Search Results (3,598)

Neurodegenerative diseases are characterized by progressive neurological decline, metabolic dysfunction, and chronic neuroinflammatory changes. Dysregulated lipid handling has emerged as an important component of these processes, but the functional significance of lipid droplets (LDs) remains strongly context-dependent. Here, we review LD biogenesis, turnover, and cell type-specific functions in the central nervous system (CNS) and critically evaluate evidence linking LD remodeling to neurodegeneration. Transient LD formation can buffer excess or oxidation-prone lipids and support metabolic adaptation, whereas persistent lipid retention in the setting of impaired lysosomal, mitochondrial, or lipid-export capacity is associated with cellular dysfunction. We compare human tissue data, genetic evidence, LD-specific perturbations, pharmacological studies, and experimental models across Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). Particular attention is given to microglial lipid-associated states, neuron–glia lipid transfer, monogenic disorders of lipid handling, and apparently opposing outcomes of LD manipulation in different disease contexts. Rather than treating LD accumulation as a universal pathogenic mechanism, we propose LD remodeling as a candidate metabolic–inflammatory convergence state whose functional consequences depend on cell type, lipid composition, turnover capacity, and disease stage. Translational strategies should therefore prioritize direct measurements of LD flux, demonstration of CNS target engagement, and biomarker-guided patient and disease-stage selection. We further define experimental findings that would support or falsify the proposed convergence model. Full article

Adult-type diffuse gliomas comprise, amongst others, biologically distinct isocitrate dehydrogenase (IDH)-mutant (IDH-MUT) astrocytomas and IDH-wildtype (IDH-WT) glioblastoma (GB). Although IDH-MUT astrocytomas generally have a more favorable prognosis, they frequently recur and progress. Despite extensive molecular characterization, key drivers of glioma progression remain elusive. CD44, a hyaluronic acid receptor, has been implicated in glioma invasion and progression. We investigated CD44 expression, localization, and spatial organization across IDH-WT GB and IDH-MUT astrocytomas and their association with tumor progression and cellular states. CD44 expression and localization were assessed in IDH-WT (n = 15) and IDH-MUT (n = 17) diffuse gliomas across WHO grades by immunohistochemistry (IHC). Multiplex IHC combined with AI-assisted digital pathology (HALO) evaluated associations between CD44, GFAP-positive astrocytic, and NeuN/RBFOX3-positive neuronal regions. Findings were validated using independent snRNA-seq data. IDH-WT GB exhibited significantly higher CD44 expression with prominent membranous localization. Lower-grade IDH-MUT astrocytomas showed reduced, diffuse staining, whereas higher-grade tumors acquired a membranous CD44 localization, resembling IDH-WT GB. CD44 was strongly associated with GFAP-positive astrocytic regions and inversely correlated with NeuN/RBFOX3-positive neuronal areas in IDH-MUT tumors. AI-assisted spatial analyses confirmed distinct CD44-positive astrocytic and NeuN-positive neuronal niches, supported by snRNA-seq demonstrating positive CD44-GFAP correlations. This association was strongest in astrocytic (AC-like) metaprograms of WHO grade 2, while in higher-grade tumors it was more pronounced in mesenchymal (MES-like) states. CD44 exhibits IDH- and grade-dependent spatial patterns marking glioma progression and astrocytic/mesenchymal tumor states. Membranous CD44 acquisition accompanies progression to higher grades in IDH-MUT astrocytomas, suggesting CD44 as a marker of glioma aggressiveness. Full article

Astrocytes are the most abundant and functionally versatile glial cells in the central nervous system, where they maintain homeostasis, regulate metabolic function, and communicate extensively with neurons, microglia and other CNS cell types. To mediate these interactions, astrocytes use G-protein-coupled receptors (GPCRs) to receive diverse extracellular signals, such as neurotransmitters, secreted signals and inflammatory factors. GPCRs translate extracellular signals into intracellular signaling cascades in astrocytes and are essential for intercellular communication. Despite decades of investigation, however, astrocytic GPCR signaling remains difficult to explain within a unified framework, as receptor activation does not necessarily produce predictable outcomes based on receptor identity or G-protein signaling alone. To address this gap, we critically examine representative studies of canonical and noncanonical GPCR signaling and astrocyte-centered cellular crosstalk, considering astrocyte state and the cellular position of receptors within communication pathways. We compare receptor-specific manipulations, functional outcomes, and methodological limitations to distinguish experimentally supported causal relationships from unresolved interpretations. This evidence-oriented approach identifies testable questions and experimental priorities for investigating astrocytic GPCR signaling in physiology and disease. Full article

Transportation noise is an established cardiovascular risk factor. More than 112 million Europeans are chronically exposed above the thresholds of the Environmental Noise Directive, with approximately 73,000 premature deaths and 1.5 million disability-adjusted life years attributed annually. Large cohort studies demonstrate near-linear exposure–response relationships with ischaemic heart disease, myocardial infarction, stroke, heart failure and type 2 diabetes, and more recently with dementia, Alzheimer’s disease and Parkinson disease, independent of air pollution, detectable below guideline limits and stronger for night-time exposure. The noise reaction model attributes these effects to annoyance, sleep fragmentation and activation of the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis, converging on oxidative stress, inflammation and endothelial dysfunction. This review argues that the phagocytic NADPH oxidase NOX-2 (gp91phox) is a decisive oxidative effector within that cascade in experimental models of noise exposure. NOX-2 is upregulated in the vasculature and brain after aircraft noise exposure, is delivered to the vessel wall largely by infiltrating myelomonocytic cells, and drives superoxide formation, peroxynitrite generation, and uncoupling of endothelial and neuronal nitric oxide synthase. Genetic deletion of Nox2 prevents, essentially, the entire vascular phenotype and attenuates cerebral oxidative stress and neuroinflammation, whereas ablation of lysozyme M-positive myeloid cells reproduces the vascular but not cerebral protection. These causal data derive predominantly from short-term rodent aircraft-noise models and require further extrapolation in chronic human exposure settings. In line with this proposed mechanism of action, noise-mediated organ damage can be mitigated by pharmacological and lifestyle-associated anti-oxidant interventions that are also briefly summarised here. Full article

Lactoferrin is present in brain cells and is known to protect against injury through anti-inflammatory and immunomodulatory processes. Furthermore, it has also been found within amyloid plaques in Alzheimer’s disease (AD), leading to the hypothesis that its presence in the AD brain may be detrimental. However, the identity of the brain cells that produce lactoferrin and how its expression changes in AD remain unclear. In this study, we examined lactoferrin expression and localization in 3- and 12-month-old male and female APP/PS1 mice. Using a microglial enrichment protocol and confocal imaging, we identified microglia as an important source of brain lactoferrin, and demonstrated that its expression is modulated by age, sex, and amyloid burden. In female mice, microglial lactoferrin expression was increased at both the mRNA and protein levels in 3-month-old APP/PS1 mice compared with age-matched wild-type controls. Conversely, lactoferrin transcript in the enrichment fraction, and protein localization were also reduced in microglia from 12-month-old female APP/PS1 mice, coinciding with increased amyloid burden. We further demonstrated that gene expression of lactoferrin follows daily variations under a light–dark cycle, similar to established microglial markers such as Iba1 and P2ry12, with alterations in this rhythmic pattern in APP/PS1 mice occurring predominantly in females. In addition, our findings suggest that neurons may internalize lactoferrin via LRP1, whose expression is downregulated by amyloid burden. This Aβ-dependent relationship was further corroborated in both microglial and neuronal in vitro models. Collectively, these findings identify microglia as an important source of lactoferrin in the brain. We suggest that sex- and age-dependent alterations in microglial lactoferrin expression may contribute to the sexual dimorphism observed in AD, possibly through alterations in LRP1-mediated neuronal uptake. Full article

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia worldwide. Among the mechanisms implicated in AD progression, brain insulin resistance has been associated with impaired synaptic function and cognitive decline. In this context, inositols have emerged as promising neuroprotective compounds, and previous studies have reported beneficial effects of early D-chiro-inositol (DCI) administration in the 3×Tg mouse model. This exploratory study aimed to evaluate whether chronic oral DCI administration initiated at an advanced stage can modulate hippocampal neuronal density, synaptic markers and signaling pathways associated with insulin resistance in aged 3×Tg mice. Methods: Male and female wild-type and 3×Tg mice received DCI in drinking water (approximately 200 mg/kg/day) from 9 to 12 months of age. Neuronal density was assessed by unbiased counting of NeuN-positive cells (cells/mm²), and hippocampal protein expression was analyzed by Western blot, including markers related to insulin signaling, Tau phosphorylation, glutamatergic and endocannabinoid pathways, neuroinflammation and synaptic integrity. Sex effects were formally evaluated by three-way ANOVA (sex × genotype × treatment). Results: 3×Tg mice showed a lower neuronal density in the dentate gyrus–CA3 circuit, females displayed lower neuronal densities than males, and synaptophysin (males) and PSD95 (females) were reduced in 3×Tg mice. DCI increased neuronal density in the CA1 region of 3×Tg females but did not restore the neuronal deficit in the dentate gyrus–CA3 circuit or the synaptic markers. Compared with wild-type mice, 12-month-old 3×Tg animals displayed limited alterations in hippocampal signaling proteins, and DCI induced only sparse, often sex-dependent changes that neither normalized insulin signaling nor reduced Tau phosphorylation. Conclusions: Late-onset administration of DCI had limited effects on hippocampal alterations in aged 3×Tg mice. Although treatment ages were not directly compared, these findings contrast with previous results in which DCI treatment initiated at 3 months of age proved effective, and support the hypothesis that the therapeutic window for DCI narrows as pathology progresses. The sex-dependent differences observed further highlight the importance of considering sex as a biological variable in the design of therapeutic studies. Full article

The localization of the proapoptotic (caspase 3) and the antiapoptotic B-cell lymphoma 2 (Bcl-2) factors in the spinal cord of 2-year-old juvenile chum salmon Oncorhynchus keta, as well as the neuron-specific marker NeuroN, was studied using IHC labeling. Scanning electron microscopy was used to obtain three-dimensional, highly detailed images of the surface structure of the primary motor neurons (MT1) and secondary motor neurons (MT2) of the ventral spinal cord column (VSCC), as well as nerve endings and interneuronal connections in the VSCC. The spatial organization of VSCC neurons, astrocytes, and the surface characteristics of membranes and cell connections in the spinal cord were examined. The localization of apoptotic markers and NeuroN was studied in intact juveniles and three days after traumatic spinal cord injury. The results showed that the pro-apoptotic factor caspase 3 (cas3) in the spinal cord of intact animals had a rather limited localization in the perikarya of primary and secondary motor neurons of the VSCC. Cas3 immunolocalization in the spinal cord of juvenile chum salmon was represented in astrocytes located within the VSCC, as well as among the fibers of the white matter. SEM revealed the morphological features of perineuronal astrocytes of the VSCC. Cas3+ microvascular sites were identified in the spinal cord, and their reactivity increased markedly after traumatic injury. Cas3 synthesis increased in the synaptic projections of VSCC neurons, as well as in blood vessels after traumatic injury. Along with various types of neurons, cas3 was expressed after injury in fibers and small adult neural stem and progenitor cells (aNSPCs) located in the dorsal horn and submarginal regions. The antiapoptotic factor Bcl-2 in intact juvenile chum salmon is relatively widespread in the perikarya of VSCC neurons, white matter interneurons, and dorsal horn cells located in the submarginal zone. In the post-traumatic period, Bcl-2 expression increased significantly both in VSCC neurons and in cells and fibers of the dorsal horn. Along with proapoptotic and antiapoptotic factors, the number of undifferentiated NeuroN-producing cells in the spinal cord of juvenile chum salmon increased dramatically in the post-traumatic period, indicating an active neurogenic post-traumatic process. Thus, in intact animals, proapoptotic and antiapoptotic factors are synthesized during growth; the balance between them determines the successful elimination of cells that have not established connections during ontogenetic growth and regulates programmed cell death. An increase in the number of intensely immunolabeled cells with an undifferentiated phenotype in the post-traumatic period indicates an intensive regenerative process, consistent with the results obtained in other models. Full article

Cyclin-dependent kinase 5 (Cdk5) is chiefly considered a neuronal kinase that is not involved in the cell cycle, like other Cdks, but is instead most active in post-mitotic neurons. Cdk5 is expressed in all the cells, while its main protein activator p35, a non-cyclin regulatory subunit, is expressed predominantly in neurons. Nonetheless, p35 expression has been detected in pancreatic β-cells, podocytes, and lymphocytes, which suggests non-neuronal roles for Cdk5/p35 activity. Due to its potentially important role in tissue development and homeostasis, we wanted to track Cdk5 activity in mice by following the expression of its key activator p35. Thereby, we knocked in the Cre recombinase under the p35 promoter and bred the resulting p35-KI-Cre mice to the lacZ reporter strain. β-gal staining was seen not only in neuronal tissues, but also in several non-neuronal tissues. The staining in non-neuronal tissues further illustrates that Cdk5/p35 activity has broader functions beyond regulating neural processes. Notably, we identified novel p35-lineage cells within the salivary gland embryonic epithelial end buds and in the adult acinar cells. The p35-KI-Cre mice thereby provide a valuable tool to determine in which cell types Cdk5/p35 kinase is active. Full article

Estimation of State of Health (SoH) of lithium-ion batteries plays a very crucial role in the efficient running of the battery and performance assessment of the battery. This paper proposes a Deep Neural Network (DNN) model for estimation of the SoH of batteries using an experimental data set containing 1945 data points with variation in battery type, temperature, load current, minimum voltage ($V_{min}$), voltage variance ($V_{Var}$), and cycles. The input features are normalized through Min-Max scaling, and the DNN structure is tuned through the activation functions, number of hidden neurons, number of hidden layers, batch sizes, optimizers, drop out rates, and kernel L2 regularization parameters. In terms of generalization capabilities, LOTO and LOBO tests are conducted, from all the configurations, 43 °C temperature the activation function of sigmoid attains the testing MAE of 2.16 with only one hidden layer having 12 neurons, drop out rate of 0.2, a kernel L2 of 0.000001, a batch size of 1, and Adam optimizer. Alongside comparisons of results from the other machine learning algorithms, such as Linear Regression, Decision Tree, Random Forest, and XGBoost. The DNN structure obtains the smallest Kullback-Leibler divergence from all the battery types and temperatures tested, implying high similarity in the distributions of SoH from the predictions and reference data. In addition, actual versus predictions charts of 43 °C indicate that the DNN is able to capture the battery SoH trend. Full article

Neuroinflammation involves coordinated interactions among microglia, astrocytes, neurons, vascular cells, and peripheral immune signals and is implicated in diverse neurological disorders. This narrative review critically examines mechanistic, preclinical, and clinical evidence concerning plant-derived bioactive compounds from three recurrent chemical groups—phenolic compounds, terpenes and terpenoids, and alkaloids—identified through the review process. An iterative search of PubMed, ScienceDirect, Web of Science, and Scopus was combined with explicit eligibility, screening, and qualitative synthesis criteria. The reviewed evidence links specific compounds and characterized preparations with modulation of nuclear factor kappa B, mitogen-activated protein kinases, Janus kinase/signal transducer and activator of transcription signaling, and the NLR family pyrin domain containing 3 inflammasome, as well as nuclear factor erythroid 2-related factor 2/heme oxygenase 1, cannabinoid receptor 2, peroxisome proliferator-activated receptor gamma, neurotrophic factor-associated signaling, and phosphoinositide 3-kinase/protein kinase B-associated responses. Reported effects include changes in glial reactivity, inflammatory mediators, redox homeostasis, neuronal injury, and selected functional outcomes; however, they depend on compound identity, dose, formulation, cell type, stimulus, and experimental model. The evidence remains predominantly mechanistic and preclinical, whereas available clinical studies are limited and heterogeneous. Uncertain blood–brain barrier penetration and central nervous system exposure, formulation-dependent bioavailability, limited target-engagement data, safety considerations, and potential drug–drug interactions continue to constrain translation. Future studies should prioritize chemically defined interventions, disease-relevant human models, direct pharmacokinetic and target-engagement measurements, and clinical outcomes linked to neuroinflammation. Full article

Following herpes simplex virus-1 (HSV-1) acute infection, sensory neurons in trigeminal ganglia (TG) are important sites for life-long latency. Acute or chronic stress increases the incidence of HSV-1 reactivation from latency, in part because the glucocorticoid receptor (GR) is activated. GR antagonists impair HSV-1 replication and explant-induced reactivation from latency. A mouse strain expressing GR with a serine 229 mutated to alanine (GR^S229A) previously revealed that female GR^S229A mice latently infected with HSV-1 shed significantly lower virus in TG during explant-induced reactivation when compared to male GR^S229A mice and wild-type (wt) C57BL/6J mice regardless of sex. A new study demonstrated that heat-stress-induced HSV-1 reactivation from latency is significantly reduced in female GR^S229A mice but not male GR^S229A mice or wt C57BL/6J mice. A mineralocorticoid receptor (MR)-specific antagonist (Esaxerenone) increased explant-induced or heat-stress-increased reactivation from latency in female GR^S229A mice but not male GR^S229A mice or wt C57BL/6J mice regardless of sex. Additional studies revealed Esaxerenone increased virus shedding in primary kidney cells prepared from GR^S229A males or females and neuroblastoma cells (Neuro-2A). In conclusion, this study revealed virus shedding was reduced in the TG of GR^S229A female mice when reactivation from latency was induced by explant or heat stress; but, Esaxerenone rescued reactivation in GR^S229A female mice. Full article

GLP-1R/GIPR agonists have emerged as the dominant pharmacological strategy for obesity, producing unprecedented weight loss. Yet why patients respond so differently to treatment remains a persistent clinical puzzle. GLP-1R agonists produce body weight reductions of up to 15–17% in clinical trials, and dual GIP/GLP-1R agonists push this further to 20–25%; despite this, the central neural mechanisms underlying this gap remain incompletely understood. This Review integrates preclinical and clinical evidence in the hypothalamic and brainstem circuits that govern energy homeostasis, with a particular focus on GLP-1R and GIPR signaling in the GABAergic neurons that co-express both receptors in the arcuate nucleus and nucleus tractus solitarius. In these neurons, the two receptors pull in opposite directions on excitability by regulating ion channels differently. GLP-1R activation hyperpolarizes the neurons and reduces GABA release, while GIPR activation promotes firing and restores GABAergic tone. Genetic deletion of GIPR in GABAergic neurons enhances GLP-1R agonist efficacy in male mice, indicating that GIPR signaling constrains GLP-1R action within this defined neuronal population. This local constraint does not generalize to GIPR biology as a whole. Dual agonists outperform GLP-1R monotherapy clinically; GIPR signaling in the median eminence oligodendrocytes enhances GLP-1R agonist brain access, and both GIPR agonism and antagonism can reduce body weight through distinct mechanisms. We propose a cell-type-resolved framework that reconciles these findings, state testable predictions that follow from it, and highlight the gaps in sex, species and human data. We conclude that no clinically validated strategy yet takes advantage of the GIPR/GLP-1R interaction, which leaves a major gap in precision obesity pharmacotherapy. Full article

Background: Glaucoma is a multifactorial optic neuropathy characterized by progressive retinal ganglion cell (RGC) loss, in which both intraocular pressure (IOP)-dependent and -independent mechanisms contribute to disease progression. Gabapentinoids target α2δ subunits of voltage-gated calcium channels (VGCCs), which regulate calcium-dependent processes relevant to both aqueous humor dynamics and retinal neuronal function. This systematic review evaluates heterogeneous evidence relevant to α2δ modulation of IOP regulation, retinal neuroprotection, and associated molecular and synaptic pathways. Methods: A systematic literature search was conducted across PubMed, Embase, Scopus, and Cochrane Library databases from inception. Studies investigating gabapentinoids or α2δ subunit modulation with outcomes related to IOP, RGC survival, or relevant molecular signaling were included. Risk of Bias (RoB) was assessed using the OHAT rating tool, and Certainty of Evidence (CoE) was rated on the GRADE four-level scale using initial confidence criteria from the OHAT approach. Due to heterogeneity in study design and outcomes, findings were synthesized narratively, with included studies divided and assessed separately within anterior segment pharmacology, anterior segment genetics, neuroprotection, and mechanistic bodies of evidence. Results: Of 1973 unique records screened, 11 studies met inclusion criteria, which were further subdivided into 15 experimental arms according to evidence type. Distinct evidence bodies were anterior segment pharmacology (5 study arms), anterior segment genetics (3 study arms), neuroprotection (4 study arms), and mechanistic (3 study arms). Across mouse and rabbit models of spontaneous ocular hypertension, topical pregabalin (PRG) consistently reduced IOP in a dose-dependent manner, with peak effects generally occurring 1.5–5 h after administration depending on strain and formulation. Plateaus in maximal IOP reduction were observed at 0.9% PRG solution in mice and 0.6–0.7% PRG microemulsion (ME) in rabbits. ME formulations of PRG consistently prolonged duration of action and increased cumulative exposure relative to non-ME PRG formulations. PRG ME achieved maximal IOP reduction comparable to that of 0.005% latanoprost solution while retaining their increased duration of action and cumulative exposure. Repeated once-daily PRG ME dosing maintained IOP-lowering responses over 21- and 60-day treatment periods. Genetic studies separately associated CACNA2D1/Cacna2d1 with IOP-related phenotypes and primary open-angle glaucoma susceptibility, providing target-level evidence. Preclinical posterior segment studies reported retinal structural preservation or improved RGC survival with PRG, while separate studies of GBP-L demonstrated RGC-survival effects associated with K-ATP channel activity rather than established α2δ modulation. Mechanistic studies separately identified thrombospondin-2 (TSP2)-α2δ1 signaling as a mediator of injury-associated synaptic remodeling, with pharmacologic disruption attenuating synaptic protein upregulation and improving axonal integrity. RoB varied across study arms and bodies of evidence. Anterior pharmacology included five Tier II study arms, anterior genetics included two Tier I arms and one Tier II arm, and all neuroprotection and mechanistic arms were Tier II. CoE was rated moderate for both anterior pharmacology and genetics, and low for both neuroprotection and mechanistic evidence. Conclusions: The available evidence is predominantly preclinical and heterogeneous. Moderate certainty within the defined anterior segment evidence body reflects consistency of the reported preclinical effect and does not establish clinical efficacy or independent reproducibility, as the topical PRG intervention literature is concentrated within a single investigative group. The neuroprotective and mechanistic findings remain hypothesis-generating and do not establish a unified mechanism or simultaneous IOP-lowering and neuroprotective action. Independent pharmacologic replication, validation in chronic glaucomatous neurodegeneration models, and long-term topical safety evaluation are prerequisites to discussions of clinical relevance. Full article

Cerebrovascular dysfunction and impaired brain energy metabolism are increasingly recognized as important contributors to neurodegenerative diseases, but their molecular regulators remain poorly understood. Here, we examined the roles of steroid receptor coactivator-2 (SRC-2/NCOA2) in the cerebrovascular and metabolic changes associated with neurodegeneration using ps19 mice as a model. In our study, we found a significant decrease in cortical SRC-2 expression in ps19 mice compared with wild-type (WT) controls, with no changes in SRC-1 and SRC-3 levels between the two groups. ps19 mice showed reduced cortical endothelial and blood–brain barrier-associated markers (CD31, occludin, claudin-5, total eNOS (endothelial nitric oxide synthase), and eNOS Ser1177) and increased eNOS Thr495 phosphorylation. HIF-1α, GLUT2, and GLUT4 were also reduced in ps19 mice, whereas GLUT1 and GLUT3 were unchanged between the groups. To examine the role of SRC-2, we used siRNA to reduce its expression in brain endothelial cells and primary neurons. In brain endothelial cells, SRC-2 knockdown reduced the expression of endothelial and BBB-associated markers, including CD31 and occludin, as well as GLUT3, while increasing inhibitory eNOS Thr495 phosphorylation and GLUT4 expression. In brain endothelial cells, SRC-2 knockdown significantly reduced the extracellular acidification rate (ECAR) and NAD⁺/NADH ratio. Knockdown of SRC-2 in primary neurons (from WT and ps19 mice) significantly reduced the oxygen consumption rate (OCR), while the NAD⁺/NADH ratio remained unchanged. These findings identify SRC-2 as a regulator of endothelial and neuronal metabolism and support further investigation of SRC-2-dependent pathways as potential therapeutic targets in neurodegenerative diseases. Full article

Background/Objectives: Narcolepsy type 1 (NT1) results from loss of hypothalamic orexin neurons. Selective orexin-2 receptor (OX2R) agonists now permit direct receptor-level restoration of deficient signaling, but recent broad reviews do not fully integrate the post-approval, trial-specific efficacy, prescribing, and safety evidence. This review asks what benefits and risks are supported by current data, which toxicities appear class-related versus molecule-specific, and how OX2R agonism should be positioned clinically. Methods: We performed a targeted narrative review of peer-reviewed human studies, major guidelines, trial registries, and regulatory documents updated through 16 October 2026. Peer-reviewed trials and regulatory sources were prioritized; conference- or sponsor-reported data were used only when peer-reviewed evidence was unavailable and were identified as provisional. Results: In the pivotal phase 3 trials, oveporexton produced placebo-adjusted improvements in MWT sleep latency of 13.8–20.1 min, ESS reductions of 8.0–9.8 points, and weekly cataplexy incidence-rate ratios of 0.25–0.38. Clinically important safety considerations include insomnia, urinary frequency/urgency, CPK elevations, CYP3A interactions, and measurable abuse potential. Alixorexton phase 2 data support OX2R agonism as a developing drug class, whereas firazorexton illustrates molecule-specific hepatotoxic risk. Conclusions: OX2R agonists are best described as mechanism-based pharmacological restoration of orexin signaling, not proven disease-modifying therapy. Their comparative clinical position remains uncertain because head-to-head trials with established therapies are lacking. Full article