Search Results (886)

Chronic pain is a major cause of disability worldwide, impacting around 20% of adults globally. Conventional mu-opioid peptide (MOP) receptor agonists provide effective analgesia; however, their prolonged use is restricted by severe dose-limiting toxicities such as opioid-induced respiratory depression, analgesic tolerance, hyperalgesia, physical dependence, and addiction. The goal of this narrative literature review was to compile the available data on NOP receptor-targeted analgesics, with a focus on dual NOP/MOP agonists and cebranopadol. The pharmacological mechanisms, preclinical and clinical evidence, safety profile, and potential therapeutic role in pain management were all highlighted. The nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor system has been identified as a new pathway for managing pain through mechanisms that differ from those of classical opioid signaling. The NOP receptor is a Class A G-protein-coupled receptor (GPCR) that preferentially couples to inhibitory G(i/o) proteins. Upon activation, it suppresses adenylyl cyclase activity, lowers intracellular cyclic adenosine monophosphate (cAMP) levels, blocks voltage-gated calcium channels, and activates G-protein-gated inwardly rectifying potassium channels, thereby hyperpolarizing neurons and decreasing excitatory neurotransmitter release. NOP receptors are anatomically distributed throughout the peripheral and central nervous systems, including primary afferent sensory neurons, dorsal root ganglia, spinal dorsal horn, periaqueductal gray, rostral ventromedial medulla, central amygdala, ventral tegmental area, and nucleus accumbens. NOP activation via these pathways offers significant pain relief in acute nociception, as well as in chronic inflammatory and neuropathic pain conditions. Supraspinal activation of NOP within the mesocorticolimbic pathway influences the emotional aspect of pain by reducing corticotropin-releasing factor signaling and decreasing mesolimbic dopamine release. NOP agonism effectively provides analgesia while also attenuating drug reward and reinforcement. The development of pharmaceuticals utilizing NOP agonism has progressed from endogenous peptide analogues to selective non-peptide agonists, and more recently to bifunctional NOP/MOP (dual NMR) agonists, such as the dual NOP/MOP agonist cebranopadol, which has passed Phase I–III clinical testing. There are still significant questions about long-term safety, comparative efficacy, and the interpretation of unpublished or preliminary Phase III results, despite the fact that available clinical trials indicate analgesic efficacy with perhaps decreased respiratory and abuse-related effects. This drug achieves equianalgesic efficacy through potent dual NOP/MOP activation while significantly reducing the risk of respiratory depression and drug-liking. However, clinical translation of NOP receptor agonism is hindered by several challenges, including supraspinal pronociceptive paradoxes, species-specific pharmacology, dose-dependent sedation, and regulatory complexities associated with mixed-mechanism ligands. NOP-targeted therapies represent a promising approach for the development of next-generation, opioid-sparing analgesics in pain medicine. Full article

Cellular senescence is characterized by stable cell-cycle arrest and a senescence-associated secretory phenotype (SASP). Recurrent desiccating, oxidative, ultraviolet, microbial, and immune-mediated insults may induce stress-induced premature senescence (SIPS) in ocular surface tissues. PubMed and Web of Science were searched from database inception to 30 June 2026. Primary human, animal, and in vitro studies were prioritized, and direct evidence of senescence was distinguished from indirect stress-related or SASP-like associations. The p53–p21^CIP1–pRB and p16^INK4a–pRB pathways mediate senescence-associated cell-cycle arrest. Reactive oxygen species (ROS)–p38 mitogen-activated protein kinase (p38 MAPK) and cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling act as stress-sensing and inflammatory pathways, whereas mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) contribute to SASP and metabolic regulation. Transient senescence may support wound repair and immune clearance, whereas persistent senescence may contribute to epithelial and endothelial dysfunction, tear-film instability, immune dysregulation, fibrosis, and extracellular matrix remodeling. Mechanistic support is strongest in selected experimental models; evidence in several human ocular surface disorders remains associative. Cellular senescence is a context-dependent contributor to ocular surface pathology. Senolytic and senomorphic strategies remain predominantly preclinical and require disease-, cell-, and stage-specific validation. Full article

Temperature is a critical environmental factor affecting fungal growth, morphogenesis, and reproduction. Schizophyllum commune, a model basidiomycete fungus, exhibits remarkable developmental plasticity under environmental fluctuations; however, the mechanisms underlying its adaptation to low-temperature conditions remain poorly understood. In this study, we show that low-temperature stress inhibited mycelial growth, delayed fruiting body development and basidiospore germination, and promoted chitin accumulation and chitin synthase genes (CHS) expression in S. commune 20R-7-F01. Low-temperature exposure triggered transient oxidative stress, followed by restoration of antioxidant capacity during acclimation. Mechanistically, mitogen-activated protein kinase (MAPK) inhibition impaired mycelial growth, whereas 3′-5′-cyclic adenosine monophosphate (cAMP) content increased under low-temperature stress, suggesting the involvement of cAMP signaling in the low-temperature response. Moreover, low-temperature exposure was associated with increased mycelial calcium (Ca²⁺) content, and Ca²⁺ chelation was accompanied by impaired cell membrane integrity and altered cell wall ultrastructure. Collectively, our findings suggest that the adaptation of S. commune 20R-7-F01 to low temperature is associated with Ca²⁺ content, cell integrity, antioxidant defense, MAPK, and cAMP. These results provide new insights into the molecular basis of fungal low-temperature acclimation. Full article

Cryo-electronmicroscopy has revolutionized the study of integral membrane proteins. In the case of adenylyl cyclase 9 (AC9)—one of nine transmembrane paralogues in mammals that produce the ubiquitous intracellular messenger cyclic AMP—the technique was instrumental in revealing the structural basis of a biological paradox, namely, that AC9 is strongly autoinhibited when in a complex with its physiological stimulus, receptor-activated Gsα. Furthermore, AC9 is also insensitive to inhibitory G proteins because it lacks the requisite binding pocket. As AC9 is widely distributed in the body, this regulatory conundrum has potentially broad implications. However, deletion of the adcy9 gene in mice causes a high level of pre-weaning lethality. Hence, our knowledge regarding the biological role of AC9 in mammals is rudimentary at best. In mammalian AC9, autoinhibition is modulated by post-translational modifications, including protein phosphorylation. However, AC9 has over 70 documented phosphorylations, the majority of them on serines in isoform-specific disordered domains. What is their functional relevance—if any? This paper reviews the current knowledge regarding the regulation of AC9, a maverick amongst transmembrane adenylyl cyclases. Full article

The escalating global burden of cardiovascular disease (CVD) necessitates a deeper elucidation of the fundamental molecular mechanisms driving its pathogenesis. Aberrant immune activation, specifically sterile inflammation, is now recognized as a core hallmark of CVD, predominantly ignited by the pathological accumulation of damaged self-DNA. As the principal cytosolic DNA sensor, the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway has emerged as a crucial mechanistic nexus translating genomic distress into robust innate immune responses. Despite its paramount importance, a comprehensive integration of how DNA damage-induced cGAS-STING activation orchestrates cardiovascular immunology remains underexplored. In this review, we comprehensively synthesize the dynamic immunological landscape of CVD, with a specific focus on the critical interplay between DNA damage and sterile inflammation. We delineate the intricate molecular cascades of the cGAS-STING pathway across diverse cardiovascular pathologies and critically evaluate its role as a master amplifier of disease progression. Furthermore, we highlight the translational trajectory of targeting the cGAS-STING axis, emphasizing how deciphering this DNA damage-immune network provides a rational blueprint for developing precision immunomodulatory therapies in cardiovascular medicine. Full article

Jujube polysaccharides (ZJPA) and cyclic adenosine monophosphate (cAMP) are bioactive compounds with antioxidant and health-promoting potential, and their combination exhibits enhanced antioxidant activity. However, their limited stability and susceptibility to gastrointestinal environmental stresses restrict their applications in functional foods. In this study, a pH-responsive composite hydrogel bead delivery system was developed using chitosan (CS) and sodium alginate (SA) as wall materials to co-encapsulate ZJPA and cAMP, aiming to protect these bioactive compounds during gastrointestinal digestion while maintaining their enhanced functionality. The hydrogel beads were fabricated via the ionotropic gelation method, and the formulation parameters were optimized using single-factor experiments combined with response surface methodology (RSM). The optimized hydrogel beads were obtained under the conditions of calcium chloride concentration of 3%, CS concentration of 0.5%, SA concentration of 3%, and core-to-wall ratio of 1:6, with a cAMP microencapsulation yield (MEY) of 97.79%. Structural characterization confirmed that ZJPA and cAMP were successfully incorporated into the CS-SA network through electrostatic interactions and intermolecular hydrogen bonding without the formation of new covalent bonds. Furthermore, the hydrogel beads exhibited distinct pH-responsive swelling and gastrointestinal release behaviors, providing effective protection under acidic gastric conditions and enabling sustained release under intestinal conditions. Importantly, the DPPH radical scavenging assay demonstrated that the co-encapsulation strategy preserved the enhanced antioxidant activity between ZJPA and cAMP. Overall, this study establishes a multifunctional hydrogel bead delivery strategy integrating enhanced bioactivity preservation, gastrointestinal protection, and controlled release, providing new opportunities for the application of jujube-derived bioactive compounds in functional foods. Full article

Background and Objectives: Liver regeneration following partial hepatectomy (PHx) is essential for restoring hepatic function. Polydeoxyribonucleotide (PDRN), an adenosine A_2A receptor (A_2AR) agonist, has demonstrated regenerative and proangiogenic properties in various tissues. However, its therapeutic potential for promoting liver regeneration after PHx has not been fully elucidated. The primary objective was to evaluate the effect of PDRN on liver regeneration after PHx, and the secondary objective was to examine associated changes in proliferation-related proteins and A_2AR/cAMP, HGF/c-Met, and VEGF/VEGFR2 signaling. Materials and Methods: A rat model of 70% PHx was established, and PDRN (8 mg/kg) was administered intraperitoneally once daily for 5 consecutive days with or without the A_2AR antagonist 3,7-dimethyl-1-propargylxanthine (DMPX; 8 mg/kg). Liver regeneration was evaluated using biochemical, histological, and molecular analyses. Results: PDRN enhanced liver regeneration following PHx, as demonstrated by reduced serum liver enzyme levels, enhanced recovery of liver mass, and improved histological architecture. PDRN also increased the expression of the proliferation-associated proteins proliferating cell nuclear antigen (PCNA) and cyclin D1. These effects were accompanied by increased A_2AR expression and cyclic adenosine monophosphate (cAMP) levels, elevated hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) levels, and enhanced phosphorylation of c-Met and VEGFR2. Co-administration of DMPX attenuated the regenerative and molecular effects of PDRN, suggesting a potential involvement of A_2AR-related signaling. Conclusions: Collectively, these findings suggest that PDRN may facilitate liver regeneration following PHx in association with increased expression of proliferation-associated proteins and changes in HGF/c-Met and VEGF/VEGFR2 signaling, supporting its potential as a therapeutic strategy following hepatic resection. Full article

Hydrogels used for fracture sealing during heavy-oil thermal recovery are repeatedly exposed to high-temperature steam, dehydration, pressure disturbance, and cooling, conditions that often lead to progressive network deterioration and loss of sealing efficiency. To address this limitation, a thermally triggered self-reinforcing covalent–physical double-network nanocomposite hydrogel was developed by combining a sparse MBAA-crosslinked P(NaAMPS-co-NVP-co-AM) covalent scaffold with a reversible Laponite-mediated physical network. The material response was systematically evaluated through cyclic hydrothermal treatment at 180 °C, while fracture-sealing and resealing performance was examined separately under steam-exposure conditions. Artifact-controlled experiments were further introduced to distinguish genuine cycle-induced reinforcement from dehydration, continued post-curing, and conventional thermal aging. The results show that the NaAMPS/NVP/AM molar ratio of 40/20/40 with 1.00 wt% Laponite provided a suitable balance between precursor processability, hydrothermal stability, and mature network stiffness. After five thermal cycles at 180 °C, the storage modulus of the Lap-DN hydrogel increased from 74.4 to 89.1 kPa, while the compressive stress at 50% strain increased from 0.641 to 0.842 MPa, corresponding to reinforcement ratios of 1.198 and 1.314, respectively. Meanwhile, the mean equivalent pore diameter decreased from 6.2 to 4.8 μm, indicating progressive refinement of the load-bearing network. The hydrogel retained 76.3% of its initial water and 81.6% of its initial volume after five cycles in the reference brine and preserved a cycle-5 modulus retention of 101.3% even at 150,000 mg/L salinity. In fracture-sealing tests, Lap-DN sustained a breakthrough pressure of 3.47 MPa and reduced fracture conductivity by 92.4% in a 1.60 mm fracture. More importantly, the same sealing body maintained a breakthrough pressure of 4.55 MPa after five steam impact–recovery cycles in a 1.20 mm fracture, corresponding to 106.1% of the first-cycle value, while 95.0% of the pre-breakthrough pressure resistance was restored within 30 min of cooling. These results are consistent with a cycle-induced reorganization of the Laponite-mediated physical constraints within the permanent covalent scaffold, although the transient dissociation and reassociation of individual polymer–Laponite junctions were not directly observed. Within this evidence-based interpretation, cyclic thermal perturbation is associated with mechanical reinforcement and repeated fracture resealing rather than acting solely as a damaging factor. This work provides a materials-design strategy for hydrogel sealing systems operating under cyclic steam and high-salinity conditions. Full article

Herpes simplex encephalitis (HSE), predominantly caused by herpes simplex virus type 1 (HSV-1), is the most common sporadic viral encephalitis worldwide and remains life threatening despite antiviral therapy. Although herpes simplex virus (HSV) infection is highly prevalent, only a minority of individuals develop HSE, highlighting the critical contribution of host-specific factors to disease susceptibility. This review summarizes current knowledge regarding HSE epidemiology, antiviral immunity, genetic susceptibility, and therapeutic advances. Underlying inborn errors of immunity fall into three mechanistic groups: impaired innate immune sensing pathways, including Toll-like receptor 3 (TLR3), retinoic-acid-inducible gene-I (RIG-I)/melanoma differentiation-associated gene 5 (MDA5), and cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING), which compromise type I interferon (IFN) production in central nervous system (CNS) resident cells; disrupted neuron intrinsic antiviral mechanisms represented by mutations in specific genes (e.g., DBR1, SNORA31, and GTF3A); and defects in other IFN signaling molecules, including interferon-α/β receptor 1 (IFNAR1) and 2 (IFNAR2), as well as signal transducer and activator of transcription 1 (STAT1) and 2 (STAT2), which further weaken antiviral defenses. These findings underscore cell autonomous antiviral responses within the brain and provide insights into the selective vulnerability to HSE. Emerging therapeutic strategies aim to integrate antiviral treatment with modulation of host immune responses and, potentially, personalized approaches based on genetic profiling. In all, we emphasize the pivotal role of CNS-intrinsic immunity and host genetic factors in shaping disease outcomes. A deeper understanding of the interplay between HSV and host defense mechanisms will facilitate the development of improved diagnostic tools and targeted therapies, ultimately reducing the burden of this devastating disease. Full article

(1) Background: Seasonal breeding constraints represent a long-standing barrier to efficient sheep production worldwide. Small Tail Han sheep, a Chinese indigenous breed that exhibits year-round estrus independent of photoperiod, offers a unique natural model for investigating the regulatory mechanisms underlying estrus cyclicity—yet the molecular basis of this remarkable trait remains largely unexplored. This study therefore aimed to compare ovarian whole-transcriptome profiles between Small Tail Han sheep (year-round estrus) and Ujumqin sheep (seasonal estrus) during estrus and diestrus. Specifically, we sought to characterize breed-specific transcriptional response strategies, identify key miRNAs associated with continuous estrus, and construct ceRNA networks that mediate ovarian estrous cycle regulation. (2) Methods: To address these objectives, we profiled ovarian transcriptomes of Small Tail Han sheep (year-round estrus) and Ujumqin sheep (seasonal estrus) during both estrus and diestrus (12 samples total) using whole-transcriptome sequencing, systematically characterizing the expression landscapes of mRNAs, miRNAs, lncRNAs and circRNAs. Through differential expression analysis, GO/KEGG functional enrichment, multi-tiered miRNA screening, and ceRNA network construction, we compared the transcriptional response strategies between the two breeds. (3) Results: Our findings revealed two unexpected and divergent patterns. Small Tail Han sheep showed 1881 differentially expressed mRNAs between estrus and diestrus, 82-fold more than the 23 in Ujumqin sheep, suggesting a broader mRNA-level transcriptional response in the year-round estrus breed. circRNAs were predominantly up-regulated (80–85%) in both breeds, while mRNAs and lncRNAs were predominantly down-regulated, uncovering a conserved “circRNA-up, mRNA-down” regulatory logic across breeds. Multi-tiered screening identified 38 “brake-releaser” miRNAs (high in diestrus, down-regulated in estrus) and 21 “accelerator” miRNAs (low in diestrus, up-regulated in estrus), which together constitute a “de-repression–activation” dual regulatory mode. ceRNA network analysis further revealed a clear functional stratification: conserved core miRNAs targeted “sensor” pathways (cAMP, PI3K-Akt, MAPK), whereas accelerator miRNAs specifically targeted “executor” pathways (estrogen signaling, progesterone-mediated oocyte maturation, Hippo signaling). Network topology analysis pinpointed miR-199a-5p, miR-204-3p and miR-199b as the core hubs bridging the two regulatory modules. (4) Conclusions: Taken together, our findings redefine the molecular basis of year-round estrus—moving beyond single-gene mutations or overexpression to an enhanced global transcriptomic responsiveness of the ovary. This work provides a fresh conceptual framework for understanding the divergence of reproductive strategies in sheep and offers actionable candidate targets for genetic improvement of continuous estrus traits. Full article

Age-related decline in learning and memory functions poses significant challenges in an aging society, with epigenetic dysregulation emerging as a key contributor to cognitive deterioration. As the most prevalent internal RNA modification, N6-methyladenosine (m6A) dynamically orchestrates neural transcriptome plasticity through its “writers,” “erasers,” and “readers,” yet its role in aging-associated cognitive impairment remains underexplored. This study employs an integrated epitranscriptomic approach to investigate m6A-mediated regulation in hippocampal aging processes. Through comparative m6A-mRNA epitranscriptomic microarray analysis of senescence-accelerated mouse prone 8 (SAMP8) and senescence-resistant SAMR1 hippocampi, we identified neural cell adhesion molecule 1 (NCAM1) as a key m6A-regulated effector whose decreased expression correlates with accelerated cognitive deterioration. Mechanistically, we revealed that Methyltransferase-like 3 (METTL3)-mediated m6A modification governs Ncam1 mRNA stability through insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) reader protein-dependent mechanisms, forming a regulatory axis that modulates cyclic AMP response element-binding protein (CREB) signaling pathway activity. Remarkably, targeting of this METTL3/IGF2BP1/NCAM1 axis significantly attenuated cognitive deficits in aged SAMP8 mice. Our findings establish an m6A methylation-dependent paradigm for NCAM1-mediated cognitive preservation during aging, uncovering a novel epitranscriptomic layer in age-related neurodegeneration. Full article

Ageing is driven by chronic inflammation, oxidative stress, and stem cell exhaustion, posing a major global health challenge. Lactic acid bacteria (LAB) fermentation is being investigated as a potential biotechnology to enhance the bioavailability and functionality of natural products, especially polyphenols and bioactive phytochemicals with anti-ageing potential. This review synthesizes recent advances in LAB-fermented natural products and their roles in modulating longevity pathways and stem cell regeneration. LAB fermentation can alter complex plant matrices by releasing or biotransforming substrate-bound phytochemicals and by generating metabolites such as organic acids, peptides, and, in some systems, short-chain fatty acids (SCFAs), cyclic dipeptides (CDPs), or bacterial extracellular vesicles (BEVs); the contribution of each component requires case-specific verification. In cellular and animal models, candidate mechanisms include modulation of nuclear factor kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), and AMP-activated protein kinase–sirtuin 1 (AMPK–SIRT1) signaling, although causal active components are often unresolved. Some LAB-fermented preparations or LAB-derived components have been associated with stem-cell-related outcomes in skin, bone, and neural cell or animal models. CDPs and BEVs are candidate fermentation-associated mediators, but evidence for their independent effects on human ageing remains preliminary. Collectively, LAB-fermented natural products are a promising research area for functional foods and nutraceuticals, but their efficacy and safety for ageing-related outcomes require clinical validation. Future research should focus on standardizing fermentation conditions, identifying active metabolites, and validating their clinical efficacy in human studies. Full article

Glucagon-Like Peptide-1 (GLP-1) is an incretin family peptide hormone with significant therapeutic applications. This study evaluated multiple functional methodologies for assessing GLP-1 agonist biological activity, encompassing in vitro cell-based bioassays and in vivo systems. We developed and comparatively analyzed cell-based bioassays measuring distinct cellular signaling events, such as β-arrestin recruitment, cyclic adenosine monophosphate (cAMP) elevation, and calcium (Ca²⁺) mobilization. Each assay was systematically evaluated for robustness and quality control applicability. All assay systems demonstrated functionality independent of the cellular mechanism employed. Real-time Ca²⁺ flux measurements confirmed the cell-based assay endpoint data, while cross-verification analyses using the oral glucose tolerance test in mice confirmed the representativeness of the cAMP formats. Initial validation studies revealed inter-assay variations, leading to the selection of the cAMP HTRF assay as the preferred quality control methodology. Further assay refinement and subsequent validation studies confirmed the cAMP HTRF assay’s suitability for quality control applications. This methodology has been successfully implemented in routine release testing of a commercially available GLP-1 agonist. Full article

Background/Objectives: Polydeoxyribonucleotide (PDRN) has anti-inflammatory and tissue-protective properties associated with activation of the adenosine A_2A receptor (A_2AR). Although hepatoprotective actions of PDRN have previously been described, its potential association with high-mobility group box 1 (HMGB1)-related inflammatory responses and hepatic macrophage accumulation during acute liver injury (ALI) is not fully understood. This study examined whether PDRN affects HMGB1- and monocyte chemoattractant protein-1 (MCP-1)-associated responses together with hepatic macrophage accumulation in ALI. Methods: ALI was induced in ICR mice by carbon tetrachloride (CCl₄) administration. PDRN was administered either alone or together with the selective A_2AR antagonist 3,7-dimethyl-1-propargylxanthine (DMPX). Serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase were quantified. Histological alterations were evaluated using hematoxylin and eosin staining. Hepatic macrophage accumulation was assessed by F4/80 immunofluorescence staining. Enzyme-linked immunosorbent assays were used to quantify HMGB1, MCP-1, interleukin-10 (IL-10), cyclic adenosine monophosphate (cAMP), and A_2AR. Results: PDRN significantly reduced serum markers of liver injury and attenuated histopathological damage following CCl₄ administration. PDRN treatment also decreased F4/80-positive macrophage accumulation in the hepatic tissue. In addition, PDRN reduced HMGB1 and MCP-1 levels in both the serum and liver tissues while significantly increasing IL-10, cAMP, and A_2AR levels. Conclusions: PDRN attenuated CCl₄-induced ALI and was associated with reduced HMGB1 and MCP-1 levels, decreased hepatic macrophage accumulation, and increased A_2AR/cAMP signaling. These findings suggest that modulation of macrophage-associated inflammatory responses may contribute to the hepatoprotective effects of PDRN. Full article

Neurotropic viruses have evolved sophisticated mechanisms to evade host immune responses within the central nervous system (CNS), enabling viral replication, persistence, latency, and neuropathogenesis while minimizing irreversible neuronal damage. Unlike peripheral tissues, the CNS requires tightly regulated antiviral immunity to balance effective pathogen control with the preservation of neural function. This review examines the diverse yet convergent immune evasion strategies employed by major neurotropic RNA and DNA viruses, including herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), rabies virus (RABV), flaviviruses, alphaviruses, enteroviruses, and JC virus (JCV). We discuss viral interference with innate immune sensing pathways, including RIG-I-like receptors (RLRs) and cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) signaling, inhibition of type I interferon induction and Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling, modulation of interferon-stimulated effector mechanisms, and disruption of antigen presentation and adaptive immune surveillance. The review further highlights the distinct roles of viral latency, long-term persistence, neuronal–glial interactions, and metabolic reprogramming in facilitating prolonged infection within the CNS. Emerging evidence indicates that successful neurotropic viruses rarely achieve immune evasion through complete suppression of host defenses; instead, they fine-tune antiviral responses to preserve host cell viability while preventing viral clearance. Finally, we discuss current knowledge gaps and emphasize the need for advanced human-relevant models, single-cell and spatial multi-omics, and systems-level approaches to better define virus–host interactions within the CNS. A deeper understanding of these integrated immune evasion networks may reveal novel therapeutic strategies that enhance antiviral immunity while limiting neuroinflammation and preserving neurological function. Full article