Search Results (3,688)

Ring finger protein 126 (RNF126) is a RING-type E3 ubiquitin ligase that has recently emerged as a multifaceted regulator of cellular homeostasis, stress adaptation, and disease progression. Through its structurally distinct zinc-finger and catalytic RING domains, RNF126 orchestrates substrate recognition and ubiquitin transfer, generating diverse ubiquitin linkages with both proteolytic and nonproteolytic functions. Initially characterized as a component of the protein quality control (PQC) machinery, RNF126 cooperates with chaperones such as BAG6 and UBQLN1 to eliminate mislocalized and misfolded proteins, thereby maintaining proteostasis. Beyond PQC, RNF126 plays pivotal roles in DNA damage response pathways by regulating homologous recombination, non-homologous end joining, checkpoint signaling, and genome stability through substrates, including MRE11, Ku80, RNF168, and 14-3-3σ. Genetic studies have further demonstrated its importance in embryogenesis and male fertility, and accumulating evidence has identified RNF126 as a critical driver of malignancy in multiple cancers. RNF126 promotes tumor progression by degrading or modulating key regulators, such as p21, PTEN, p53, PDKs, and LKB1, thereby enhancing proliferation, metabolic reprogramming, anoikis resistance, metastasis, and chemo/radioresistance. Intriguingly, RNF126 exhibits context-dependent functions, acting as an oncogene or tumor suppressor depending on the tissue type and substrate selection. In addition to cancer, RNF126 has been implicated in neurodegeneration, cardiac pathology, antiviral immunity and adaptive immune regulation. This review summarizes the current knowledge of RNF126 structure, ubiquitin signaling mechanisms, physiological functions, and pathological roles, while discussing emerging therapeutic strategies and future challenges for targeting RNF126 in precision medicine. Full article

Respiratory syncytial virus (RSV) remains a major cause of severe respiratory disease worldwide, particularly affecting young children and immunocompromised individuals, highlighting the need for additional therapeutic strategies. In this study, the antiviral activity of the Petasites hybridus extract Ze 339 was investigated in RSV-infected cell-culture models. Antiviral efficacy was assessed using plaque reduction assays, reporter virus analyses, and proteomic profiling to elucidate potential mechanisms of action. Ze 339 potently reduced the infectivity of both RSVA and RSVB in vitro and retained antiviral activity when administered up to six hours post-infection, resulting in markedly reduced plaque formation and viral protein biosynthesis without inducing cytotoxicity. Proteomic analyses revealed that Ze 339 modulates host cell pathways associated with reduced cell proliferation, attenuated immune signaling, and enhanced cholesterol and lipid metabolism. These changes were more pronounced in infected than in uninfected cells and coincided with a marked downregulation of viral proteins. The observed proteomic signature suggests a host-directed antiviral effect and identifies altered lipid metabolism and cell-cycle-associated pathways as potential contributors to reduced RSV replication. Taken together, these findings demonstrate the antiviral activity of Ze 339 against RSV and support the hypothesis that modulation of host cell pathways contributes to its antiviral effects, providing a rationale for further evaluation of Ze 339 as a repurposed therapeutic candidate for RSV infection. Full article

Pollen constitutes the primary source of proteins, amino acids, lipids, sterols, vitamins, and minerals for honey bees. However, not all pollen types provide the same resources or have the same biological value. Its chemical composition changes according to botanical origin, geographic location, and environmental conditions. This variability can influence metabolism, the immune system, oxidative balance, and the ability to resist or tolerate infections. This article examines the available evidence on the relationship between pollen chemical quality and the dynamics of Deformed Wing Virus (DWV) infection in Apis mellifera. The analysis is approached from molecular, physiological, ecological, and seasonal perspectives. Current findings suggest that more diverse and higher-quality pollen diets are generally associated with greater colony survival and improved health status, although their effects on viral load are more heterogeneous and context-dependent. In some studies, pollen intake is linked to a reduction in DWV, whereas in others viral loads remain stable or even increase despite improvements in survival, physiological condition, or colony performance. These differences suggest that pollen may act not only by enhancing resistance to the virus but also by increasing tolerance to infection-associated damage. The potential role of pollen bioactive compounds, particularly flavonoids and phenolic acids, is also discussed. Nevertheless, evidence of direct antiviral action of these compounds in bees remains limited, as many proposed mechanisms derive from other organisms. This synthesis provides an integrative perspective on pollen nutrition and its relevance for colony resilience against viral infections. Full article

Gold nanoparticles (AuNPs) have emerged as versatile antiviral nanoplatforms because their size, morphology, plasmonic properties, and surface chemistry can be precisely engineered. In this review, we summarize the core design principles of antiviral AuNPs from a structure–function–mechanism perspective. We first outline representative synthetic and interface-programming routes for AuNP preparation, including citrate reduction, Brust–Schiffrin synthesis, seed-mediated growth, green synthesis, direct thiol-conjugation, and mixed-ligand shell strategies, emphasizing how these approaches define particle size, morphology, surface accessibility, interfacial composition, and downstream biofunctionalization potential. We then discuss major surface engineering strategies, including polyethylene glycol, nucleic acids, antibodies and nanobodies, peptides, glycans, antiviral drugs, and biomimetic coatings, with particular attention to how ligand density, orientation, flexibility, and interfacial stability determine biological performance. Next, we examine how functionalized AuNPs inhibit different stages of the viral life cycle, including viral attachment and entry, intracellular replication, assembly and egress, photothermal inactivation, and immune modulation or vaccine delivery. Finally, we highlight current challenges, including incomplete structure–activity relationships, dynamic nano–bio interactions under physiological conditions, limited standardization across studies, and translational barriers related to safety, reproducibility, and scale-up. This review provides a conceptual framework for the rational development of next-generation AuNP-based antiviral nanotherapeutics. Full article

Interferons (IFNs) play vital roles in antiviral immunity, yet the functional diversity of type I IFNs in teleosts remains incompletely characterized. In this study, we identified and characterized a group II type I interferon, designated IFNc (MsIFNc), from largemouth bass (Micropterus salmoides). The cDNA sequence of MsIFNc is 660 bp in length, encoding a 184-amino-acid polypeptide containing a signal peptide and four conserved cysteines predicted to form two disulfide bonds. Phylogenetic analysis confirmed its classification within the teleost IFNc subgroup. Tissue expression profiling revealed constitutive MsIFNc transcription in all examined tissues, with the highest levels in the liver, intestine, and spleen. Moreover, MsIFNc expression was significantly upregulated in the spleen following polyinosinic–polycytidylic acid (polyI:C) stimulation. Recombinant MsIFNc (rMsIFNc) was successfully expressed in Pichia pastoris and significantly enhanced the viability of primary hepatocytes infected with Micropterus salmoides rhabdovirus (MSRV). These results demonstrate that IFNc is an important component of the immune response in largemouth bass, providing a basis for understanding the function of fish IFNc. Full article

Crimean–Congo hemorrhagic fever virus (CCHFV) remains a major public health threat due to its high mortality rates and the absence of approved antiviral therapies. The viral ovarian tumor (OTU) protease is a critical virulence factor that suppresses host innate immunity through its deubiquitinase activity, making it an attractive therapeutic target. In this study, we employed a structure-guided approach to identify and validate novel small-molecule inhibitors targeting the non-catalytic Y89-W99 pocket of the OTU protease. Recombinant OTU protease was successfully expressed, purified, and refolded, yielding a soluble and enzymatically active protein. Cellular assays confirmed that the enzyme retains robust deubiquitinase activity, significantly reducing global ubiquitin conjugates in mammalian cells. In silico analysis of a putative DUB inhibitor library identified several candidate inhibitors with favorable binding interactions within the Y89-W99 pocket. Biochemical validation using a fluorometric Ub-AMC assay revealed that multiple small molecules strongly inhibit OTU activity, including OTUi-10 (~93% inhibition), OTUi-13 (~87%), OTUi-1 (~85%), OTUi-4 and OTUi-11 (~81%), and OTUi-9 (~76%). Additional moderate inhibitors included OTUi-12 (~67%), OTUi-19 and OTUi-21 (~66%), and OTUi-5 (~57%). In silico drug-likeness and toxicity profiling filtered the library to four fully compliant candidates, OTUi-4, OTUi-10, OTUi-11, and OTUi-12, all free of predicted toxicity alerts. These findings suggest that the Y89–W99 pocket may be a pharmacologically relevant site worthy of further investigation and identify OTUi-10, OTUi-4, and OTUi-11 as promising preliminary hit compounds. The results also provide initial insights that may guide future optimization and mechanistic studies of OTU protease inhibitors targeting CCHFV. Full article

Viral myocarditis (VMC), predominantly driven by Coxsackievirus B3 (CVB3) infection and the resultant excessive immune response, lacks effective treatments and specific antiviral drugs in clinical practice. Chlorogenic acid (CGA) has been proven to have significant antiviral and anti-inflammatory properties. This study evaluated the potential and mechanism of action of CGA against CVB3-induced viral myocarditis. Our research results showed that CGA significantly alleviated myocardial tissue damage in vivo. This protective effect was accompanied by effective inhibition of myocardial inflammatory responses and viral replication. Further in vitro experiments confirmed that CGA significantly inhibited the replication of CVB3 in a dose-dependent manner, and its inhibitory effect mainly targeted the replication stage of the viral life cycle. Mechanistically, CGA treatment correlates with reduced ZBP1 expression and accelerated ZBP1 degradation involving the ubiquitin–proteasome pathway, accompanied by suppressed activation of PANoptosis markers. These findings suggest that CGA alleviates CVB3-induced myocarditis through concerted antiviral and anti-inflammatory effects, with ZBP1-mediated PANoptosis as a potential contributing mechanism. Full article

Dengue virus (DENV) and chikungunya virus (CHIKV) co-circulate in many regions and present with overlapping clinical features, which complicate accurate diagnosis and disease management. This study develops an integrative transcriptomic framework to identify robust host gene signatures that distinguish between dengue, chikungunya, and healthy states. Publicly available RNA sequencing (RNA-seq) datasets derived from human blood samples were analyzed using a cross-validation design to ensure robustness and prevent information leakage. Differential expression analysis was performed independently within each dataset using the Generalized Linear Models with Quasi-Likelihood F-tests and Magnitude–Altitude Scoring (GLMQL-MAS) framework, followed by Cross-Magnitude–Altitude Scoring (Cross-MAS) integration to identify shared and virus-specific gene signatures. A strict consensus approach across folds was applied to derive reproducible gene sets. These signatures were used for dimensionality reduction and multinomial logistic regression to evaluate classification performance. A small subset of selected genes showed strong discriminative performance within the cross-validation framework, with test balanced accuracy reaching 0.97, which improved upon models using all genes. Biologically, both infections exhibited a shared antiviral response characterized by interferon signaling and innate immune activation. However, distinct virus-specific patterns were identified. Dengue infection was associated with cell-cycle and DNA replication pathways, while chikungunya infection showed stronger enrichment of inflammatory and immune signaling pathways, including NF-kappaB and Toll-like receptor signaling. Overall, this study provides a cross-validation-based framework for integrative transcriptomic analysis and identifies compact, reproducible host-response signatures with strong discriminative signals in the analyzed cohorts. These signatures require validation in larger independent cohorts before any clinical or diagnostic application. Full article

O’nyong-nyong virus (ONNV) is a mosquito-borne alphavirus responsible for large-scale epidemics in sub-Saharan Africa. As the closest evolutionary relative of Chikungunya virus (CHIKV), ONNV shares substantial genetic similarity and overlapping clinical manifestations with CHIKV. Mechanistic understanding of ONNV infection has therefore largely been extrapolated from CHIKV rather than directly established. However, ONNV exhibits distinct biological features, including predominant transmission by Anopheles mosquitoes and a clinical presentation characterized by prominent lymphadenopathy with limited acute joint edema. These distinctions underscore the need for an integrated synthesis of experimentally validated determinants of ONNV infection. In this review, we summarize current evidence on molecular and immunological factors regulating ONNV infection in mammalian hosts and mosquito vectors. We first discuss species-specific viral clearance, host dependency factors, intrinsic antiviral restriction mechanisms, protective innate immunity, inflammatory pathology, and mechanism-informed therapeutic strategies in mammalian hosts. We then examine stage-specific immune regulation in Anopheles mosquitoes, emphasizing mechanisms that constrain viral replication while permitting persistent infection and transmission. Finally, we discuss nsP3-dependent vector specificity and the potential contribution of alternative mosquito species to ONNV ecology. Together, this review provides an integrated framework for understanding how host factors, immune responses, and vector-specific adaptations shape ONNV infection, pathogenesis, and transmission. Full article

Type I interferons (IFN-I), including IFN-α, IFN-β, and IFN-ω, are central to antiviral defence and immune regulation. Autoantibodies targeting IFN-I (anti-IFN-I AAbs) have emerged as key pathogenic factors in severe coronavirus disease 2019 (COVID-19) and are detectable in systemic lupus erythematosus (SLE), a prototypic IFN-driven autoimmune disease. Here we compare the prevalence and clinical impact of anti-IFN-I autoantibodies (Aabs) in COVID-19 and SLE based on a structured review of 53 studies from 2014 to 2025 and highlight the clinical associations and therapeutic opportunities presented by these autoantibodies. In COVID-19, neutralising anti-IFN-α and/or anti-IFN-ω AAbs were consistently associated with severe disease and impaired antiviral responses, particularly in older male populations. In SLE, anti-IFN-α AAbs were variably detected; neutralising antibodies were associated with reduced interferon gene signatures in some cohorts but inconsistent correlations with disease activity. Therapeutically, anti-IFN-I AAbs in COVID-19 may inform risk stratification and early antiviral strategies, whereas in SLE, IFN-α blockade, including IFN-α kinoid vaccination, demonstrates modulation of IFN signatures but variable clinical benefit. Notably, these findings reveal an immunological paradox: the same neutralising mechanism that impairs antiviral defence in COVID-19 may attenuate chronic IFN-driven inflammation in SLE. Taken together, anti-IFN-I AAbs exert context-dependent effects: pathogenic in acute viral infection yet potentially modulatory in chronic IFN-driven autoimmunity. Prospective longitudinal studies are required to further clarify their translational utility and long-term clinical impact. Full article

Background and Aims: TDF is a first-line antiviral for CHB with pleiotropic effects including immunomodulation and fibrosis regression, but its virus-independent mechanisms are unclear. This study delineates TDF’s direct molecular and metabolic landscape in vivo using multi-omics. Methods: Wild-type mice received TDF or vehicle for 4 months. Liver tissues underwent RNA-seq and targeted metabolomics, followed by integrative systems biology. Results: TDF caused no hepatotoxicity but induced transcriptomic reprogramming: broad upregulation of immune/inflammatory pathways and suppression of metabolic pathways. Metabolomics confirmed perturbations in amino acid and fatty acid homeostasis. Multi-omics revealed coordinated downregulation of arginine/proline, alanine/aspartate/glutamate, and phenylalanine metabolism, restricting fibrogenic amino acids. TDF also suppressed the TCA cycle (downregulating Idh, Sdh, and Mdh), suggesting a metabolic bottleneck that was associated with paradoxically accumulated succinate and oxoglutarate—immunomodulatory danger signals. Conclusions: This first integrated atlas shows TDF actively remodels the hepatic microenvironment independent of viral infection, bridging metabolic suppression with immune activation. These findings provide an immunometabolic framework that offers new perspectives for understanding the clinical application of TDF and identifies potential biomarkers for CHB therapy. explaining TDF’s clinical superiority and identifying potential biomarkers for CHB therapy. Full article

C-type lectins (CTLs) are proteins with carbohydrate-recognition domains. These macromolecules interact with pathogen components, thereby playing important roles in the immune system. Current studies indicate that silkworm CTLs are involved in Bombyx mori nucleopolyhedrovirus (BmNPV) infection. Nevertheless, the molecular mechanisms through which these CTLs affect viral infection remain unclear. In this study, B. mori C-type lectin 16 (BmCTL16) was identified in the silkworm. Its expression was significantly downregulated upon BmNPV infection. Functional assays showed that BmCTL16 overexpression suppressed BmNPV proliferation, whereas its knockdown enhanced BmNPV proliferation. Protein–protein interaction assays confirmed that BmCTL16 interacts with BmNPV protein Bm9 in the cytoplasm. Notably, BmCTL16 promoted the degradation of Bm9 via the ubiquitin–proteasome system. Knockdown of Bm9 by siRNA significantly reduced BmNPV proliferation, confirming that Bm9 is the key target for BmCTL16 to exert its antiviral function. Collectively, this study reveals a novel CTL-mediated antiviral mechanism. BmCTL16 interacts with Bm9 and promotes its ubiquitin–proteasome degradation, thereby inhibiting viral proliferation. Furthermore, BmNPV evades this host defense by downregulating BmCTL16 expression. These findings enhance our understanding of silkworm CTL-mediated antiviral defense and offer novel perspectives on host–virus interactions in B. mori. Full article

Mitochondria are central hubs of antiviral immunity and cellular metabolism, yet the links between SARS-CoV-2–induced mitochondrial remodeling, antiviral gene regulation, and post-translational control remain incompletely understood. Here, we investigated mitochondrial–immune remodeling in SARS-CoV-2–infected lung-derived LC-HK2 cells at 48 and 96 h post-infection using confocal and high-content imaging, colocalization analysis, CellProfiler quantification, RT-qPCR, proteomics, cytokine profiling, and conditioned-medium analysis. Infection induced a time-dependent mitochondrial phenotype. At 48 hpi, cells displayed early mitochondrial stress and fission-associated signatures, including increased DRP1, transient upregulation of mitochondrial respiratory genes, and reduced MFN1/2. At 96 hpi, mitochondria shifted toward elongated perinuclear networks, accompanied by increased fusion/biogenesis markers and partial ISG15–MFN2 colocalization, indicating a spatial association between ISG15-related antiviral/stress responses and mitochondrial remodeling. Antiviral and ISG-related transcripts were consistently upregulated, but IFN-α2 secretion remained limited, suggesting partial uncoupling between antiviral transcriptional activation and downstream interferon output. SUMO2/3 was dynamically modulated and showed time-dependent colocalization with mitochondrial dynamics proteins and MAVS. Together, these data support a coordinated mitochondrial–immune regulatory axis involving mitochondrial remodeling, ISG15-associated responses, and SUMO-dependent regulation during SARS-CoV-2 infection. Full article

Interferons (IFNs) are antiviral cytokines that serve as key mediators of the innate immune response, and their production is induced in the majority of cells within hours of pathogen entry. IFNs are predominantly produced by pathogen-infected cells; however, their antiviral effects extend to surrounding cells through autocrine and paracrine signaling mechanisms, inducing the transcription of hundreds of antiviral genes. Numerous gene products either interfere directly with viral replication or play regulatory roles that influence the progression and strength of the ensuing immune response. Viruses, on the other hand, have devised techniques to circumvent the host antiviral immune response and establish infection. This review focuses on the current state of evidence demonstrating how certain viral proteins block antiviral responses via immunomodulatory strategies and discusses how to overcome these immune evasion tactics. Full article

The influenza A virus (IAV) has been responsible for multiple seasonal epidemics and poses a pandemic threat, and the growing number of variant strains constitutes a persistent threat to humanity. This study aimed to identify anti-influenza compounds from a traditional Chinese medicine (TCM) monomer library using a machine learning approach, with calmodulin as a hypothesis-driven target. The antiviral efficacy of the compounds with the highest predicted binding scores from virtual screening was evaluated using integrated computational and experimental approaches. A pre-trained protein language model (ConPLex) was employed for virtual screening. Molecular docking was used to predict binding characteristics, and network pharmacology was applied to generate hypotheses on multi-target mechanisms. The cytotoxicity and anti-H1N1 activity of the selected compounds were assessed in vitro, followed by in vivo evaluation of survival, lung pathology, viral load, and inflammatory mediators in a lethal mouse infection model. Sodium deoxycholate (NaDC) and deoxycholic acid (DCA) were identified as promising lead compounds. Both exhibited dose-dependent inhibition of viral replication in vitro with low cytotoxicity. Treatment with NaDC and DCA significantly improved survival rates and reduced lung pathology in H1N1-infected mice. Treatment was associated with suppression of nuclear factor kappa-B (NF-κB) activation, reduced pro-inflammatory cytokines, and elevated interleukin-10 (IL-10) levels. Molecular docking predictions indicated that NaDC and DCA exhibit moderate binding affinity for calmodulin, with binding energies of −8.38 kcal/mol and −7.61 kcal/mol, respectively. Furthermore, network pharmacology analysis suggested that these compounds may modulate pathways related to viral infection, inflammation, and immune regulation. NaDC and DCA demonstrate anti-influenza activity both in vitro and in vivo, reducing viral replication and alleviating inflammatory lung injury. These findings position NaDC and DCA as promising lead compounds for anti-influenza drug development and provide a foundation for further mechanistic validation. Full article