Search Results (658)

Background: Anorexia Nervosa (AN) is a severe eating disorder. Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are two Neurodevelopmental Disorders (NDDs), frequently co-occurring with each other (ADHD+ASD). The present study aimed to clarify cognitive and behavioral profiles, with a specific focus on emotional regulation, executive functions and empathy, in three groups of female adolescents. Methods: A total of 102 female adolescents aged 12–18 years were recruited. Participants were divided into three groups (AN: n = 30, ADHD: n = 47, ADHD+ASD: n = 25). All participants underwent a psychometric and a multidimensional clinical assessment. Group differences were analyzed through ANOVA with Bonferroni corrections. Results: Adolescents with ADHD+ASD scored significantly higher than the ADHD group in verbal comprehension. The AN group performed significantly better than both the ADHD and ADHD+ASD groups in working memory, and significantly better than the ADHD+ASD group in processing speed. Both the AN and ADHD+ASD groups were characterized by significantly greater impairment in global functioning than the ADHD group. No significant differences were found among the three groups on the Attention Switching, Attention to Detail, and Imagination subscales of the Autism Spectrum Quotient. Behaviorally, AN participants exhibited higher internalizing symptoms (anxiety and depression), the ADHD group presented more prominent externalizing behaviors (aggressive, rule-breaking, and attention problems), and the comorbid ADHD+ASD group demonstrated significantly more pronounced social problems. Most measures used to assess emotional dysregulation did not reveal significant differences among the three groups. Both the ADHD and ADHD+ASD groups showed significantly greater impairment in executive functioning than the AN group. Regarding empathic abilities, mixed results emerged. Conclusions: Findings suggest the coexistence of condition-specific features and shared vulnerabilities in female adolescents with AN, ADHD, and ADHD+ASD. These data underscore the importance of investigating the female phenotype from a transdiagnostic perspective to facilitate early detection and tailored interventions. Full article

Abiotic stresses, including drought, salinity, alkalinity, temperature extremes, flooding, heavy metals, and emerging pollutants, challenge plant growth and productivity by disturbing water relations, ion balance, redox homeostasis, membrane stability, energy metabolism, and developmental progression. Although substantial progress has been made in the identification of stress-responsive hormones, second messengers, kinases, transcription factors, transporters, and metabolic regulators, plant stress adaptation cannot be fully explained by linear signaling cascades or single tolerance genes. A major unresolved question is how early molecular events are reorganized into coordinated physiological and developmental outputs that support survival, recovery, and productivity. In this review, we propose an intermolecular interaction-driven adaptive remodeling framework for plant abiotic stress responses. This framework emphasizes that stress tolerance emerges from dynamic changes in receptor–ligand recognition, protein–protein interactions, calcium decoding, redox-sensitive modification, phosphorylation networks, transcriptional regulation, chromatin-associated control, and metabolite-mediated feedback. We further emphasize ROS as integrative redox switches that connect stress sensing, defense activation, senescence-related transitions, and recovery, and chromatin-associated mechanisms as regulators that may stabilize primed or memory-like adaptive states. We discuss how these interaction networks converge on core signaling hubs, including abscisic acid, reactive oxygen species, Ca²⁺, and kinase/phosphatase systems, and how they remodel stomatal behavior, root architecture, ion and pH homeostasis, redox buffering, metabolism, development, and reproductive resilience. We further highlight how natural variation, multi-omics, genome editing, high-throughput phenotyping, and field validation can translate interaction-centered stress biology into crop resilience. This perspective provides a conceptual bridge between molecular stress perception, network behavior, physiological adaptation, and climate-resilient agriculture. Full article

Vein graft restenosis is a leading cause of long-term failure after coronary artery bypass grafting (CABG), driven by maladaptive vascular smooth muscle cell (VSMC) responses to arterialization-induced inflammation. The key molecular mediators of this pathological remodeling, however, remain incompletely defined. Here, we integrated multi-omics analyses of human and canine vein graft specimens with in vitro functional assays to identify tenascin-C (TNC)—a matricellular extracellular matrix protein—as a critical regulator of VSMC dysfunction. TNC was specifically enriched in a synthetic, pro-inflammatory VSMC subpopulation. Pro-inflammatory stimuli potently induced TNC expression, which was functionally linked to VSMC phenotypic modulation, hyperproliferation, and enhanced migration. Mechanistically, TNC acts upstream of NF-κB signaling; siRNA-mediated TNC knockdown significantly reduced nuclear p65 protein levels and attenuated inflammatory responses. Our integrated computational and experimental data suggest that TNC, NF-κB, and TNF-α function within a sequential pro-inflammatory signaling cascade that sustains vascular inflammation and promotes neointimal hyperplasia. These findings reposition TNC from a passive structural component to an active driver of vascular pathology and highlight the TNC–NF-κB axis as a candidate target for therapeutic intervention to improve vein graft patency. Full article

Umbilical cord mesenchymal stromal cells (UC-MSCs) are a key element of regenerative medicine due to their ability to secrete growth factors that stimulate proliferation and angiogenesis, and modulate the inflammatory response. Despite their widespread use, the influence of the perinatal microenvironment on their biological properties remains poorly understood. The aim of this study was to assess the influence of pH and blood gas parameters in umbilical cord blood on the global transcriptomic profile of UC-MSCs and to analyze the correlation between the metabolic status of the newborn and the expression of key trophic factors: EGF, FGF2, FGFR1, FGFR3, GDNF, HGF, IGF1, NES, NGF, and PGF. Methods: The study was conducted in two stages. In the first phase, transcriptomic screening was performed using Affymetrix HuGene 2.0 ST microarray on cells isolated from three environmental groups defined by cord blood pH: acidic (pH < 7.35), physiological (7.35–7.39), and alkaline (pH ≥ 7.4). In the second phase, the results were validated using qPCR on an expanded study group (N = 50). Gene expression levels (RQ) were related to blood gas parameters (pH, pCO₂, pO₂, cHCO₃) and the presence of clinical features of threatened neonatal asphyxia. Results: Microarray analysis revealed that environmental pH acts as a molecular phenotypic switch. Under low pH conditions (<7.35), a shift in cell profile from proliferative to structural–migratory was observed. Significant overexpression of genes responsible for extracellular matrix (ECM) organization and adhesion (e.g., COMP, DCN, LUM, FMOD) was observed, while pathways related to cell cycle and cell division (↓CDK1, AURKA, TOP2A) were downregulated. qPCR validation confirmed these observations, demonstrating a strong positive correlation between blood pH and the expression of regenerative mediators: FGFR1 (r = 0.28), EGF (r = 0.30), NGF (r = 0.39), and IGF1 (r = 0.30). A negative correlation was also found between carbon dioxide pressure (pCO₂) and the expression of NGF, FGFR1, and EGF. A significant clinical finding was that in newborns diagnosed with threatened asphyxia, EGF, FGFR1, and NGF gene expression was significantly reduced, indicating impaired trophic potential of the cells in response to metabolic stress. Conclusions: These results indicate that cord blood gas parameters are critical regulators of the genetic activity of UC-MSCs. Metabolic and respiratory acidosis not only inhibit the cells’ proliferative potential but also force them into a matrix remodeling mode, permanently modifying their transcriptomic profile. This suggests that the neonatal acid–base status may serve as an objective indicator of the “biological quality” of isolated stromal cells, which has significant implications for their future applications in cell therapies. Full article

Inflammatory bowel disease (IBD) with an onset in childhood is characterized by a more extensive phenotype, a more aggressive clinical course, and a higher risk of long-term complications, including growth retardation, compared to adult-onset disease. While tumor necrosis factor-alpha (TNF-α) inhibitors are the cornerstone of therapy, achieving sustained remission in children is often hindered by unique pharmacokinetic challenges, such as accelerated drug clearance and a higher propensity for immunogenicity. This review explores the evolving role of therapeutic drug monitoring (TDM), specifically the paradigm shift from reactive to proactive strategies. While proactive TDM remains a subject of debate in adult IBD, emerging pediatric data strongly support its routine use to optimize treatment durability and prevent secondary loss of response. Evidence-based target trough concentrations for pediatric patients are critical for achieving mucosal healing: 8–13 µg/mL at week 6 and >5–7 µg/mL during maintenance for infliximab, and >13–14 µg/mL post-induction for adalimumab. Beyond clinical outcomes, this review emphasizes the economic viability of proactive TDM, which has been shown to reduce total healthcare expenditures by 18–30% by minimizing hospitalizations and avoiding premature treatment switches. By integrating pharmacological data with clinical pathways, proactive TDM serves as an essential tool for personalized medicine, ensuring safer and more cost-effective management of pediatric IBD. Full article

Periodontitis is closely linked to atherosclerosis; however, the role of the keystone periodontal pathogen Porphyromonas gingivalis (P. gingivalis), particularly its virulence factor, outer membrane vesicles (OMVs), in vascular smooth muscle cell (VSMC) dysfunction remains unclear. This study aimed to explore the effects of P. g-OMVs on mouse aortic smooth muscle cells (MOVAS) and the potential involvement of cytoskeleton-associated protein 4 (CKAP4) in this process. OMVs were isolated by ultracentrifugation and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting. MOVAS cells were treated with OMVs; cellular functions were evaluated using CCK-8, colony formation, scratch wound-healing, ELISA, and Western blotting assays. Lentiviral vectors were used to construct CKAP4 overexpression and knockout cell models. Results showed that after P. g-OMVs were internalized by MOVAS cells, the cells showed cytoskeletal disorganization, promoting cell proliferation, wound closure, and contractile-to-synthetic phenotypic switching (decreased α-SMA and increased OPN expression), and enhancing extracellular matrix (ECM) remodeling (upregulated expression of type I collagen, type III collagen, fibronectin, matrix metalloproteinase-2 and -9, and tissue inhibitor of metalloproteinase-1). At the protein level, P. g-OMV treatment was associated with upregulated expression of CKAP4, integrin α5, and integrin β1; CKAP4 overexpression synergized with OMV stimulation to amplify these phenotypic alterations, whereas CKAP4 knockout attenuated these cellular changes. These findings suggest an association between CKAP4 upregulation and P. g-OMV-induced MOVAS dysfunction, indicating that CKAP4 may serve as a potential target in periodontitis-associated atherosclerosis. Full article

Background: The clinical relevance of circulating B-cell subpopulations during the early period after kidney transplantation remains incompletely understood. Methods: In this prospective single-center study, frequencies and absolute numbers of peripheral B-cell subpopulations were longitudinally assessed by flow cytometry in 71 kidney transplant recipients before transplantation (T0) and at 3 (T3), 6 (T6) and 12 months (T12) post-transplant. Associations with graft function, rejection episodes and clinical variables were explored. Results: During the first post-transplant year, relative frequencies of total and naïve B cells declined, whereas absolute counts showed modest increases. Memory B-cells expanded over time, driven by both class-switched (CSBC) and class-non-switched (CNSBC) subsets. Transitional regulatory B cells (tBregs) and plasmablasts decreased significantly, while memory regulatory B cells (mBregs) remained stable. Pre-transplant B-cell profiles did not differ between recipients experienced rejection and those with stable graft function. At T12, rejection was associated with a shift toward a memory-dominant peripheral profile, characterized by reduced naïve representation. tBregs showed modest positive associations with graft function during follow-up. Hierarchical clustering identified naïve- and memory-dominant phenotypes representing distinct post-transplant immune compositions. Conclusions: Early post-transplant peripheral B-cell landscapes are dynamic and heterogeneous. Peripheral B-cell phenotyping shows limited value as a standalone clinical monitoring tool. Full article

Coronary artery bypass grafting (CABG) using the autologous saphenous vein (SV) remains widely performed for obstructive atherosclerosis; however, vein graft disease drives recurrent ischaemia through early thrombosis and progressive intimal hyperplasia, and accelerated atherosclerosis developing within the grafts. Extracellular vesicles (EVs) are membrane-bound particles that transfer proteins, lipids, and microRNAs between cells. They modulate endothelial dysfunction, vascular smooth muscle cell phenotypic switching, inflammation, and coagulation, which are core processes in vein graft remodelling. Arterialisation exposes the vein to abrupt rises in shear stress, cyclic stretch, and intraluminal pressure. These forces increase EV release and reshape EV cargo in experimental systems, suggesting a potential mechanism for amplifying early graft injury which warrants direct investigation in vein tissue. This review synthesises current evidence for cell-specific EV contributions from ECs, vascular smooth muscle cells, platelets, and macrophages, and appraises EV-associated microRNAs with biomarker potential relevant to graft failure pathways. We also review therapeutic strategies that may modulate EV signalling including antiplatelet therapy, statins, KCa3.1 inhibition, and pro-reparative mesenchymal stromal cell-derived EVs. No published clinical studies evaluate EV-based biomarkers specifically for saphenous vein graft patency, and none prospectively predict saphenous graft failure. CABG provides a well-defined time zero event that enables longitudinal sampling and risk stratification. Prospective studies linking EV phenotypes and miRNA signatures to imaging-defined graft outcomes are needed to support clinical translation. Full article

Background/Objectives: Inflammation is a critical contributor to the development of diabetic retinopathy (DR). In the early stages of DR, the compromised permeability of the blood–retina barrier facilitates the infiltration of macrophages and the activation of microglia. These specific retinal immune cells can adopt morphologies M1 or M2, linked to pro- or anti-inflammatory responses, respectively. This dual response represents a new therapeutic target against DR progression. This study aimed to investigate the modulation of the response M1/M2 and the molecular mechanism of two algal diterpenoids, rugukadiol A (RK) and ruguloptone A (RL), in the early inflammatory events associated with DR. Methods: LPS-stimulated microglial (Bv.2) and macrophage (RAW264.7) cells and an ex vivo physiological model of DR were used to analyze the effects of RK and RL on M1 and M2 inflammatory markers. Results: Compounds RK and RL, besides decreasing the expression of the M1 pro-inflammatory factors iNOS, Il6 mRNA, and NLRP3 in LPS-stimulated Bv.2 cells, caused enhancements in Arg-1 mRNA and Il10 mRNA expression consistent with the induction of an M2 anti-inflammatory response. RK promoted p38α-MAPK phosphorylation, suggesting a non-classical activation of p38α related to the induction of anti-inflammatory responses. Consistently, treatment of retinal explants of BB rats in the early stages of DR with RL decreased M1 pro-inflammatory mediators and induced M2 anti-inflammatory markers, with a reduction in gliosis and a phenotype switch from activated to resting microglia. Conclusions: This study provides the first evidence of algal diterpenoids attenuating pro-inflammatory mediators and promoting the resolution of inflammation in a diabetic retinopathy context, thus opening the way to further explore this class of marine natural products and analogs for early DR management. Full article

Nematode-trapping fungi are saprophytic organisms that can transform their mycelium into a parasitic lifestyle, forming traps to capture and feed on nematodes. Although this transition is triggered by environmental conditions, the genetic regulation of this metabolic shift remains unclear. This study assessed the effects of nutritional stress on mycochemical synthesis, trap morphogenesis, and Aomae1 gene expression in Arthrobotrys oligospora and Arthrobotrys musiformis. Fungal biomass was subjected to the following three-stage successive culture model: (i) nutrient-rich (Czapek–Dox broth), (ii) nutritional stress (water), and (iii) media enriched with live prey (Haemonchus contortus Hc-L₃). Samples were taken for molecular analysis, and liquid culture filtrates (LCFs) were recovered for chromatographic identification of mycochemical groups. To assess trap formation (traps/cm²), mycelia from each culture model was transferred to water agar plates and defied with Hc-L₃. Results showed a significant bioenergetic trade-off. Both starvation and larval presence induced a downregulation of mycochemical synthesis, which resulted in the total loss of nematocidal activity in LCfs, while triggering a morphogenetic response. Arthrobotrys musiformis showed the most aggressive phenotype with 3.8-fold increase in trap formation and a massive 429.05-fold overexpression of Aomae1 under predatory challenge. While A. oligospora showed a similar but less pronounced trend (2.4-fold increase in trap formation and 44.48-fold Aomae1 overexpression), our findings suggest that Aomae1 expression plays a critical role in the metabolic switch that regulates and redirects energy resources, prioritizing mechanical trapping mechanisms over secondary metabolism during nutrient scarcity. These findings highlight Aomae1 as a possible key activator for virulence, which offers strategic targets for the optimization of biocontrol agents against gastrointestinal nematodes in livestock. Full article

Background and Objectives: The therapeutic role of surgery in Crohn’s disease has evolved in the era of advanced biologic therapies, particularly in patients with complex and treatment-refractory disease. This study aimed to evaluate the relationship between preoperative biologic exposure and surgical outcomes, with a focus on predictors of more extensive surgical procedures, postoperative biological response, and postoperative biologic management. Materials and Methods: We conducted a retrospective cohort study including 60 patients with Crohn’s disease who underwent CD-related surgical interventions between January 2011 and December 2024. Clinical, surgical, and therapeutic data were collected. Combined resection procedures were defined as intestinal resections associated with additional surgical interventions. Postoperative biological response was defined as an exploratory composite endpoint reflecting the simultaneous normalization of hemoglobin, serum albumin, and C-reactive protein at six months. Statistical analyses, including univariable and multivariable methods, were performed. Results: Combined resection procedures were associated with advanced disease, particularly penetrating phenotypes and intra-abdominal sepsis, and with more frequent postoperative biologic intensification (OR 5.56, 95% CI: 1.05–29.57, p = 0.044). Postoperative biologic management included maintenance and intensification strategies (initiation or switching of biologic therapy). At six months, postoperative biological response was achieved in 20.7% of patients (12/58). No significant associations were observed between biological response and preoperative anti-TNF exposure or postoperative biologic intensification. Despite the relatively low rate of complete biological normalization, hemoglobin and albumin normalization were observed in 79.3% and 69.0% of patients, respectively, while the median fecal calprotectin decreased from 820 µg/g preoperatively to 130 µg/g at follow-up. Endoscopic remission was observed in 47.6% of patients with available SES-CD assessment. Conclusions: In patients with complex Crohn’s disease, surgical intervention remains an essential component of multidisciplinary management. While complete postoperative biological normalization was achieved in a limited proportion of patients, surgery was associated with consistent improvements in inflammatory and nutritional parameters. Further prospective studies are needed to better define predictors of postoperative recovery and to clarify the role of surgery within modern treatment algorithms. Full article

Introduction: Despite proven efficacy of anti-TNF agents in inflammatory bowel disease, primary non-response affects up to one-third of patients, while secondary loss of response occurs at 13–21% per patient-year, often requiring dose optimization or switching to alternative advanced therapies. Methods: The present single-center cohort study at the University Hospital of Ioannina included biologic-naïve patients receiving anti-TNF therapy as their first biologic treatment. First anti-TNF treatment failure was defined as discontinuation due to persistent IBD activity despite maximal dose optimization (infliximab 10 mg/kg every 4 weeks, adalimumab 40 mg weekly). Patients with measurable anti-drug antibodies prior to anti-TNF dose intensification or discontinuation were excluded. Of 528 anti-TNF-treated patients, 286 (173 with CD, 113 with UC) met the inclusion criteria and were included in the final statistical analysis. Results: Anti-TNF failure occurred in 32.7% of Crohn’s (CD) and 32.9% of ulcerative colitis (UC) patients. Multivariable Cox regression identified complicated phenotype (stricturing or/and penetrating CD; HR = 1.9, p = 0.032) and concomitant corticosteroid use at anti-TNF initiation (HR = 2.03, p = 0.012) as independent predictors of anti-TNF failure in CD. Age at CD diagnosis showed a trend for statistical significance (HR = 1.02, p = 0.061), and after stratification, age at diagnosis ≥ 40 years conferred higher risk (HR = 1.93, p = 0.016), alongside persistent effects of complicated phenotype (HR = 1.83, p = 0.027) and corticosteroid use (HR = 2.01, p = 0.013). In UC patients, female sex predicted anti-TNF failure (HR = 2.13, p = 0.025). IBD-related bowel resection occurred in 26.6% of patients with CD and in 5.3% of patients with UC. Conclusions: Anti-TNF failure remains common despite optimization. Identifying immunogenicity-independent predictors may enable personalized treatment strategies and improve outcomes. Full article

The remarkable ecological success of fungi is supported by their capacity for rapid and often reversible molecular responses to fluctuating environments. While conventional evolutionary theory has largely emphasized mutation and selection as central drivers of adaptation, many environmentally responsive fungal traits are also shaped by molecular processes that generate reversible phenotypic variation on ecological or developmental timescales. This review synthesizes current knowledge on reversible genetic and epigenetic mechanisms underlying fungal phenotypic plasticity by integrating insights from programmed genetic rearrangements such as mating-type switching, transposable element activity, variation in tandem repeats and the behavior of accessory chromosomes, together with dynamic epigenetic processes including histone modifications, DNA methylation, chromatin remodeling and RNA mediated regulation. Together, these mechanisms form an interconnected framework that enables rapid and, in many cases, reversible phenotypic diversification, although their consequences range from transient regulatory shifts to partially or fully irreversible sequence-level changes. We highlight the molecular machinery that governs reversibility and its evolutionary implications for fungal pathogenesis, symbiosis, and biotechnology. By uniting genetic and epigenetic perspectives, this review advances a holistic framework in which reversibility is treated as a key property of fungal phenotypic plasticity, helping fungi balance stability with flexibility under environmental challenge. Understanding these mechanisms provides new insights into fungal evolution, and opens new avenues for antifungal intervention and the rational design of industrially valuable fungal strains. Full article

Vascular remodeling driven by the phenotypic switching of vascular smooth muscle cells (VSMCs) poses a significant health risk to astronauts during long-duration spaceflight. While the morphological and molecular changes are well recognized, the underlying metabolic drivers and potential translational countermeasures remain elusive. To investigate the metabolic determinants of VSMCs phenotypic switching, human aortic smooth muscle cells (HASMCs) were subjected to cyclic mechanical stretch, an in vitro model offering indirect mechanistic insights into mechanical loading conditions relevant to spaceflight-associated hemodynamic alterations. An integrated approach combining quantitative proteomics, flux analysis (Seahorse), and functional assays (cell cycle, wound healing, transwell) was used to characterize the accompanying metabolic and phenotypic alterations. Molecular mechanisms were assessed using immunoprecipitation, protein crosslinking, and immunofluorescence. Mechanical stretch triggered a contractile-to-synthetic phenotypic switch in HASMCs, accompanied by a shift from oxidative phosphorylation to aerobic glycolysis. Pyruvate kinase M2 (PKM2) was identified as a central metabolic regulator of this process, its silencing reversed the pro-synthetic phenotype. Notably, lactate, a glycolytic product, was found to exert a self-limiting feedback signal. Exogenous lactate suppressed the synthetic switch in associated with increased PKM2 lactylation. Further analysis indicated that PKM2 lactylation was associated with enhanced stability of its active tetrameric conformation, which was associated with a metabolic shift toward oxidative phosphorylation and restored expression of contractile markers. Although specific lactylation sites on PKM2 were not identified in this study, and direct causality between lactylation and tetramerization remains to be established, these findings identify a previously unrecognized association. This study reveals a novel metabolic regulatory mechanism in which lactate correlates with the suppression of synthetic switching of VSMCs, linked to PKM2 lactylation and tetramer stabilization. The observed lactate-PKM2 axis represents a candidate metabolic node associated with VSMCs phenotype regulation and offers a potential therapeutic target for modulating vascular remodeling. Upon direct validation under relevant conditions in future studies, this mechanism may inform the development of novel therapeutic strategies for managing vascular adaptation during long-duration spaceflight and other aerospace-related physiological challenges. Full article

Intracranial atherosclerosis (ICAS) is a distinct, inflammation-dominant vasculopathy and a leading cause of global stroke morbidity. Unlike extracranial atherosclerosis (ECAS), which often utilizes compensatory positive remodeling to maintain patency, ICAS is characterized by a unique architecture and a localized antioxidant gap that favor maladaptive negative remodeling. We critically analyze the molecular cascade initiated by the breakdown of the Piezo-type mechanosensitive ion channel component 1 (PIEZO1) and the Krüppel-like factor 2/4 (KLF2/4) mechanotransduction axis, which triggers endothelial nitric oxide synthase (eNOS) uncoupling and establishes a state of chronic inflammation. This environment facilitates the subendothelial lipid retention of oxidized low-density lipoprotein (oxLDL), a process exacerbated by the intracranial deficiency of Apolipoprotein A-I (ApoA-I) and impaired glymphatic clearance. Crucially, we evaluate how these metabolic and mechanical insults drive vascular smooth muscle cell (VSMC) phenotypic switching; the transdifferentiation of contractile VSMCs into macrophage-like foam cells accounts for up to 60% of the plaque’s lipid-laden pool and destabilizes the fibrous cap. This vascular failure directly compromises the neurovascular unit (NVU), leading to pericyte dropout and blood–brain barrier breakdown. Beyond environmental stressors, we highlight the ring finger protein 213 (RNF213) variant as a critical genetic determinant of this susceptibility. Shifting the clinical paradigm from simple luminal narrowing toward the identification of the vulnerable plaque, we discuss how High-Resolution Vessel Wall Imaging (HR-VWI) and microRNA biomarkers can identify unstable lesions. By integrating these molecular and imaging signatures, we propose a precision medicine framework centered on the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the NVU to effectively mitigate the high residual recurrence risk that persists under conventional therapy. Full article