Interferon Production Research Articles

An independent association between insulin resistance and cancer has been consistently reported in humans. Patients with cancer display insulin resistance or its clinical manifestations, and this metabolic adaptation precedes the clinical diagnosis of cancer. Insulin resistance in cancer patients is associated with a metabolic switch from oxidative metabolism toward glycolysis that spares oxygen to be used in anabolic processes and facilitates the fast production of energy and intermediate metabolites required for the rapid proliferation of cancer cells. In malignant cells, glucose consumption via glycolysis occurs under normoxic conditions (aerobic glycolysis). Pathogenic mechanisms underlying insulin resistance in cancer patients include hypoxia-inducible factor-1 upregulation and overproduction of cytokines, such as interferon, interleukin-6, interleukin-18, and interleukin-1β. Deficit of 2-oxoglutarate (α-ketoglutarate) has been detected in cancer cells and may facilitate hypoxia-inducible factor-1 assembly and activity. Overproduction of cytokines in cancer patients follows activation of the immune system by abnormal nucleic acid variants. Anomalous DNA or RNA structures are recognized by immune sensors and stimulate signaling pathways that ultimately increase cytokine production. Likewise, interferon overproduction occurs in congenital disorders that feature ineffectively repaired DNA lesions, such as Werner syndrome, Bloom syndrome, mutations in DNA polymerase-δ1, and ataxia telangiectasia. These diseases cause simultaneous insulin resistance and a high tendency to develop cancer, highlighting the relationship between the two processes. Defectively repaired DNA injury endangers genomic integrity, predisposing to cancer, and activates the immune system to increase interferon production and subsequent insulin resistance. Hypoxia-inducible factor-1 and cytokines induce insulin resistance by suppressing peroxisome proliferator-activated-γ in the subcutaneous adipose tissue.

Tumor necrosis factor-α inhibitors (TNFis) are associated with a risk of paradoxical psoriasis, but quantitative data remain limited. One proposed mechanism is the induction of interferon (IFN) production following TNFi administration. Etanercept and certolizumab pegol, which contain immunoglobulin fragments in their structures, reportedly induce IFN production in T cells more than monoclonal antibody (mAb) TNFi agents. Based on this, we hypothesized that non-mAb TNFi agents might carry a higher risk of paradoxical psoriasis than mAb agents. This study compared the risk of paradoxical psoriasis between mAb and non-mAb TNFi agents in rheumatoid arthritis (RA) patients. Using a claims database, we identified 1577 subjects in the mAb group and 1517 in the non-mAb group. Patient characteristics, including sex, age, and prior RA treatment, were extracted, and the onset of psoriasis was identified. Multivariable Cox regression analysis showed the hazard ratio (HR) for psoriasis onset in the mAb group versus the non-mAb group was 1.66 (95% confidence interval [CI]: 0.79-3.48). Subgroup analyses revealed that compared to etanercept, the HR for adalimumab was 1.43 (95% CI: 0.49-4.19), and compared to certolizumab pegol, it was 0.67 (95% CI: 0.19-2.39). These findings suggest that our hypothesis was not supported and that the risk of paradoxical psoriasis may vary even among non-mAb agents, as indicated by differences observed between etanercept and certolizumab pegol.

Inborn errors of immunity (IEI) are heterogeneous genetic disorders that are susceptible to frequent bacterial, fungal, and viral infections. Herpes simplex virus type 1, 2 (HSV1, 2) is the most common and important cause of viral encephalitis. Innate and acquired immunity have a central role in controlling HSV infection. There is incomplete evidence about the increased susceptibility to herpes simplex encephalitis (HSE) in HSV-infected patients. Studies strongly suggest that HSE has a genetic susceptibility at least in some people. Several studies have shown that defects in the Toll-like Receptor (TLR)3 signaling and interferon (IFN) production and IFN-independent cell-intrinsic mechanisms contribute to HSE. We searched the Web of Science, PubMed, Scopus, and Google Scholar databases to select the latest and most reliable papers and articles published in English and Persian. In the present review, we discuss IEI and genetic abnormalities that predispose individuals to HSE. Genetic defects in components of the TLR3 signaling pathway, such as TLR3, UNC93B1, TRIF, TRAF3, IRF3, and Signal transducer and activator of transcription 1 (STAT1), have been reported as responsible genes for HSE. Other genetic mutations have also been found as the etiology of HSE in some people. Despite HSE being a rare complication of HSV, genetic evaluation of these patients can diagnose some IEI and may give us new insights for future investigations in the fields of diagnosis, treatment, and prophylaxis

In response to various intracellular stress or damage-associated signals, inflammasomes can be activated and trigger a pyroptotic cell death process through the sequential assembly of structurally compatible and interacting filamentous oligomers involving the pyrin domains (PYD) of important inflammasome components. The PYD-containing interferon-inducible protein 16 (IFI16) has been suggested as a viral DNA sensor that can induce inflammasome formation, but it also has other inflammasome-independent functions, including interferon production. Here, the cryo-EM structure of the filament assembled by the PYD of human IFI16 reveals a helical architecture distinct from inflammasome PYD filaments. In silico interface energy calculations suggest that the helical architecture of the IFI16PYD filament prevents interactions with inflammasome PYD filaments. Biochemical and cell biology experiments consistently demonstrate that IFI16 does not directly interact with inflammasome pyrin domains. Together, our results provide insights into the structural basis of the inflammasome-independent functions of IFI16, and also show that strict architectural compatibility requirements for interactions contribute to the signal transduction specificity in inflammasome signaling.

Introduction: Myocarditis, defined as an inflammatory injury to the myocardium, is irreversible with a 20% fatality rate in 2 years and a 50% fatality rate in 5 years. The most common causes of myocarditis are viruses, such as influenza A (IAV). IAV is a cardiotropic virus that can disseminate from the lungs to infect heart tissue, particularly during severe infections. Despite the implications for public health, little is known about the underlying mechanisms by which IAV causes heart pathology. Methods: To investigate the role of the novel E3 ligase TRIM47 in IAV-induced myocarditis, we utilized both in vitro and in vivo approaches. In vivo , wild-type (WT) and TRIM47 knockout (KO) mice were challenged intranasally with IAV to induce myocarditis. Survival, heart function (echocardiography), and cardiac pathology (histology, viral load by RT-PCR, cytokine levels by ELISA) were evaluated. In vitro , bone marrow-derived macrophages (BMDM) from WT and TRIM47 KO mice were infected with IAV and interferon production was detected by ELISA. To elucidate molecular mechanisms, co-immunoprecipitation and Western blotting were used to confirm TRIM47-MAVS interaction and ubiquitination patterns. Furthermore, recombinant protein expression, mutagenesis, and co-expression studies were used to map binding sites and identify specific ubiquitination types and sites on MAVS. Results: TRIM47 KO mice exhibited significantly reduced survival rates compared to WT controls following IAV infection, along with higher viral loads, diminished type I interferon levels, and increased histopathological damage in lungs and hearts. Consistently, TRIM47 KO BMDMs produced substantially lower interferon levels upon IAV challenge. Mechanistically, TRIM47 was found to directly bind MAVS at an endogenous level and promoted the ubiquitination of MAVS, facilitating its aggregation and subsequent activating downstream antiviral signaling pathways. Conclusions: Our findings establish macrophage expressed TRIM47 as a critical regulator of the innate immune response to IAV-induced myocarditis. This study provides the first in vivo evidence of TRIM47’s role in controlling IAV-induced myocarditis and highlights the TRIM47- MAVS axis as a promising therapeutic target for viral-associated cardiovascular diseases.

Porcine epidemic diarrhea virus (PEDV) NSP8 is a highly conserved protein that plays a crucial role in viral replication. Investigating the functional mechanisms of NSP8 contributes to a deeper understanding of PEDV pathogenesis and supports the development of antiviral strategies against coronaviruses. In this study, we elucidate how NSP8 suppresses type Ⅲ interferon (IFN-Ⅲ) production by promoting pexophagy through the downregulation of PEX13. We demonstrate that NSP8 directly interacts with PEX13 and enhances the ubiquitination of PEX5, leading to reduced peroxisome abundance and impaired mitochondrial antiviral-signaling protein (MAVS)-mediated IFN-Ⅲ signaling. These findings suggest that NSP8 hijacks the PEX13-dependent pexophagy pathway as a means of evading host antiviral defenses. This work provides critical insights into the interplay between viral proteins and host cellular machinery and highlights the NSP8-PEX13 axis as a promising target for therapeutic interventions aimed at enhancing antiviral immunity against PEDV and related coronaviruses.

Background: Vascular endothelial cell (EC) damage and subsequent cardiovascular (CV) events occur in patients with type 2 diabetes (T2D) despite aggressive medical therapy. This study investigated the key vascular EC pathways in T2D vs controls at baseline and after aggressive lipid lowering therapy (LLT) to improve our mechanistic understanding of CV risk reduction strategies in T2D. Methods: CHORD (CHOlesterol lowering and Residual Risk in Diabetes) is a clinical trial of LLT with PCSK9 inhibitor plus high-intensity statin or ezetimibe for 1-month to evaluate mechanisms of CV risk in T2D and non-T2D (controls) free of clinical CV disease with an LDL-C > 100 mg/dL. In a subset of participants, EC harvesting was performed at baseline and follow-up by inserting a J-wire through an angiocatheter into the brachial vein. ECs were isolated with magnetic beads directed against CD146, and transcript expression assessed using next generation RNA sequencing. Results: We performed EC harvesting in 15 participants with DM (median age 55 years, 60% male, HbA1c 6.7%, LDL-C 131 mg/dL) and 25 controls (median age 37 years, 56% male, HbA1c 5.2%, LDL-C 142 mg/dL). After adjustment for age and sex, EC RNA sequencing in T2D (vs controls) demonstrated 1126 upregulated and 204 downregulated genes (nominal p<0.05) with dysregulated pathways in T2D (vs controls) involved in lipid metabolic process, apoptosis, interferon signaling, and leukocyte vascular adhesion. After lipid-lowering (LDL-C decreased by 70% in both T2D and controls), 839 genes were upregulated, and 1271 genes were downregulated (nominal p<0.05) with upregulated EC pathways related to EC health, nitric oxide, and IL-10 signaling. Downregulated EC pathways after LLT included interferon production, inflammasome signaling and NFkB production (Figure). When compared to controls, T2D showed preferential reduction in endothelial inflammatory pathways yet upregulation in those related to platelet activation and hemostasis (Figure). Following LLT, the dysregulated pathways between T2D and controls at baseline (lipid process, apoptosis, interferon signaling, leukocyte vascular adhesion) were no longer significantly different between groups. Conclusion: While individuals with and without T2D derive improvement in vascular endothelial function, aggressive lipid lowering appears to have a more robust anti-inflammatory impact in T2D yet no impact on those related to hemostasis.

Fowl adenovirus serotype 4 ORF1B protein suppresses type I interferon production by inhibiting IRF7 nuclear translocation.

Genistein, a natural isoflavonoid found predominantly in legumes and soy-based foods, has garnered significant attention due to its multifaceted mechanisms and potential therapeutic applications. Chemically, genistein is a 4',5,7-Trihydroxyisoflavone having a molecular formula of C15H10O5, which enables its interactions with diverse biological targets. The main objective of this review is to summarize the pharmacological effects of genistein, elucidating its potential mechanisms of action. Furthermore, the review emphasizes genistein's impact on human health when used as a dietary supplement. The authors have gone through a vast number of article sources from various scientific databases like Google Scholar, PubMed and Web of Science. Genistein exhibits antioxidant properties by countering free radicals and reducing lipid peroxidation. Genistein's anti-inflammatory effects involve inhibiting proinflammatory pathways and cytokine production. Notably, it shows anticancer potential against various malignancies by promoting apoptosis, inhibiting angiogenesis, and hindering metastasis. Moreover, genistein has antidiabetic properties, enhancing insulin secretion, protecting β-cells, and improving glucose tolerance. Its antiviral and antibacterial actions contribute to inhibiting pathogen growth and viral replication. Genistein accelerates wound healing by minimizing oxidative stress, facilitating reepithelialization, and suppressing inflammation. Its potential in peptic ulcer treatment is supported by anti-inflammatory and antioxidant effects. Hepatoprotective activities include inhibiting lipid peroxidation, bolstering antioxidant defences, and modulating metabolic enzymes. Furthermore, genistein positively impacts the immune response, influencing cytokine levels, lymphocyte proliferation, and interferon production. Genistein's multifaceted pharmacological activities render it a promising dietary supplement with implications for diverse health conditions, warranting further comprehensive research to optimize its clinical utility.

eIF4A3 inhibits pseudorabies virus replication by facilitating antiviral immune response.

Deacetylase SIRT1 modulates antiviral innate immunity and autoimmune diseases.

Resveratrol inhibits porcine deltacoronavirus infection by activating SIRT1 to promote interferon production in vitro.

As more women with HIV survive into older age, the menopausal transition has emerged as a critical yet underexplored determinant in HIV pathogenesis. Declining exposure to estrogens during menopause alters innate and adaptive immunity, driving inflammation, comorbidities, and viral persistence. Estrogen influences both innate and adaptive immune responses. Estradiol enhances plasmacytoid dendritic cell type I interferon (IFN) production through Toll-like Receptor 7 (TLR7), promotes natural killer (NK) cell activity, and tempers monocyte/macrophage activation. Menopause reverses these effects, contributing to elevated inflammatory mediators. On the adaptive side, estrogen loss increases T-cell activation and exhaustion, impairs B-cell responses, and removes estrogen receptor (ER)-mediated suppression of HIV transcription. Together, these shifts may promote stabilization or expansion of the HIV reservoir in perimenopausal women with HIV, in contrast to the gradual decay often observed in men on antiretroviral therapy (ART). Estrogen depletion during menopause reshapes immunity in women with HIV, fueling chronic inflammation, comorbidity risk, and HIV reservoir persistence. Integrating reproductive aging into HIV cure and comorbidity research, and testing hormone-based and anti-inflammatory interventions, will be essential to improve health outcomes for aging women with HIV.

Endosomal toll-like receptors TLR7 and TLR8 are critical sensors of microbial RNA that initiate antiviral and antibacterial immune responses through type I interferon (IFN) and proinflammatory cytokine production. While TIRAP is traditionally associated with plasma membrane TLR signaling, recent evidence suggests that it also contributes to signaling via endosomal TLRs. Here, we examined the role of TIRAP in TLR7/8 signaling using P7-Pen, a novel SLAMF1-derived peptide that disrupts the TIRAP-MyD88 interaction. In primary human monocytes and a whole blood model, P7-Pen inhibited TLR7- and TLR8-induced expression and secretion of IRF5-regulated cytokines IFNβ, IL-12p40, and IL-12p70, without effect on TNF or IL-6. Mechanistically, P7-Pen blocked TIRAP recruitment to the TLR8-MyD88 complex, leading to reduced late-stage IRAK1 activation, Akt and IKKα/β phosphorylation, and downstream IRF5 dimerization and nuclear translocation. Inhibition of Staphylococcus aureus-induced cytokine production by P7-Pen was associated with reduced bacterial phagocytosis, impairing endosomal delivery of bacterial RNA. Notably, P7-Pen failed to inhibit murine TLR7 responses, which correlated with a lack of TIRAP recruitment to MyD88 in mouse macrophages following TLR7 ligand stimulation, highlighting species-specific differences in TLR signaling mechanisms. These findings support a noncanonical role for TIRAP in regulating IRF5-dependent signaling downstream of human TLR7 and TLR8, and demonstrate that selective disruption of TIRAP recruitment by a SLAMF1-derived peptide effectively attenuates IFNβ production. This strategy may hold therapeutic potential in diseases characterized by dysregulated type I IFN responses, such as systemic lupus erythematosus and chronic infections.

Coronaviruses cause upper and lower respiratory tract infections ranging from mild infections to severe conditions such as pneumonia and acute respiratory distress syndrome (ARDS). One factor contributing to the pathogenesis of viral infection is the ability to avoid or downregulate the activation of interferon (IFN)-induced antiviral immunity. We show that the seasonal human coronavirus HCoV-229E readily replicated in human lung A549 and human hepatoma Huh7 cells, but the infection did not induce type I or type III IFN gene expression and IFN-induced MxA expression. Total cellular RNA isolated from HCoV-229E-infected A549 or Huh7 cells transfected into uninfected A549 cells failed to induce significant IFN gene expression, indicating that HCoV-229E RNA is likely not recognized by RIG-I-like receptors. However, in similar experiments, influenza A virus (IAV) infection or cellular RNA from IAV-infected cells induced strong IFN responses. Pretreatment of A549 cells with IFN-α showed some inhibitory activity against HCoV-229E replication, but the level of inhibition was weaker than that observed against IAV. Additionally, the ability of type I IFNs to induce MxA protein expression was almost completely blocked in HCoV-229E-infected A549 cells. This phenomenon was observed both at early (8 h) and late (24 h) time points of HCoV-229E infection, indicating that the infection efficiently blocks IFN signaling. Our data show that HCoV-229E can efficiently avoid cellular IFN responses.IMPORTANCEThis study uncovers some of the potential mechanisms by which the seasonal coronavirus HCoV-229E evades host innate immune responses, providing valuable insights into general coronavirus pathogenesis. Unlike IAV, HCoV-229E infection does not induce type I IFN production and IFN-induced antiviral MxA expression. Cellular RNA from HCoV-229E-infected cells fails to induce IFN gene expression, indicating that HCoV-229E virus-specific RNA molecules are not recognized by pattern recognition receptors (PRRs). This immune evasion allows the virus to replicate and produce proteins that further inhibit host defenses. These findings challenge prior reports on IFN responses to seasonal coronaviruses and highlight differences in immune evasion between seasonal and more pathogenic coronaviruses like SARS-CoV-2. By elucidating these mechanisms, the study paves the way for identifying antiviral targets across the coronavirus family and understanding the balance between immune evasion and disease severity, ultimately contributing to the development of broad-spectrum antiviral strategies.

STING activates the innate immune system by inducing type-1 interferon (IFN) production and has been pursued as a therapeutic option in immuno-oncology. The targeted delivery of STING agonists to CCR2+ immune cells could enhance the therapeutic window of the agonists by selectively activating the STING pathway within targeted immune cells. The chemistry strategy was established to enable the targeted delivery of the cyclic dinucleotide STING agonist dazostinag to CCR2+ cells through an antibody-drug conjugate (ADC) approach. A self-immolative spacer between the adenine of dazostinag and the Cathepsin-B cleavable Val-Ala dipeptide linker rendered a linker payload that exhibits strong plasma stability while allowing the rapid payload release upon internalization into lysosomes. The stochastic cysteine conjugation of the dazostinag containing these linkers provided ADC TAK-500 and its mouse surrogate mTAK-500 with DAR = 4. In syngeneic tumor-bearing mouse models, mTAK-500 showed target specific antitumor activity as well as the induction of immune-stimulating cytokines.

Subasumstat (TAK-981) is a first-in-class inhibitor of SUMOylation that can engage innate and adaptive immune responses in tumors by enhancing type I interferon (IFN-I) production. We conducted a phase I/II dose escalation/expansion study (NCT03648372) to investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of subasumstat as a single agent in patients with advanced/metastatic solid tumors and relapsed/refractory hematologic malignancies. Eligible patients received subasumstat intravenously at escalating doses twice-weekly (BIW, days 1, 4, 8, and 11) or once-weekly (days 1 and 8) in 21-day cycles until disease progression or unacceptable toxicity. A total of 109 patients were enrolled (solid tumors: n = 100; lymphomas, n = 9). In phase I, four patients reported dose-limiting toxicities of grade 3 ALT/AST elevation, pneumonitis, stomatitis, and cognitive disorder; 120 mg BIW was determined as the maximum tolerated dose. The most common adverse events were fatigue (47%), nausea (41%), diarrhea (36%), and pyrexia (36%). Pharmacodynamic analyses demonstrated target engagement and SUMOylation pathway inhibition, induction of an IFN-I-regulated gene signature and cytokine production, and activation of innate and adaptive immune cells. Based on safety, pharmacokinetic, and pharmacodynamic findings, 90 mg BIW was proposed as the recommended phase II dose. Overall, three and 26 patients achieved a partial response and stable disease, respectively. Subasumstat had a manageable safety profile, with evidence of innate and adaptive immune response engagement in patients with advanced/metastatic solid tumors and relapsed/refractory hematologic malignancies. Further studies are needed to determine the role of subasumstat in cancer treatment.

Disclosure: M. Shiina: None. M. Yokoyama: None. T. Tanaka: None. A. Nakayama: None.The contribution of vascular endothelial cells to lifestyle- related diseases and aging-related diseases is widely recognized. Although aging and obesity are systemic conditions, their pathological effects vary by organ. Based on this background, we hypothesized that endothelial cells exhibit organ-specific stress responses. To investigate this, we performed single-cell RNA sequencing on endothelial cells isolated from key metabolism-related mouse organs: adipose tissue, heart, skeletal muscle, and liver.In this study, our purpose was to elucidate organ-specific molecular changes in endothelial cells under aging and obesity stress, with a focus on transcription factors (TFs) regulating these changes. We identified significantly differentially expressed genes (DEGs), especially the top 100 upregulated genes in each condition. To interpret their functions, we used scGSVA to visualize pathway activity at the single-cell level. For TF analysis, we applied SCENIC, which infers regulatory activity based on co-expression between TFs and their target genes. TFs were ranked based on activation scores in both conditions. By integrating DEGs and TFs, we construct stress-related regulatory networks.Under aging stress, we observed a shared response across organs, activation of interferon (IFN) signaling pathways. These pathways promote immune defense via IFN production. Despite organ-specific gene expression, IFN pathway activation was a consistent functional feature. Additionally, TF analysis revealed that aging-related expression changes were commonly regulated by IFN-related TFs (Irf7, Irf9, Stat1, Stat2) in all organs. Thus, both pathway and TF analyses consistently support IFN pathway activation as a hallmark of aging stress.In contrast, obesity stress has induced distinct organ-specific responses:•Adipose tissue: Activation of fatty acid metabolism•Heart: Vascular function and cell signaling changes•Skeletal muscle: Enhanced antioxidant activity and protein synthesis•Liver: Altered energy metabolism and ion channel regulationTFs involved in obesity responses showed little overlap across organs. Although Pparg was activated in adipose tissue, muscle, and liver, its regulon targets varied, suggesting that even shared TFs may exhibit organ-specific regulatory functions depending on the cellular context.Presentation: Saturday, July 12, 2025

Cellular uptake of nanomaterials is based on endocytosis with their endosomal–lysosomal entrapment resulting in enzymatic hydrolysis. Besides biodegradation, the antigen presentation induces innate and adaptive immunity. Our goal was isolation of extracellular particles to study their structures, penetration into cells, stability, intracellular distribution, and interferon (IFN) production. Extracellular nanomaterials were isolated from conditioned culture media of human embryonic and cancer cells by two-stage differential centrifugation. Cellular uptake of Cy5-labeled particles was evaluated using spectrofluorimetry and confocal fluorescent microscopy. IFN gene expression was analyzed by reverse transcription with real-time PCR and ELISA. Vesicles of 10–200 nm were isolated by centrifugation at 20,800× g at +4 °C for 30 min. The fluorescent vesicles were gradually accumulated inside cells for seven days. Intracellular distribution patterns of the Cy5-labeled vesicles differed from lysosomes stained with LysoRed tracker. IFNs α, β and γ were not detected after treatment with the vesicles. IFN λ was found in cells in the presence of allogenic but not autologous particles. The gradual cellular uptake occurred without significant differences between autologous and heterologous vesicles. Different localization of the extracellular vesicles (EV) and lysosomes along with weak innate immune response (if any) suggested membrane fusion.

Integrins are cell surface adhesion molecules. They bridge the intracellular and extracellular environments, enabling bidirectional transmembrane signaling and regulating immune responses. However, it remains unclear whether integrin protein β1 (ITGβ1) is involved in innate immune responses. In our previous study, we demonstrated that porcine epidemic diarrhea virus (PEDV) can induce type I interferon (IFN-I) production. In this study, we observed that ITGβ1 expression is rapidly induced following PEDV infection and further established that PEDV infection primarily promoted ITGβ1 expression through upregulation of the transcription factor c-Myc. We hypothesized that ITGβ1 might be involved in PEDV-induced innate immune responses through IFN-I production. Our investigation revealed ITGβ1 overexpression promotes the phosphorylation and subsequent nuclear translocation of both interferon regulatory factor 3 (IRF3) and NF-κB, thereby enhancing SeV-induced IFN-β promoter activity. Furthermore, we showed that ITGβ1 functions as an activator in the melanoma differentiation-associated protein 5 (MDA5)-mediated IFN-I signaling pathway. More importantly, we demonstrated that ITGβ1 is critically involved in PEDV-induced IFN-I antiviral responses. Mechanistically, ITGβ1 facilitates MDA5 oligomerization by specifically interacting with its caspase activation and recruitment domain (CARD), thereby enhancing dsRNA-recruitment capacity. In summary, the findings of this study indicate that ITGβ1 acts as an activator of the MDA5-dependent IFN-I antiviral innate immune response and positively regulates the MDA5-mediated RIG-I-like receptor signaling pathway.IMPORTANCEPorcine epidemic diarrhea virus (PEDV), an alpha coronavirus, severely impacts newborn piglets, leading to acute manifestations including vomiting, diarrhea, dehydration, and high mortality rates in suckling piglets. These consequences have devastating implications for the global swine industry. Within the host's innate antiviral response, RIG-I-like receptors (RLRs) are critical for the activation of the interferon signaling pathway. Integrin proteins, known for their role in regulating bidirectional signal transduction across the cell membrane, are associated with numerous viral infections. In this study, utilizing PEDV as an infection model, we demonstrated that overexpression of ITGβ1 suppresses PEDV replication, while knockdown of ITGβ1 expression enhances it. Additionally, ITGβ1 significantly augments PEDV-induced type I interferon production in host cells. We further elucidated that ITGβ1 interacts with the 2CARD region of MDA5, promoting MDA5 oligomerization and the transmission of activation signals. These findings establish ITGβ1 as a positive regulatory factor in MDA5-mediated RLR signaling pathway. These findings not only identify ITGβ1 as a novel host antiviral protein against PEDV but also reveal, for the first time, a previously unrecognized function of ITGβ1 in the cellular innate antiviral immune response.