Search Results (715)

With estrus confined to three winter months, early pregnancy detection is essential for reproductive management in farmed sika deer. However, the development of reliable non-invasive early pregnancy detection techniques has been hindered by limited understanding of their reproductive physiology. To identify pregnancy-specific biomarkers in sika deer, we performed RNA-sequencing (RNA-Seq) on maternal peripheral blood collected on days 0, 7, 15, and 20 after artificial insemination. Using time-series clustering analysis and weighted gene co-expression network analysis (WGCNA), we identified key genes and pathways at each stage. Notably, maternal-fetal recognition-related interferon-stimulated genes (ISGs; IFNAR1/2, STAT1/2, MX1/2, and RSAD2), anti-apoptotic and immune-regulatory genes (BCL2, XIAP, and IL10), and cysteine metabolism genes (CTH, CBS, GCLC, and GCLM) were upregulated by day 7, suggesting their role in supporting corpus luteum development through immune regulation and redox homeostasis. By days 15–20, upregulated genes were enriched in pathways related to mitochondrial function, cell adhesion, and cell cycle regulation, indicating their involvement in embryo adhesion and syndesmochorial placentation. In conclusion, this study demonstrates that ISGs, immune-regulatory genes and cysteine metabolism genes are detectable as early as day 7 post-insemination, highlighting their promise as early pregnancy biomarkers and providing a molecular basis for non-invasive diagnostic development in sika deer. Full article

Excessive production of type I interferons (IFNs) underlies the immunopathogenesis of autoimmune disorders, including systemic lupus erythematosus and autoimmune pancreatitis. Whether type I IFNs play pathogenic or protective roles in the development of inflammatory bowel diseases (IBD) has been a matter of debate. The production of type I IFNs is tightly regulated by the conjugation and removal of polyubiquitin chains on or from intracellular signaling molecules. OTU deubiquitinases 3 (OTUD3) and 5 (OTUD5) are enzymes that cleave various polyubiquitin chains from target proteins. OTUD3 and OTUD5 deubiquitinate key critical intracellular molecules of the type I IFN signaling pathways, stimulator of interferon genes (STING), and TNF receptor-associated factor 3 (TRAF3), respectively, and thus regulate the production of type I IFNs by innate immune cells. Recent studies provided evidence that the impaired function of OTUD3 and OTUD5 increases susceptibility to human and experimental IBD owing to the excessive production of type I IFNs caused by the activation of STING and TRAF3, respectively. Collectively, OTUD3 and OTUD5 play protective rather than pathogenic roles in the development of IBD through the negative regulation of type I IFN-mediated signaling pathways. In this review article, we discuss the association between the development of IBD and impaired function of OTUD3 or OTUD5 by focusing on their deubiquitinase activity and type I IFN responses. Full article

Interferons (IFNs) are key cytokines at the intersection of innate and adaptive immunity. While their antiviral and antitumor roles are well recognized, emerging evidence implicates IFNs—particularly types I, II, and III—in the initiation and progression of autoimmune diseases (ADs). This review synthesizes current data on IFN biology, their immunoregulatory and pathogenic mechanisms, and their contributions to distinct AD phenotypes. We conducted a comprehensive review of peer-reviewed literature on IFNs and autoimmune diseases, focusing on publications indexed in PubMed and Scopus. Studies on molecular pathways, immune cell interactions, disease-specific IFN signatures, and clinical correlations were included. Data were extracted and thematically organized by IFN type, signaling pathway, and disease context, with emphasis on rheumatic and systemic autoimmune disorders. Across systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, systemic sclerosis, idiopathic inflammatory myopathies, multiple sclerosis, type 1 diabetes, psoriasis, and inflammatory bowel diseases, IFNs were consistently associated with aberrant activation of pattern recognition receptors, sustained expression of interferon-stimulated genes (ISGs), and dysregulated T cell and B cell responses. Type I IFNs often preceded clinical onset, suggesting a triggering role, whereas type II and III IFNs modulated disease course and severity. Notably, IFNs exhibited dual immunostimulatory and immunosuppressive effects, contingent on tissue context, cytokine milieu, and disease stage. IFNs are central mediators in autoimmune pathogenesis, functioning as both initiators and amplifiers of chronic inflammation. Deciphering the context-dependent effects of IFN signaling may inform targeted therapeutic strategies and advance precision immunomodulation in autoimmune diseases. Full article

Background: Treatment with androgen receptor (AR) signaling inhibitors, such as enzalutamide, can induce neural lineage plasticity in prostate cancer, potentially progressing to t-NEPC. However, the molecular mechanisms underlying this enzalutamide-driven plasticity, particularly the contribution of immune signaling pathways, remain poorly understood. Methods: We analyzed transcriptomic profiles of patient samples and prostate cancer cell lines to investigate changes in immune signaling pathways. Interferon gamma (IFNγ), interferon alpha (IFNα), and interleukin 6 (IL6)-Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling were assessed in enzalutamide-sensitive and -resistant prostate cancer cells. Functional assays were conducted to examine cell responsiveness to cytokine stimulation and susceptibility to STAT1 inhibition using fludarabine. Results: Immune-related pathways, including IFNγ, IFNα, IL6-JAK-STAT3, and inflammatory responses, were significantly suppressed in NEPC patient samples compared to those with castration-resistant prostate cancer (CRPC). Enzalutamide-resistant and NEPC cells exhibited markedly impaired IFNγ and IL6 signaling. In contrast, early-stage enzalutamide treatment paradoxically enhanced IFNγ and IL6 responsiveness. Transcriptomic profiling revealed coordinated upregulation of E2F target genes and activation of IFNα/IFNγ and JAK/STAT signaling pathways during early treatment. Importantly, these early-stage cells remained highly sensitive to IFNγ and IL6 stimulation and showed increased susceptibility to STAT1 inhibition by fludarabine, a sensitivity that was lost in resistant cells. Conclusions: Early enzalutamide treatment enhances immune responsiveness, while the development of resistance is associated with suppressed immune signaling and increased lineage plasticity. These results suggest a therapeutic window where combining enzalutamide with STAT inhibitors may delay or prevent lineage plasticity and resistance. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recognized by pattern recognition receptors (PRRs), which play a vital role in triggering innate immune responses such as the production of type I and III interferons (IFNs). While modest PRR activation helps to defend against SARS-CoV-2, excessive or sustained activation can cause harmful inflammation and contribute to severe Coronavirus Disease 2019 (COVID-19). Altered expression of Toll-like receptors (TLRs), which are among the most important members of the PRR family members, particularly TLRs 2, 3, 4, 7, 8 and 9, has been strongly linked to COVID-19 severity. Furthermore, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), collectively known as RLRs (RIG-I-like receptors), act as sensors that detect SARS-CoV-2 RNA. The expression of these receptors, as well as that of different DNA sensors, varies in patients infected with SARS-CoV-2. Changes in PRR expression, particularly that of TLRs, cyclic GMP-AMP synthase (cGAS), and the stimulator of interferon genes (STING), have also been shown to play a role in the development and persistence of long COVID (LC). However, SARS-CoV-2 has evolved strategies to evade PRR recognition and subsequent signaling pathway activation, contributing to the IFN response dysregulation observed in SARS-CoV-2-infected patients. Nevertheless, PRR agonists and antagonists remain promising therapeutic targets for SARS-CoV-2 infection. This review aims to describe the PRRs involved in recognizing SARS-CoV-2, explore their expression during SARS-CoV-2 infection, and examine their role in determining the severity of both COVID-19 and long-term manifestations of the disease. It also describes the strategies developed by SARS-CoV-2 to evade PRR recognition and activation. Moreover, given the considerable interest in modulating PRR activity as a novel immunotherapy approach, this review will provide a description of PRR agonists and antagonists that have been investigated as antiviral strategies against SARS-CoV-2. This review aims to explore the complex interplay between PRRs and SARS-CoV-2 in depth, considering its implications for prognostic biomarkers, targeted therapeutic strategies and the mechanistic understanding of long LC. Additionally, it outlines future perspectives that could help to address knowledge gaps in PRR-mediated responses during SARS-CoV-2 infection. Full article

As cancer incidence continues to rise and conventional therapies remain of limited effectiveness, the search for novel and innovative cancer treatments is ongoing. In recent years, immunotherapies, including checkpoint inhibitors and cell-based approaches such as CAR-T cell therapy, have revolutionized the treatment of cancer. However, response rates even to well-established immunotherapies remain low in several types of cancer. Therefore, various novel immunomodulatory substances are currently under investigation, among them agonists of the intracellular signaling protein STING (STimulator of INterferon Genes). Activation of the STING signaling pathway can alter the cytokine profile within the tumor microenvironment (TME) and reshape the function of various immune cells. STING agonists have yielded promising results in preclinical studies, but this success has not yet been replicated in clinical trials. Consequently, STING agonists are optimized for greater potency and combined with nanotechnologies to enhance biodistribution and achieve sustained accumulation within the TME. This review summarizes a selection of STING agonists evaluated in clinical trials to date and discusses their effects on tumor-infiltration immune cells, especially macrophages. It highlights emerging candidates currently under investigation in preclinical studies, and explores nanotechnological approaches for their combinational use to enhance therapeutic efficacy. Full article

Type 2 diabetes mellitus (T2DM), characterized by insulin resistance and chronic hyperglycemia, markedly increases the incidence and mortality of cardiovascular disease (CVD). Emerging preclinical evidence identifies the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS–STING) pathway as a critical mediator of diabetic cardiovascular inflammation. Metabolic stressors in T2DM—hyperglycemia, lipotoxicity, and mitochondrial dysfunction—induce leakage of mitochondrial and microbial double-stranded DNA into the cytosol, where it engages cGAS and activates STING. Subsequent TBK1/IRF3 and NF-κB signaling drives low-grade inflammation across cardiomyocytes, endothelial cells, macrophages, and fibroblasts. Genetic deletion of cGAS or STING in high-fat-diet-fed diabetic mice reduces NLRP3 inflammasome-mediated pyroptosis, limits atherosclerotic lesion formation, and preserves cardiac contractile performance. Pharmacological inhibitors, including RU.521 (cGAS antagonist), C-176/H-151 (STING palmitoylation blockers), and the TBK1 inhibitor amlexanox, effectively lower pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and improve left ventricular ejection fraction in diabetic cardiomyopathy and ischemia–reperfusion injury models. Novel PROTAC degraders targeting cGAS/STING and natural products such as Astragaloside IV and Tanshinone IIA further support the pathway’s druggability. Collectively, these findings position the cGAS–STING axis as a central molecular nexus linking metabolic derangement to cardiovascular pathology in T2DM and underscore its inhibition or targeted degradation as a promising dual cardiometabolic therapeutic strategy. Full article

Mammals exhibit unique and highly variable mechanisms for the establishment and maintenance of pregnancy. Ruminants (e.g., sheep, cows, and goats) have novel mechanisms whereby the conceptus (embryo and its extra-embryonic membranes) signals for the establishment of pregnancy and exhibits unique metabolic pathways favoring conceptus development. Embryos of ruminants reach the spherical blastocyst stage at 5 to 10 mm in diameter and then elongate rapidly to elongated filamentous conceptuses of greater than 250 mm as they make contact with the uterine luminal epithelium (LE) for implantation. During conceptus elongation the trophectoderm cells secrete interferon tau (IFNT), a novel pregnancy recognition signal for ruminants to ensure maintenance of a functional corpus luteum (CL) to secrete progesterone (P4) required for pregnancy. P4 induces uterine epithelia cells to express the endogenous Jaagsiekte Retrovirus (enJSRV) that may transactivate toll-like receptors 7 and 8 in the conceptus trophectoderm to induce secretion of IFNT, a classical viral–antiviral mechanism. IFNT silences expression of receptors for estradiol (E2) and oxytocin (OXTR), which abrogates the mechanism whereby oxytocin from CL and posterior pituitary would otherwise induce large pulses of prostaglandin F_2α (PGF) by uterine epithelia to cause regression of the CL and its secretion of P4. IFNT has another novel role in silencing expression of not only ESR1 and OXTR, but all classical interferon-stimulated genes in the uterine LE and superficial glandular epithelium (sGE), but with P4 increasing expression of genes for transport of nutrients such as glucose and arginine into the uterine lumen to support conceptus development. Ruminant conceptuses convert glucose to fructose, a novel hexose sugar that cannot be transported back to the maternal circulation. Fructose is converted to fructose-1-PO4 for metabolism, not via the pathway for glycolysis but via the novel fructolysis pathway uninhibited by low pH, citrate, or ATP as is the case for glycolysis. Thus, fructose and its metabolites support the pentose cycle, hexosamine biosynthesis pathway, one-carbon metabolism, and the citric acid cycle for all cells of the conceptus. Arginine is another key nutrient transported into the uterine lumen by the uterine LE/sGE in response to P4 and IFNT. Arginine is metabolized to generate nitric oxide, polyamines, and creatine, essential for conceptus growth and development, while enhancing production of IFNT as a novel pregnancy recognition signal, and upregulating expression of genes in the uterine LE/sGE for transport of nutrients. Fructose is the major hexose sugar supporting major metabolic pathways required for conceptus growth and development in ruminants. Full article

Air pollution, particularly exposure to fine particulate matter (PM_2.5), poses a substantial risk to human health. Diesel exhaust particles (DEPs), a major constituent of PM_2.5, contain chemically reactive components that promote inflammation, oxidative stress, and immune dysfunction. Although the acute toxicity of PM_2.5 and DEPs has been extensively studied, their effects under “sub-toxic” conditions—defined here as exposures that do not cause measurable cytotoxicity based on LDH release but still impair cellular function—remain poorly understood. This study investigated the impact of low-toxicity exposure to DEPs and PM_2.5 on dendritic cell (DC) function using the human plasmacytoid DC-like cell line PMDC05. Cells exposed to DEPs or PM_2.5 exhibited minimal cytotoxicity but accumulated intracellular particles, resulting in impaired endocytosis, phagocytosis, and interferon gene expression upon TLR7 stimulation. These functional impairments were not observed following TLR4 stimulation, suggesting a selective disruption of endolysosomal signalling. The findings demonstrate that DEPs and PM_2.5 can impair innate immune responses without inducing cell death, likely through lysosomal overload and altered intracellular trafficking. This study identifies a non-cytotoxic pathway through which particulate air pollution may compromise antiviral immunity, thereby increasing susceptibility to infection in polluted environments. Strategies aimed at preserving lysosomal integrity and dendritic cell function may help mitigate the immunotoxic effects of airborne particles. Full article

Objectives: Immunotherapy combining agonists of the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway with PD-1/PD-L1 blockade shows promising preclinical results, although in clinical practice, it faces pharmacokinetic barriers, systemic toxicity, and an immunosuppressive tumor microenvironment (TME). Recent advances in and expansion of the cGAS-STING pathway as a therapeutic target have further highlighted its central role in innate and adaptive immune activation. The aim of this paper is to review combination strategies of STING and PD-1/PD-L1 checkpoint blockade therapies, triple-therapy strategies using a third component such as chemotherapy, radiotherapy, photodynamic therapy (PDT), and others, and the use of nanoparticles as carriers for these drugs. Methods: Reports in the literature on the mechanisms of STING + PD-1/PD-L1 synergy, as well as with the use of a third component and delivery systems, were analyzed. Current challenges and limitations, as well as prospects for the development of these therapies, are noted. Results: Activation of the cGAS-STING synergizes with blocking the PD-1/PD-L1 axis. The addition of a third component further enhances the anti-tumor effect through a stronger induction of immunogenic cell death (ICD), increased production of interferons and pro-inflammatory cytokines, repolarization of macrophages, and enhanced infiltration of T lymphocytes. Conclusions: Therapy with STING agonists and PD-1/PD-L1 checkpoint inhibitors, supported by nanotechnology vehicles and using a third therapeutic component, overcomes key pharmacological and immunological limitations. This multimodal immunotherapeutic strategy holds high translational promise, offering more effective and safer solutions in cancer immunotherapy. Full article

Viral infection is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (Allo-HSCT), largely due to its impact on and interaction with immune reconstitution. Both innate and adaptive immunity are essential for effective viral control, yet their recovery post-transplant is often delayed or functionally impaired. Emerging evidence suggests genetic variation, particularly polymorphisms in the IL28B gene (encoding IFN-λ3), as a critical factor influencing the quality and timing of immune responses during the early post-transplant period. This review explores the role of IL28B polymorphisms in shaping antiviral immunity, in general, as well as after Allo-HSCT. IL28B variants have been implicated in modulating interferon-stimulated gene (ISG) expression, natural killer (NK) cell activity, and type I/III interferon signaling, all central components of innate immune defense against viral infections. Furthermore, IL28B polymorphisms, particularly rs12979860, have been shown in both general populations and limited HSCT cohorts to alter T cell response and interferon production, affecting reactivation and clearance of multiple viruses such as cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), COVID-19, and BK polyomavirus (BKPyV) as well as Graft vs. Host disease, thereby affecting adaptive immune reconstitution and long-term viral control. Understanding how IL28B genotype alters immune dynamics in transplant recipients could enhance risk stratification for CMV and other diseases and inform personalized prophylactic or therapeutic strategies. Therefore, this review highlights IL28B as a promising biomarker and potential immunoregulatory target in the management of viral infection post-Allo-HSCT. Full article

Breast cancer (BC) remains a leading cause of cancer-related mortality worldwide, with limited treatment options for triple-negative breast cancer (TNBC). The RNA-binding protein non-POU domain-containing octamer-binding protein (NONO) has emerged as a critical regulator of tumorigenesis, but its role in immune signaling remains unexplored. We analyzed the effect of NONO protein by modulating its expression using short hairpin RNA (shRNA) and a chemical inhibitor (R)-SKBG-1. We demonstrate that NONO depletion in MDA-MB-231 TNBC cells leads to cytoplasmic DNA accumulation, micronuclei formation, and activation of the cyclic GMP-AMP synthase—stimulator of interferon genes (cGAS/STING) pathway, resulting in enhanced modulation of the immune response. NONO-deficient cells showed increased cGAS and STING activation, Tank-binding kinase 1 (TBK1) phosphorylation, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear localization, and transcription of pro-inflammatory genes such as CC Motif Chemokine Ligand 5 (CCL5). These effects were recapitulated by pharmacological inhibition using (R)-SKBG-1, confirming NONO’s immunosuppressive function. Our findings establish NONO as a key modulator of immune activation in TNBC and suggest that its inhibition may enhance anti-tumor immunity. This work paves the way for potential combination strategies involving NONO inhibitors and immune checkpoint blockade, particularly in tumors with homologous recombination deficiencies or limited immune infiltration. Full article

Cattle marketed through auction market systems and/or that remain unvaccinated are considered higher risk for BRD, but impacts on host response remain unclear. We sought to identify specific genomic patterns of beef calves vaccinated against BRD viruses or not and commercially marketed or directly transported in a split-plot randomized controlled trial. Forty-one calves who remained clinically healthy from birth through backgrounding were selected (randomly stratified) from a larger cohort of cattle (n = 81). Treatment groups included VAX/DIRECT (n = 12), VAX/AUCTION (n = 11), NOVAX/DIRECT (n = 7), and NOVAX/AUCTION (n = 11). Blood RNA was acquired across five time points, sequenced, and bioinformatically processed via HISAT2 and StringTie2. Significant transcriptional changes (FDR < 0.05) were observed at backgrounding entry (T5) in NOVAX/AUCTION cattle exhibiting 2809 uniquely differentially expressed genes and relative activation of immune, inflammatory, and metabolic pathways with upregulation of interferon-stimulated genes (e.g., IFIT3, MX2, and TRIM25) and downregulation of specialized proresolving mediator (SPM) enzymes (ALOX5 and ALOX15). VAX/AUCTION cattle exhibited modulated immune activation and preserved expression of SPM-associated genes when compared to NOVAX/AUCTION cattle. Both marketing route and vaccination shape the molecular immune landscape during high-stress transitions, with preweaning vaccination potentially modulating this response. This study provides mechanistic insight into how management practices influence immunological resilience and highlights the value of integrating transcriptomics into BRD risk mitigation. Full article

Background: Irradiation (IR) targets cancer cells, but also the tumor microenvironment, including the tumor’s blood vessels. In addition to tumor endothelial cell (TEC) apoptosis, IR can lead to TEC activation, potentially increasing immune cell infiltration. However, the changes underlying the IR-induced activation of endothelial cells (ECs) are poorly understood. This study investigated dose- and time-dependent molecular and functional responses of murine and human EC lines to IR in vitro and TECs in vivo in murine tumor models of colorectal carcinoma. Methods: HUVEC, EA.hy926, and Hulec5a, as well as murine bEND.3, 2H11, and SVEC4-10 EC lines, were irradiated with single doses of 2–10 Gy. EC proliferation and survival after IR were assessed by staining all nuclei (Hoechst 33342) and dead cells (propidium iodide) every 24 h for 5 days using the Cytation 1 Cell Imaging Multi-Mode Reader. RNA sequencing analysis of HUVECs irradiated with 2 Gy and 5 Gy at 24 h and 72 h after IR was conducted, focusing on processes related to EC activation. To validate the RNA sequencing results, immunofluorescence staining for proteins related to EC activation, including Stimulator of Interferon Response cGAMP Interactor 1 (STING), Nuclear factor kappa B (NF-κβ), and Vascular cell adhesion molecule 1 (VCAM-1), was performed. To validate the in vitro results, the response of TEC in vivo was analyzed using publicly available RNA sequencing data of TECs isolated from MC38 colon carcinoma irradiated with a single dose of 15 Gy. Finally, murine CT26 colon carcinoma tumors were immunofluorescently stained for STING and NF-κβ 24 and 48 h after IR with a clinically relevant fractionated regimen of 5 × 5 Gy. Results: Doses of 2, 4, 6, 8, and 10 Gy led to a dose-dependent decrease in proliferation and increased death of ECs. RNA sequencing analysis showed that the effects on the transcriptome of HUVECs were most pronounced 72 h after IR with 5 Gy, with 1014 genes (661 down-regulated and 353 up-regulated) being significantly differentially expressed. Irradiation with 5 Gy resulted in HUVEC activation, with up-regulation of the immune system and extracellular matrix genes, such as STING1 (log₂FC = 0.81) and SELE (log₂FC = 1.09), respectively; and down-regulation of cell cycle markers. Furthermore, IR led to the up-regulation of immune response- and extracellular matrix (ECM)-associated signaling pathways, including NF-κβ signaling and ECM–receptor interaction, which was also observed in the transcriptome of irradiated murine TECs in vivo. This was confirmed at the protein level with higher expressions of the EC activation-associated proteins STING, NF-κβ, and VCAM-1 in irradiated HUVECs and irradiated TECs in vivo. Conclusions: IR induces changes in ECs and TECs, supporting their activation in dose- and time-dependent manners, potentially contributing to the anti-tumor immune response, which may potentially increase the infiltration of immune cells into the tumor and thus, improve the overall efficacy of RT, especially in combination with immune checkpoint inhibitors. Full article

Porcine deltacoronavirus (PDCoV), an emerging enteropathogenic coronavirus, has inflicted substantial economic losses on the global swine industry. While the severity of infectious disease depends on the dynamic interplay between inoculum dose and host response, the molecular mechanism by which PDCoV dose modulates host immunity remains unclear. Hence, we systematically compared the transcriptomic changes in intestinal epithelial cells infected with different doses of PDCoV, and investigated the relationships between inoculum dose, host immune responses, and disease progression. PDCoV replication peaked at 24 h post-infection, and host responses showed a distinct dose-dependent pattern, with high-dose infection inducing more extensive transcriptional remodeling than low-dose infection. Both doses significantly activated the transcription of STAT1 and its downstream interferon-stimulated genes, while high-dose infection additionally triggered a cytokine storm characterized by excessive IL-6 and TNF-α expression. Functional validation demonstrated that STAT1 overexpression markedly inhibited PDCoV infection by enhancing ISRE promoter activity, and overexpression of its downstream ISG15 and MX2 also exerted independent and significant antiviral effects. These findings reveal the biphasic nature of PDCoV dose-dependent regulation of immunopathological mechanisms and identify STAT1 and specific ISGs (ISG15, MX2) as potent antiviral effectors, providing crucial insights into PDCoV pathogenicity and offering promising targets for developing immunomodulatory therapeutics or vaccines to control PDCoV outbreaks in swine. Full article