Molecular immunology最新文献

{"title":"OPTN knockout alleviates OVA-induced airway inflammation in a mouse model of asthma","authors":"Yujing Zhang ,&nbsp;Zixian Wang ,&nbsp;Jing Chen ,&nbsp;Yufeng Wan","doi":"10.1016/j.molimm.2026.02.007","DOIUrl":"10.1016/j.molimm.2026.02.007","url":null,"abstract":"<div><h3>Objective</h3><div>Asthma is a common inflammatory disease of the respiratory system. This study aimed to investigate the effect of optineurin (OPTN) gene knockout on airway inflammation in an ovalbumin (OVA)-induced asthma mouse model.</div></div><div><h3>Methods</h3><div>An OVA-induced chronic asthma model was established in 6–8-week-old C57BL/6 wild-type and OPTN knockout mice. Lung inflammation and goblet cell hyperplasia were respectively evaluated by hematoxylin and eosin (H&amp;E) staining and periodic acid–Schiff (PAS) staining. Levels of epithelial-derived alarmins (IL-33, TSLP, and IL-25), Th2 cytokines (IL-4, IL-5, and IL-13), and serum immunoglobulin E (IgE) were measured by enzyme-linked immunosorbent assay (ELISA). To further assess autophagic flux, additional experimental groups treated with the lysosomal inhibitor chloroquine were included, and autophagy-related markers were examined by immunohistochemistry and Western blotting.</div></div><div><h3>Results</h3><div>Histological analyses demonstrated that OPTN deficiency markedly attenuated OVA-induced asthma-like airway inflammation, as evidenced by reduced inflammatory cell infiltration, basement membrane thickening, goblet cell hyperplasia, and mucus secretion. ELISA results showed that serum IgE levels, the concentrations of alarmins and inflammatory cytokines in bronchoalveolar lavage fluid were significantly decreased in the OPTN^⁻/⁻ group compared with the wild-type group. Furthermore, immunohistochemical and Western blot analyses revealed altered expression of the autophagy-related markers LC3 and p62 in OPTN-deficient lungs. The chloroquine treatment experiment suggested that OPTN might be involved in the regulation of autophagy in the lungs, but the relevant difference did not reach statistical significance.</div></div><div><h3>Conclusion</h3><div>OPTN knockout effectively alleviates asthma-like airway inflammation, and the underlying mechanism may be associated with the regulation of autophagy.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"191 ","pages":"Pages 107-113"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146220394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S1PR3 antagonism ameliorates endothelial dysfunction in septic acute kidney injury through the ROCK1–Drp1 signalling pathway","authors":"Zhipeng Xu ,&nbsp;Jueyue Yan ,&nbsp;Gan Luo ,&nbsp;Qinghui Fu ,&nbsp;Hanbin Wang ,&nbsp;Jue Zhang ,&nbsp;Xing Fang ,&nbsp;Shaoyang Zhang ,&nbsp;Baoli Cheng ,&nbsp;Xiangming Fang","doi":"10.1016/j.molimm.2026.02.004","DOIUrl":"10.1016/j.molimm.2026.02.004","url":null,"abstract":"<div><h3>Objective</h3><div>Sphingosine-1-phosphate receptor 3 (S1PR3) is predominantly expressed in endothelial cells and plays important roles in inflammatory responses. However, its contribution to the pathogenesis of septic acute kidney injury (S-AKI) remains poorly defined. This study aimed to elucidate the role and underlying mechanisms of S1PR3 in endothelial dysfunction during S-AKI.</div></div><div><h3>Methods</h3><div>S-AKI was induced in mice by intraperitoneal lipopolysaccharide (LPS) injection. Renal endothelial function and mitochondrial integrity were assessed by flow cytometry, Evans blue dye (EBD) assays and transmission electron microscope (TEM). Mechanistic studies were conducted in human umbilical vein endothelial cells (HUVECs) using the S1PR3 antagonist TY-52156 and liposomal formulations.</div></div><div><h3>Results</h3><div>Serum creatinine (SCr), blood urea nitrogen (BUN) and renal S1PR3 expression were significantly increased 24 h after LPS challenge in wild-type mice, with S1PR3 predominantly localised to endothelial cells. Compared with <em>S1pr3</em>^{<em><strong>+ /+</strong></em>} mice, <em>S1pr3</em>^{<em><strong>-/-</strong></em>} mice exhibited improved renal function, reduced leukocyte infiltration and enhanced ATP production. S1PR3 activation was associated with mitochondrial dysfunction, cytoskeletal remodelling and increased endothelial permeability. In vitro, TY-52156 reduced mitochondrial Ca^{<strong>2+</strong>} accumulation, restored ATP levels and preserved cytoskeletal organisation and adherens junction integrity. To improve solubility and biocompatibility, TY-52156 was encapsulated into negatively or neutrally charged liposomes, of which LP-Neg-TY-52156 showed superior efficacy. In vivo, LP-Neg-TY-52156 alleviated endothelial leakage, mitochondrial injury and renal dysfunction in S-AKI.</div></div><div><h3>Conclusion</h3><div>Endothelial S1PR3 is a key mediator of mitochondrial dysfunction and barrier disruption in S-AKI. Liposomal delivery of S1PR3 antagonists represents a promising therapeutic strategy for preserving endothelial integrity and attenuating septic renal injury.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"191 ","pages":"Pages 85-96"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146190801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of anti-inflammatory microglia interleukins with clinical and radiological parameters in patients with multiple sclerosis - a single-centre study in a Polish population","authors":"Hubert Mado ,&nbsp;Artur Stasiniewicz ,&nbsp;Natalia Nafalska ,&nbsp;Malgorzata Stopyra ,&nbsp;Tomasz Furgoł ,&nbsp;Marcin Jezierzański ,&nbsp;Weronika Kisielewska ,&nbsp;Katarzyna Kubicka-Bączyk ,&nbsp;Natalia Niedziela ,&nbsp;Paweł Sowa ,&nbsp;Monika Adamczyk-Sowa","doi":"10.1016/j.molimm.2026.02.005","DOIUrl":"10.1016/j.molimm.2026.02.005","url":null,"abstract":"<div><h3>Introduction</h3><div>Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system characterized by immune-mediated demyelination and neurodegeneration. Currently, the prevailing concept emphasizes autoimmune mechanisms, with recent studies highlighting a critical role of microglial cytokines.</div></div><div><h3>Study objective</h3><div>To determine the association between the anti-inflammatory microglial cytokines (IL-10, IL-4, IL-13) and selected clinical and radiological parameters of MS patients.</div></div><div><h3>Material and methods</h3><div>The study included 96 MS patients undergoing immunomodulatory therapy and 73 healthy controls. Venous blood samples (10 ml) were obtained from all participants.</div></div><div><h3>Results</h3><div>Serum IL-10 levels were significantly lower in the MS group compared to the controls. IL-10 levels differed across Expanded Disability Status Scale (EDSS) scores, with the highest median concentration observed in patients with an EDSS score ≥ 4.0. A moderate negative correlation was identified between IL-13 and C-reactive protein (CRP) levels. No significant associations were observed between cytokine concentrations and recent clinical relapses.</div></div><div><h3>Conclusions</h3><div>Higher IL-10 concentrations were associated with greater disability, suggesting its potential utility as a biomarker of MS progression, particularly in non-RRMS phenotypes. The negative correlation between IL-13 and CRP suggests the systemic anti-inflammatory effects of IL-13.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"191 ","pages":"Pages 79-84"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146190802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic immune yin-yang in chronic myeloproliferative neoplasms mechanisms, therapeutic implications, and future directions","authors":"Hanlu Zhang ,&nbsp;Hao Xiong ,&nbsp;Xuege Guo ,&nbsp;Qing Ma ,&nbsp;Yongqiang Wang ,&nbsp;Lijuan Li ,&nbsp;Liansheng Zhang","doi":"10.1016/j.molimm.2026.02.002","DOIUrl":"10.1016/j.molimm.2026.02.002","url":null,"abstract":"<div><div>Chronic myeloproliferative neoplasms (MPNs) are associated with dynamic and multifaceted changes in their immune microenvironment. Throughout disease progression, the interplay between pro-inflammatory (“yang”) and immunosuppressive (“yin”) cytokines and immune cells shapes the immune milieu and drives clinical progression. Sustained production of pro-inflammatory cytokines—such as interleukin-6 (IL-6) and interleukin-1β (IL-1β)—promotes clonal expansion and accelerates disease progression. Conversely, immunosuppressive mediators, including transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), allow malignant clones to evade immune surveillance through the suppression of effector T-cell and natural killer (NK) cell cytotoxic functions. This dualistic immune state, with hyperactivation in early disease and immunosuppression in advanced stages, reflects the clinical and biological heterogeneity observed in MPNs. Emerging immunomodulatory therapies—such as interferon-α, Janus kinase (JAK) inhibitors, and other immunoregulatory agents—have demonstrated efficacy primarily by restoring immune balance. This review outlines the dual roles of immune cells and cytokines in MPN pathophysiology, emphasizes the significance of immune yin-yang imbalance, and evaluates current and prospective immunotherapeutic strategies for targeted immunologic intervention.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"191 ","pages":"Pages 60-69"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146157774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling immune evasion in the tumor microenvironment: Mechanisms, therapeutic strategies, and future directions in cancer immunotherapy","authors":"Geeth Harini Chandrasekar","doi":"10.1016/j.molimm.2026.01.013","DOIUrl":"10.1016/j.molimm.2026.01.013","url":null,"abstract":"<div><div>The immune evasion that is encouraged by the tumor microenvironment (TME) is a key factor in the failure of cancer immunotherapies. This review addresses how tumor cells avoid immune surveillance, which is critically dependent on cellular and molecular events associated with immune checkpoint signaling, the capture of immune surveillance cells, metabolic restructuring, and physical and hypoxic barriers. We also discuss the latest therapeutic options, including immune checkpoint blockers, metabolic and angiogenic combination therapies, and Macrophage reprogramming of tumors. Nonetheless, such challenges as therapeutic resistance and patient heterogeneity are still significant challenges. In the future, individualized immunotherapy with the use of precision oncology tools that integrate multi-omics profiling, artificial intelligence, and manipulation of the gut microbiome a promising opportunity. A better understanding of the dynamic TME and the individualized immune landscape is the key to effective immunotherapy and the attainment of durable clinical responses to various types of cancers.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"191 ","pages":"Pages 70-78"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing two subtypes of osteosarcoma using G2M checkpoint-related genes and revealing its immune landscape","authors":"Zhuobin Yang,&nbsp;Song Hong","doi":"10.1016/j.molimm.2026.01.014","DOIUrl":"10.1016/j.molimm.2026.01.014","url":null,"abstract":"<div><h3>Background</h3><div>Although the G2M checkpoint has been implicated in cancer metastasis in numerous studies, the genetic characteristics associated with the G2M checkpoint in Osteosarcoma (OS) remain unexplored.</div></div><div><h3>Methods</h3><div>Through univariate Cox regression analysis, we screened for G2M checkpoint-related genes associated with OS survival. The <em>ConsensusClusterPlus</em> R package was employed for clustering analysis of the TARGET-OS dataset. Finally, the immune infiltration, biological function, mutation and drug sensitivity of different clusters were analyzed. Furthermore, the functional mechanism of KIF20B was elucidated through <em>in vitro</em> experiments.</div></div><div><h3>Results</h3><div>The TARGET-OS cohort was clustered into two distinct clusters (Cluster 1 and Cluster 2). Compared to Cluster 2, Cluster 1 showed a trend towards higher overall survival rates, with higher immune scores, stromal scores, and ESTIMATE scores, alongside lower tumor purity. Additionally, the infiltration levels of immune cells were substantially higher in Cluster 1. <em>In vitro</em> experiments confirmed that overexpression of KIF20B promoted the proliferation and invasion of SOSP-9607 cells and induced G2/M phase arrest, upregulating the expression of core proteins in the G2/M pathway. Overexpression of KIF20B enhanced the sensitivity of cells to zoledronic acid, while the G2/M pathway inhibitor AZD-1775 reversed this effect.</div></div><div><h3>Conclusion</h3><div>This study elucidates the prognostic and immune microenvironmental characteristics of G2M checkpoint-related genes in OS, and validates the critical oncogenic function of KIF20B and its regulatory role in drug sensitivity. This study provides novel potential targets and strategies for molecular subtyping and targeted therapy of OS.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"191 ","pages":"Pages 10-21"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CYP1B1 as a therapeutic target for S. aureus-induced mammary gland inflammation","authors":"Shaodong Fu,&nbsp;Shiyang Zhao,&nbsp;Yingzou Fang,&nbsp;Bo Yang,&nbsp;Chengsen Yang,&nbsp;Jiarui Liu,&nbsp;Huanhuan Wang,&nbsp;Yuanyuan Xu,&nbsp;Jinfeng Miao","doi":"10.1016/j.molimm.2026.02.006","DOIUrl":"10.1016/j.molimm.2026.02.006","url":null,"abstract":"<div><div><em>Staphylococcus aureus</em> (<em>S. aureus</em>) is a predominant zoonotic pathogen responsible for the most severe forms of mastitis, posing a major challenge to global dairy production and health of women. Its sophisticated pathogenesis renders it resistant to conventional therapies. In this study, we demonstrate that <em>S. aureus</em> infection triggers a concurrent upregulation of cytochrome P450 1B1 (CYP1B1) and vascular endothelial growth factor A (VEGFA), with CYP1B1 expression being regulated by the VEGFA-mediated signaling pathway. Furthermore, CYP1B1 exacerbates <em>S. aureus</em>-induced inflammatory damage and oxidative stress through estrogen metabolism. Notably, pharmacological inhibition of CYP1B1 significantly mitigates these detrimental effects. Our findings highlight the pivotal role of CYP1B1 in modulating the inflammatory response to <em>S. aureus</em> infection, identifying it as a promising therapeutic target for combating <em>S. aureus</em>-associated mastitis.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"191 ","pages":"Pages 97-106"},"PeriodicalIF":3.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic applications of human umbilical cord-derived mesenchymal stem cell secretome in chronic inflammatory diseases and cancer: A recent update","authors":"Keerthi Nethaji ,&nbsp;P. Ashiq Shibili ,&nbsp;Amit Dey ,&nbsp;Sibin Nambidi ,&nbsp;Antara Banerjee ,&nbsp;Silvia Barbon ,&nbsp;Surajit Pathak ,&nbsp;Asim K. Duttaroy","doi":"10.1016/j.molimm.2026.01.006","DOIUrl":"10.1016/j.molimm.2026.01.006","url":null,"abstract":"<div><div>Chronic inflammatory disorders and cancer remain major global health challenges driven by persistent immune activation and tissue damage. The human umbilical cord-derived mesenchymal stem cell (hUC-MSC) secretome has emerged as a promising cell-free therapeutic alternative owing to its potent anti-inflammatory, immunomodulatory, and regenerative properties. Comprising of cytokines, chemokines, growth factors, and extracellular vesicles enriched with bioactive miRNAs, the hUC-MSC secretome exerts its effects primarily through paracrine signaling. For this review, relevant literature was collected from established databases, including ScienceDirect, PubMed, and Google Scholar, using key terms such as “hUC-MSC secretome,” “chronic inflammation,” “exosomes,” “tumor microenvironment,” and “preconditioning.” The search focused on studies published within the last five years, emphasizing <em>in vitro</em> and <em>in vivo</em> preclinical studies, original research, and review articles. Only studies specifically exploring hUC-MSC-derived secretomes were included, whereas those addressing cell-based therapies or secretomes from other MSC sources were excluded. Cumulative findings indicate that the hUC-MSC secretome alleviates chronic inflammation by releasing anti-inflammatory cytokines such as IL-10 and TGF-β, as well as regulatory miRNAs such as miR-29a-3p, miR-100-5p, and miR-125b-5p, which act via key signaling pathways including PI3K/AKT, Wnt/β-catenin, and JAK/STAT. These mechanisms collectively mediate anti-inflammatory responses, suppress epithelial-mesenchymal transition, enhance chemosensitivity, and promote tissue repair. This review aims to consolidate the emerging evidence that positions the hUC-MSC secretome as a next-generation cell-free therapeutic strategy for chronic inflammatory diseases, including major cancers, inflammatory bowel disease, rheumatoid arthritis, and neurodegenerative disorders, while highlighting current limitations and strategies to enhance the therapeutic efficacy and clinical applicability of the hUC-MSC secretome.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"190 ","pages":"Pages 140-151"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hippo signaling as a therapeutic switch for T cell functions and tumor immunity","authors":"Jie Fan ,&nbsp;Farooq Riaz ,&nbsp;Fan Pan","doi":"10.1016/j.molimm.2025.12.013","DOIUrl":"10.1016/j.molimm.2025.12.013","url":null,"abstract":"<div><div>The Hippo signaling pathway is a fundamental regulator of organ growth, tissue regeneration, and cellular homeostasis, with far-reaching implications in cancer biology and immunology. Dysregulation of this pathway, particularly through its downstream effectors YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif), is closely associated with oncogenic transformation and the establishment of an immunosuppressive tumor microenvironment (TME). This review discusses current knowledge on the multifaceted roles of Hippo signaling in cancer, focusing on its interactions with T cell–mediated immunity and mechanisms of tumor immune regulation. Aberrant YAP/TAZ activation enhances cancer cell proliferation, remodels the TME, and reprograms immune responses to favor tumor growth and immune evasion. The review explores how modulation of Hippo pathway components influences both tumor progression and immune cell function, highlighting its central role in shaping anti-tumor immunity. Furthermore, the therapeutic potential of targeting YAP/TAZ signaling is discussed in the context of advancing precision medicine and improving immunotherapeutic outcomes. Collectively, this work highlights the Hippo signaling cascade as both a key driver of tumorigenesis and a crucial regulator of immune modulation. A comprehensive understanding of its molecular interactions with T cells and the TME will support the development of innovative YAP/TAZ-targeted strategies that integrate molecular signaling and immune modulation, offering new directions for effective cancer therapy.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"190 ","pages":"Pages 11-20"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145886476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of RNase L enhances the expression efficiency of mRNA-LNPs","authors":"Hong-My Nguyen ,&nbsp;Britteny Cassaidy ,&nbsp;Mark Collinge ,&nbsp;James C. Hickey ,&nbsp;Jin Li ,&nbsp;Amir Arellano-Saab ,&nbsp;Steven W. Kumpf ,&nbsp;Mitchell Thorn","doi":"10.1016/j.molimm.2026.01.003","DOIUrl":"10.1016/j.molimm.2026.01.003","url":null,"abstract":"<div><div>mRNA-LNPs offer a promising platform for therapeutic protein expression, however, achieving efficient and sustained translation remains a significant challenge. One of the major barriers to mRNA-LNP efficacy is the activation of innate immune responses that recognize foreign RNA and suppress subsequent protein synthesis. Among these, the OAS-RNase L pathway, involved in degradation of cytoplasmic mRNA, plays a key role. This study examined the impact of RNase L and RNase L blockade on mRNA-LNP expression efficiency. In THP-1 cells, which express high endogenous levels of RNase L, both genetic ablation and pharmacological inhibition of RNase L led to a marked increase in protein expression. In contrast, HeLa cells, which exhibit low RNase L expression, showed minimal response to RNase L inhibition. In human peripheral blood mononuclear cells (PBMCs), RNase L inhibition also enhanced mRNA expression, while blocking other RNA sensors such as TLR7/8, RIG-I, TLR3, or MAVS, did not. Activation of the OAS–RNase L pathway may be driven by double-stranded secondary structure formed by therapeutic mRNA, resulting in mRNA recognition and degradation. RNase L acts as a key post-transcriptional regulator of mRNA stability and translation. Targeting this pathway offers a strategy to improve the performance of mRNA-based therapeutics.</div></div>","PeriodicalId":18938,"journal":{"name":"Molecular immunology","volume":"190 ","pages":"Pages 101-109"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}