1 association, consequently blocking RIPK1/3-MLKL necroptosis signaling. In vivo, CTL is capable of effectively alleviating DSS-induced colitis via blocking RIPK1/3-MLKL axis activation.</div></div><div><h3>Conclusion</h3><div>Our findings highlight Cys572/564 as a druggable site for allosteric HSP90 inhibition and propose that CTL acts as a promising chemical scaffold for developing therapeutics targeting necroptosis- and HSP90-driven pathologies, such as UC.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116348"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146193110","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":"GPR132 drives macrophage M1 polarization and aggravates inflammation-associated liver injury","authors":"Chen Cheng ,&nbsp;Chuanying Xie ,&nbsp;Anping Chen ,&nbsp;Panpan Zhou ,&nbsp;Haoqi Wang ,&nbsp;Yuanhao Li ,&nbsp;Jing Li ,&nbsp;Jingjing Cong ,&nbsp;Xuefu Wang","doi":"10.1016/j.intimp.2026.116349","DOIUrl":"10.1016/j.intimp.2026.116349","url":null,"abstract":"<div><div>Macrophage polarization plays a critical role in the pathogenesis of hepatic inflammation and injury triggered by diverse insults. However, the regulators of macrophage polarization in hepatic inflammation remain largely undefined. In this study, we reported that GPR132 activation promoted macrophage M1 polarization and suppressed macrophage M2 polarization, whereas GPR132 inhibition shifted macrophages toward an anti-inflammatory and tissue-repairing M2 phenotype. Notably, genetic deletion of <em>Gpr132</em> prevented hepatic macrophage M1 polarization and markedly alleviated hepatic inflammation and injury in methionine-choline-deficient (MCD)-induced metabolic dysfunction-associated steatohepatitis (MASH), choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced MASH, and drug-induced liver injury (DILI). Furthermore, pharmacological inhibition of GPR132 substantially mitigated hepatic inflammation and injury in MASH and DILI. Taken together, our study identifies GPR132 as a critical regulator of macrophage polarization and highlights GPR132 as a potential target for the treatment of MASH and DILI.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116349"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179472","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":"Development and In vitro antitumor evaluation of a novel anti-p16 antibody fragment-drug conjugate","authors":"Hui He ,&nbsp;Xiaoling Chen ,&nbsp;Yueqiu Chen ,&nbsp;Qingpeng Li ,&nbsp;Fan Yang ,&nbsp;Lin Zhou","doi":"10.1016/j.intimp.2026.116359","DOIUrl":"10.1016/j.intimp.2026.116359","url":null,"abstract":"<div><div>The cell cycle regulator p16 is overexpressed in multiple cancers, and its elevated expression frequently correlates with aggressive tumor behavior and poor prognosis. However, the development of therapeutic agents directly targeting p16 has remained challenging. Antibody-drug conjugates (ADCs) represent an established modality for targeted drug delivery. To explore alternative formats that may address inherent challenges of conventional ADCs—such as potentially limited tumor penetration due to their large size and the risk of immunogenicity associated with the Fc domain—we engineered a novel p16-targeting antibody fragment-drug conjugate (AFDC). This conjugate is based on a humanized single-chain variable fragment (scFv) fused to a cell-penetrating peptide, aiming to achieve efficient intracellular delivery of the cytotoxic payload doxorubicin via p16-mediated targeting.</div><div>We isolated five unique p16-specific scFvs from hybridoma cells. Following humanization, each was fused with a cell-penetrating peptide (CPP) S4₁₃ to construct scFv-p16-S4₁₃ variants. Following affinity assessment, scFv-p16-S4₁₃–04 was selected as the backbone and conjugated to doxorubicin via a chemical linker to generate the AFDC. In cellular assays, the resulting AFDC exhibited a p16 expression-dependent selectivity, showing stronger cytotoxicity against p16-high cancer cells (HeLa, BT-549) than against p16-low cells (MDA-MB-231, LO2, HEK-293 T). This selective activity correlated with target-dependent internalization. Furthermore, in p16-positive triple-negative breast cancer (TNBC) organoid models, AFDC treatment markedly reduced cell viability, underscoring its potent antitumor activity.</div><div>Collectively, this proof-of-concept study supports the potential therapeutic value of a p16-targeted AFDC for p16-high tumors and illustrates the viability of the AFDC platform as an emerging strategy to target intracellular proteins.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116359"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192730","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":"Bee sting acupuncture mitigates osteoarthritis in male mice via PPAR-γ activation: integrated network pharmacology, transcriptomics, and experimental validation","authors":"Zhiyuan Feng ,&nbsp;Jiali Yang ,&nbsp;Ya Zhu ,&nbsp;Lini Lei ,&nbsp;Yi Zhang ,&nbsp;Linbing Cheng ,&nbsp;Hongxia Zhao ,&nbsp;Hong Yao ,&nbsp;Peiying Shi","doi":"10.1016/j.intimp.2026.116352","DOIUrl":"10.1016/j.intimp.2026.116352","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a chronic progressive joint disease. In China, bee sting acupuncture (BSA) has been widely used to treat OA. However, the molecular mechanisms underlying the therapeutic effects of BSA against OA remain unexplored. This study aims to further investigate the role and potential mechanism of BSA in treating OA. Live bee stings alternately acupunctured two acupoints, Zusanli (ST36) and Xuehai (SP10) of monosodium iodoacetate-induced OA mice for 6 weeks. BSA treatment alleviated the pathological changes of articular cartilages and reduced serum CTX-II levels in OA mice. Network pharmacology and molecular docking predicted that pro-inflammatory factors, extracellular matrix (ECM) degrading enzymes and apoptosis-related factors could be the key targets of bee venom (BV)’ effects on OA-related diseases. Experimentally, BSA treatment reduced the serum IL-1β and TNF-α levels, and diminished the expression of IL-1β, IL-6, NF-κB, MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, ADAMTS 5, Bax, Caspase 9 and Caspase 3, and increased that of Bcl-2 in knee joints of OA mice. Furthermore, it was confirmed that BSA treatment could activate PPAR-γ in knee joints of OA mice with RNA-seq and Western blot assays. Moreover, BV application significantly increased cell viability and proliferation, and PPAR-γ expression compared with PPAR-γ antagonist GW9662 treatment alone or combined with BV in IL-1β-induced mouse primary chondrocytes. This research revealed that BSA treatment could inhibit NF-κB signaling pathway by activating PPAR-γ, thereby alleviated cartilage inflammation, ECM degradation and apoptosis in OA mice, which provided a basis for BSA therapy in treating OA.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116352"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192733","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":"Chronic psychological stress induces pulmonary dysfunction through alveolar macrophage-mediated activation of apoptotic signaling pathways","authors":"Lingmin Zeng ,&nbsp;Zihui Jin ,&nbsp;Yue Wang ,&nbsp;Xin Ning ,&nbsp;Zhou Yi ,&nbsp;Wangkai Chen ,&nbsp;Baichuan Wang ,&nbsp;Xinyu Li ,&nbsp;Tingting Zeng ,&nbsp;Jiaqi Zhao ,&nbsp;Cailian Fang ,&nbsp;Sitao Xie ,&nbsp;Lihong Li ,&nbsp;Run Xiao","doi":"10.1016/j.intimp.2026.116345","DOIUrl":"10.1016/j.intimp.2026.116345","url":null,"abstract":"<div><div>Anxiety and depressive disorders are frequently comorbid with respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma. Yet the mechanisms linking these conditions remain poorly understood. Previous studies have focused on the regulatory role of stress response on neuroendocrine pathways, while the role of immune regulatory networks in this process remains elusive. Here, we established a chronic restraint stress (CRS) mouse model to investigate how chronic psychological stress affects pulmonary function by regulating the immune system. CRS markedly impaired lung function and induced emphysema-like pathological changes. Mechanistically, CRS induced excessive recruitment and activation of alveolar macrophages, which in turn triggered a cascade of apoptosis-related signaling events. Specifically, alveolar macrophages exhibited upregulated Fas ligand (FASL) expression, which promoted the Fas death receptor signaling pathway and activated downstream effector caspases (Caspase-3, Caspase-6 and Caspase-7). The activation of this pathway ultimately triggered extensive apoptosis of lung parenchymal cells, resulting in significant tissue damage. Moreover, depletion of alveolar macrophages significantly attenuated apoptosis in pulmonary parenchymal cells and restored lung function. Collectively, our study identifies an important regulatory axis linking chronic psychological stress to macrophage recruitment and pulmonary dysfunction. These findings provide a novel mechanistic framework for understanding the comorbidity between psychological stress and respiratory diseases.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116345"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179436","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":"Dual-drug nanoplatform HPA@NPs reprograms the fibrotic microenvironment by suppressing EMT and M2 macrophage polarization in pulmonary fibrosis","authors":"An Chang ,&nbsp;Yi Wang ,&nbsp;Zan Cui ,&nbsp;Yuan-Yuan Liu ,&nbsp;Ling-Qi Meng ,&nbsp;Jia-Shi ,&nbsp;Zhi-Yong Qin ,&nbsp;Jia-Ning Gong","doi":"10.1016/j.intimp.2026.116362","DOIUrl":"10.1016/j.intimp.2026.116362","url":null,"abstract":"<div><div>Pulmonary fibrosis (PF) is a progressive and lethal interstitial lung disease, characterized by excessive extracellular matrix deposition and architectural distortion of the lung parenchyma. Its pathogenesis involves interconnected pathological events, including dysregulated epithelial-mesenchymal transition (EMT), chronic inflammation driven by M2-polarized macrophages, and abnormal fibroblast activation. These intertwined mechanisms contribute to the limited efficacy of current anti-fibrotic therapies, which often fail to achieve lesion-specific targeting and disease reversal. Moreover, the clinical utility of existing drugs is further hampered by poor bioavailability and insufficient accumulation at fibrotic sites. To overcome these challenges, we developed a multifunctional nanotherapeutic platform, termed HPA@NPs, through co-assembly of hyaluronic acid-platycodin D (HA-PD) and aspirin-platycodin D (ASA-PD) conjugates. This nanosystem enables concurrent modulation of multiple PF-relevant pathological features. Physicochemical characterization showed that HPA@NPs possess uniform nanoscale size, low critical aggregation concentration, and excellent colloidal stability, supporting prolonged blood circulation. In vitro, HPA@NPs showed efficient cellular uptake consistent with their HA-based design and were accompanied by inhibition of EMT, fibroblast activation, and M2 macrophage polarization, together with reduced expression of IL-10 and Arg-1. In bleomycin-induced PF mice, HPA@NPs significantly improved pulmonary function and attenuated histopathological damage. At the molecular level, HPA@NPs down-regulated fibrosis-related markers (Col1a1, TGF-β1, α-SMA), while up-regulating the epithelial tight-junction protein ZO-1 and down-regulating mesenchymal markers (N-cadherin, vimentin), confirming effective reversal of EMT. The therapeutic outcome of HPA@NPs surpassed that of monotherapy, highlighting a synergistic anti-fibrotic effect. Importantly, HPA@NPs exhibited no detectable cytotoxicity, hemolytic activity, or major organ toxicity at therapeutic doses, demonstrating favorable biocompatibility. In summary, HPA@NPs integrate precise targeting, multi-pathway synergy, and excellent biosafety, offering a promising translational strategy for PF treatment.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116362"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179518","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":"Unraveling the matrix stiffness landscape in idiopathic pulmonary fibrosis: GSN and ARG1 as novel diagnostic biomarkers and potential therapeutic targets","authors":"Jian Chen ,&nbsp;Jingjing Meng ,&nbsp;Xiaolong Tang ,&nbsp;Guanchu Liu ,&nbsp;Keping Zhang","doi":"10.1016/j.intimp.2026.116334","DOIUrl":"10.1016/j.intimp.2026.116334","url":null,"abstract":"<div><h3>Background</h3><div>Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition and tissue stiffening. Matrix stiffness is a key driver of fibrosis, yet diagnostic biomarkers directly linked to this physical property are lacking. This study aimed to identify robust matrix stiffness-related diagnostic biomarkers and potential therapeutic targets for IPF using an integrated machine learning approach.</div></div><div><h3>Methods</h3><div>Gene expression profiles were obtained from the GEO database (Training set: GSE33566; Validation set: GSE93606). Differentially expressed genes (DEGs) were intersected with a matrix stiffness-related gene set. Three machine learning algorithms (SVM-RFE, LASSO, and Naive Bayes) were employed to screen diagnostic feature genes. A diagnostic nomogram was constructed and evaluated. Functional enrichment (GO/KEGG/GSEA), immune infiltration (ssGSEA), and molecular docking analyses were performed to explore biological functions and predict therapeutic drugs.</div></div><div><h3>Results</h3><div>Eighteen matrix stiffness-related DEGs were identified. Through machine learning screening, GSN and ARG1 were determined as robust key genes, exhibiting high diagnostic accuracy (AUC &gt; 0.7) in both training and validation cohorts. Functional analysis revealed that GSN is involved in actin cytoskeleton regulation, while <em>ARG1</em> participates in immune response modulation. Both genes showed strong positive correlations with the infiltration of macrophages and neutrophils. Furthermore, molecular docking identified RA-2 as a potential therapeutic agent targeting <em>ARG1</em> with high binding affinity (−9.2 kcal/mol).</div></div><div><h3>Conclusion</h3><div>We identified <em>GSN</em> and <em>ARG1</em> as novel matrix stiffness-related diagnostic biomarkers for IPF, linking mechanotransduction to immune microenvironment remodeling. The diagnostic nomogram offers high clinical predictive value, and <em>RA-2</em> emerged as a putative ARG1-targeting compound with favorable docking energy and warrants further experimental validation as a potential antifibrotic agent.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116334"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165309","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":"Lactate targeting: Regulatory networks and therapeutic potential in bone diseases","authors":"Xiyue Zhang ,&nbsp;Xiaoyuan Yan ,&nbsp;Wenqing Gao ,&nbsp;Jiawei Ma ,&nbsp;Zhuoyang Wu ,&nbsp;Na An ,&nbsp;Lihong Qiu ,&nbsp;Jiajie Guo","doi":"10.1016/j.intimp.2026.116376","DOIUrl":"10.1016/j.intimp.2026.116376","url":null,"abstract":"<div><div>Lactate, once regarded as a metabolic waste product, has emerged as a multifunctional regulator in skeletal pathophysiology. This review systematically elucidates the pivotal mechanisms underlying the role of lactate in bone-related pathologies, including inflammatory arthritis, osteoarthritis, osteoporosis, nonunion fractures, and primary bone tumors. Lactate functions through five integrated mechanisms: <em>i</em> serving as a rapid energy substrate; <em>ii</em> acting as an immunomodulatory mediator; <em>iii</em> enhancing osteoclast-mediated bone resorption through microenvironmental acidification; <em>iv</em> driving inflammatory cascades via G protein-coupled receptors (GPCRs); and <em>v</em> functioning as an epigenetic effector through histone and protein lactylation (Kla) to reprogram osteoblast and macrophage transcription. This review details the cell-specific effects of lactate on key bone-associated cells, including dynamic lactate-driven macrophage polarization, suppression or reprogramming of dendritic- and T-cell effector functions, glycolytic activation of fibroblast-like synoviocytes promoting joint inflammation, stimulation of osteoclastogenesis and bone resorption, and dose-dependent regulation of osteoblast differentiation and chondrocyte degradation. Therapeutic strategies targeting lactate metabolism, including lactate dehydrogenase A (LDHA) and pyruvate kinase M2 (PKM2) inhibitors, glycolysis modulators, monocarboxylate transporter (MCT) inhibitors, and potential interventions targeting “writers/readers/erasers” of lactylation, are evaluated. Finally, we propose future research directions regarding the role of lactate in bone diseases. This review highlights lactate as a strategic node that coordinates the bone immune–metabolic network, offering a promising target for the precise regulation of skeletal homeostasis and inflammation.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116376"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192728","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":"An In Silico-Designed Chimeric Antigen Confers Broad Protection Against Major Diarrheal Pathogens (Shigella, ETEC, and EHEC) in Preclinical Models","authors":"Abbas Hajizade ,&nbsp;Ali Hatef Salmanian ,&nbsp;Firouz Ebrahimi ,&nbsp;Ayyoob Arpanaei ,&nbsp;Jafar Amani","doi":"10.1016/j.intimp.2026.116358","DOIUrl":"10.1016/j.intimp.2026.116358","url":null,"abstract":"<div><div>Diarrheagenic <em>E. coli</em> (DEC) and <em>Shigella</em> species are leading causes of under-5 mortality globally, prompting the development of a broad-spectrum vaccine. Here, we rationally designed a novel chimeric antigen (\"SEISL\") incorporating five virulence determinants: StxB and EspA (EHEC), LTB and a detoxified STa (ETEC), and the N-terminal domain of IpaD (<em>Shigella</em>). Bioinformatically optimized for maximal antigenicity, SEISL was expressed in <em>E. coli</em> BL21(DE3), purified from inclusion bodies under denaturing conditions, and confirmed by western blot. Immunization with SEISL + Freund’s adjuvants in pathogen-specific models elicited robust protection in all models.In rabbits (ETEC challenge), serum IgG significantly increased and ileal loop assays with virulent ETEC H10408 showed a significant reduction in fluid accumulation (p&lt;0.05). The Guinea pigs exhibited 71.4% protection against <em>Shigella flexneri</em>-induced keratoconjunctivitis in Sereny tests, and finally the mice (EHEC challenge) demonstrated elevated serum IgG and significant reduction in fecal shedding of EHEC O157:H7 post-challenge (p&lt;0.05). These results demonstrate that the SEISL antigen elicits broad protection immune responses against three critical diarrheal pathogens in preclinical models, providing proof-of-concept support for its continued development as a multipathogen vaccine candidate.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116358"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192738","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}