Search Results (3,170)

Oncogenic driver mutations in non-small cell lung cancer (NSCLC) activate defined signaling pathways that sustain tumor growth and influence the immune landscape. Yet, how coordinated interactions among diverse cell populations within the tumor immune microenvironment (TIME) contribute to this process remains largely unresolved. To address this, we profiled approximately 200,000 single cells from 45 treatment-naïve NSCLC patients representing seven major driver mutations. This analysis uncovered five multicellular modules (CM1–5) with distinct functional properties, each linked to specific malignant regulatory programs. Among them, CM2 and CM5 exhibited pronounced invasive features and were associated with unfavorable clinical outcomes. CM2 was predominantly observed in EGFR- and MET-driven brain metastases and was defined by strong crosstalk between astrocytes and myofibroblasts. Factors such as SPP1, PTN, and PSAP, together with metabolic alterations, contributed to a microenvironment supportive of metastatic colonization in the brain. By contrast, CM5 was enriched in ROS1-, KRAS-, and EGFR-mutant tumors and consisted of diverse myeloid and endothelial subsets characterized by immunosuppressive and pro-angiogenic signaling, including MIF, GALECTIN, and RETN, collectively facilitating immune escape and vascular remodeling. We further constructed and validated a driver mutation-specific prognostic signature (DMSP.sig) model integrating receptor–ligand interactions and core transcription factors, which effectively stratified patient survival. Leveraging this model, we also identified potential therapeutic candidates linked to these prognostic features, highlighting opportunities for clinical intervention. In summary, our study delineates how oncogenic drivers give rise to distinct TIME architectures, providing a framework for prognostic assessment and precision immunotherapy in high-risk NSCLC. Full article

Neurodegenerative diseases, characterized by progressive neuronal loss and functional decline, impose a substantial global health burden. Autophagy, the principal intracellular degradative pathway for clearing misfolded proteins and damaged organelles, is vital for neuronal homeostasis, whereas maladaptive neuroinflammation is increasingly being recognized as a central driver of disease progression. A growing body of evidence indicates a bidirectional, tightly coupled relationship between autophagy and neuroinflammation: impaired autophagic flux promotes accumulation of damage-associated molecules that activate innate immune responses, while sustained inflammatory signaling further disrupts autophagy, together forming a self-reinforcing cycle that accelerates neurodegeneration. This interplay is regulated by diverse genetic, molecular, cellular, and environmental factors and manifests in cell-type-specific ways across microglia, astrocytes. Therapeutic strategies emerging from these insights include modulation of autophagic pathways (e.g., mTOR, AMPK, TFEB), targeted inhibition of inflammasome and pro-inflammatory mediators (notably NLRP3-related signaling), and delivery platforms for small molecules or nucleic acids, with increasing interest in multi-target and stage-specific interventions. This review integrates mechanistic evidence and translational advances, highlights gaps in cell-type and stage-specific understanding, and outlines priorities for developing safe, effective therapies that target the autophagy–neuroinflammation axis in neurodegenerative disorders. Full article

Astrocytes are now recognized as active and essential participants in neural circuit function, extending far beyond their traditional roles as passive support cells. Emerging evidence highlights their critical involvement in synaptic modulation, information processing, and complex behaviors, making them key targets for understanding cognitive dysfunction in psychiatric disorders. This narrative review synthesizes current findings from rodent models to elucidate the relationship between astrocytic networks and multidomain cognitive performance. We first outline the morphological and physiological features of astrocytes, followed by a comprehensive overview of the modern experimental toolkit, including observational markers and advanced interventional strategies. Next, we evaluate commonly used behavioral assays that capture distinct cognitive domains, ranging from basic spatial and recognition memory to higher-order executive functions, cognitive flexibility, and social cognition. By integrating recent experimental evidence, we detail the specific mechanistic pathways, such as intracellular calcium signaling, gliotransmission, and neuroinflammatory reactivity, through which astrocytes directly govern these cognitive processes. Finally, we highlight critical knowledge gaps stemming from methodological limitations, arguing for the integration of more ethologically relevant, high-throughput behavioral tasks alongside highly specific targeting tools to better capture the functional heterogeneity of astrocytes in cognitive health and disease. Full article

Extracellular vesicles (EVs) are nanoscale membrane-bound particles that mediate intercellular communication by transferring proteins, nucleic acids, lipids, and metabolites. Increasing evidence implicates EVs in Alzheimer’s disease (AD) pathogenesis through the propagation of amyloid-β, tau, and neuroinflammatory signals across neural and glial networks. In parallel, EVs isolated from biofluids have emerged as promising sources of disease-associated biomarkers and potential therapeutic carriers. This review aims to synthesize current evidence on EV-mediated mechanisms in AD, evaluate the diagnostic value of EV-associated biomarkers, and discuss emerging EV-based and bioengineered therapeutic strategies. We summarize how EVs derived from neurons, astrocytes, microglia, and peripheral cells contribute to amyloid-β and tau spread, neuroinflammation, synaptic dysfunction, and metabolic stress in AD. Disease-associated alterations in EV cargo from blood, cerebrospinal fluid, and urine are critically assessed for biomarker applications. We further highlight advances in EV bioengineering, including cargo loading, surface modification, targeting strategies, and modulation of EV biogenesis. Finally, key translational challenges—such as EV heterogeneity, biodistribution, immune clearance, and standardization—are discussed to define future directions for leveraging EVs as diagnostic and therapeutic platforms in AD. Full article

Background/Objectives: Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by severe hepatic steatosis, lobular inflammation, and fibrosis. Although hesperidin, a citrus-derived flavanone, has been reported to exert metabolic and anti-inflammatory effects, its role in severe inflammatory and fibrotic conditions such as MASH remains incompletely understood. This study aimed to evaluate the effects of hesperidin in MASH using integrated in silico and in vivo approaches. Methods: Potential targets of hesperidin were identified using network pharmacology and molecular docking. For in vivo validation, C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet for five weeks, with oral administration of hesperidin (150 or 300 mg/kg/day) starting from week two. The MCD model induces severe hepatic inflammation and fibrosis but does not fully reflect metabolic features such as obesity and insulin resistance. Hepatic histology, serum transaminases, immune cell populations, and hypothalamic neuroinflammatory markers were assessed. Results: In silico analyses suggested that hesperidin interacts with key regulators associated with MASH, including PPARG, TGFB1, and TNF. In the in vivo MCD-induced model, hesperidin treatment reduced hepatic lipid accumulation and collagen deposition, accompanied by significant decreases in serum ALT and AST levels (by approximately 30–34% and 42–53%, respectively, depending on dose). These effects were associated with downregulation of pro-inflammatory and pro-fibrogenic gene expression and increased expression of antioxidant markers. In addition, hesperidin decreased circulating Ly6C^high monocytes and hepatic Kupffer cells, along with reduced hypothalamic microglial and astrocyte activation. Conclusions: Hesperidin attenuated key pathological features of MASH, including steatosis, inflammation, and fibrosis, and was associated with modulation of peripheral immune responses and central neuroinflammatory markers. These findings suggest that hesperidin may influence the liver–immune–brain axis and warrant further investigation in models that more closely reflect human metabolic conditions. Full article

Background: Neurodegenerative diseases (NDs) are mainly considered disorders marked by severe immunometabolic imbalance, characterized by ongoing neuroinflammation and glial activation. While mitochondrial dysfunction and oxidative stress are well-known features, the upstream metabolic factors linking these pathological processes remain poorly understood. Methods: In this review, we examined recent preclinical and clinical studies exploring the connections between lipid metabolism, glial immunometabolism, and regulated cell death pathways. Our focus was on how long-chain fatty acids (LCFAs) facilitate communication among mitochondria, reactive oxygen species (ROS), and ferroptosis in Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Results: New evidence shifts LCFAs from merely being passive indicators of cellular damage to active, upstream regulators of the neuroimmune response. Existing research shows that excess LCFA intake can overload astrocytic mitochondrial oxidative phosphorylation, leading to abnormal lipid droplet buildup and reactive astrogliosis. This lipid-driven reactivity promotes microglial polarization toward a persistent pro-inflammatory state. Notably, high levels of specific LCFAs, especially arachidonic acid, increase ROS production and lipid peroxidation. This lipotoxic environment ultimately triggers ferroptosis, an iron-dependent form of cell death shared across multiple NDs. Conclusions: The harmful interaction among mitochondrial dysfunction, lipid peroxidation, and ferroptosis is driven by an imbalance in LCFA levels. Addressing current challenges, such as the complex effects of polyunsaturated fatty acid supplementation, requires advanced techniques like single-cell multi-omics and artificial intelligence. Understanding this intricate lipidomic-transcriptomic crosstalk is crucial for moving toward personalized neuroimmunometabolism and developing new treatments to prevent ferroptosis. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline and neuropathological hallmarks such as amyloid-β plaques and neurofibrillary tangles. In recent years, chronic neuroinflammation has emerged as a central mechanism linking genetic, metabolic, and immune dysfunctions in AD. Activated microglia and astrocytes release pro-inflammatory cytokines and reactive oxygen species that exacerbate synaptic and neuronal injury, while impaired clearance mechanisms and blood–brain barrier disruption further sustain inflammation. A growing body of research highlights the role of immunometabolism—the bidirectional interaction between immune activation and cellular metabolism—in shaping glial phenotypes and disease progression. Dysregulation of glucose, lipid, and amino acid metabolism, together with alterations in key metabolites such as lactate, NAD⁺, and reactive oxygen species, promotes a maladaptive inflammatory state. Genetic factors including APOE4 and TREM2 variants affect microglial lipid handling pathways, while systemic metabolic disorders and gut microbiota alterations amplify neuroinflammatory cascades. Natural bioactive compounds, particularly polyphenols, have gained attention for their ability to modulate immunometabolic pathways. By activating AMPK and SIRT1 and inhibiting mTOR and NLRP3 inflammasome signaling, polyphenols may tune mitochondrial function, redox homeostasis, and autophagy, promoting adaptation to chronic metabolic stress. Therefore, metabolic-immune interactions represent pleiotropic therapeutic avenues for AD. Understanding how immunometabolites and nutrient-sensing pathways regulate compartmentalized inflammation in the CNS may pave the way for novel interventions that combine metabolic precision with neuroprotective efficacy. Full article

Background/Objectives: Alzheimer’s disease (AD) remains a progressive neurodegenerative disorder with limited therapeutic options. This study aimed to develop an integrative multi-omics computational pipeline to identify diagnostic biomarkers and prioritize druggable therapeutic targets for AD. Methods: We integrated transcriptomic data from 1047 samples (547 AD, 500 controls) using weighted gene co-expression network analysis (WGCNA) and three machine learning algorithms (LASSO, Random Forest, SVM) with strict separation of training, feature selection, and evaluation. Single-cell RNA sequencing of 48,481 nuclei from entorhinal cortex, two-sample Mendelian randomization (MR) with Bayesian colocalization, and structure-based molecular docking with triplicate 500 ns molecular dynamics (MD) simulations were also employed. Results: Machine learning identified 10 consensus biomarker genes involved in synaptic vesicle cycling, ion transport, and calcium homeostasis (internal test AUC = 0.891, 95% CI: 0.836–0.946; external validation on GSE48350: AUC = 0.847, 95% CI: 0.798–0.896). Covariate-adjusted differential expression and MR with Bayesian colocalization converged on eight immune-related therapeutic targets including APOE, TREM2, and TYROBP ($p<0.05$; Bonferroni-corrected threshold $p<0.00625$). Single-cell analysis revealed oligodendrocyte expansion in AD (28.5% versus 24.8%), with target genes predominantly expressed in microglia and astrocytes. Virtual screening of 2634 FDA-approved drugs prioritized 10 exploratory repurposing candidates; indomethacin–TREM2 and celecoxib–CSF1R are primary exploratory candidates given structurally validated binding pockets. Triplicate MD simulations (15 $\mathsf{\mu }$s aggregate) showed force-field-consistent structural stability (RMSD ≤ 3.2 Å). A quantitative multi-omics convergence framework identified four Tier 1 targets (APOE, TREM2, TYROBP, CX3CR1) supported by ≥5 analytical layers ($P_{\mathrm{perm}}=0.0003$; note: three of five layers share the same transcriptomic input). Conclusions: These findings provide a multi-evidence computational framework linking diagnostic biomarkers and druggable neuroinflammatory targets for AD. All predictions require experimental validation in biochemical and cellular models before clinical conclusions can be drawn. Full article

Glioblastoma (GB) classical treatment with the alkylating drug temozolomide (TMZ) is not effective mainly due to chemoresistance mechanisms, particularly those mediated by O6-methylguanine-DNA methyltransferase (MGMT). In this context, polyethylene glycol (PEG)-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were developed to deliver tamoxifen (TAX), a clinically approved non-alkylating drug with reported anti-GB activity. The NP formulation was optimized using a factorial design and subsequently functionalized with lactoferrin (Lf) to enhance GB targeting. The Lf-conjugated optimized formulation exhibited a mean diameter of 193 ± 6 nm, a polydispersity index (PDI) of 0.11 ± 0.04, a zeta potential of −18.2 ± 6.8 mV, and an encapsulation efficiency (EE) of 68.6 ± 1.8%. The NPs exhibited a sustained release profile for up to 23 days, and remained stable under physiological conditions. Cell uptake studies, conducted in human GB cells (U87, U251, and T98G) and healthy astrocytes, demonstrated enhanced internalization of Lf-NPs in GB cells compared with non-conjugated NPs, suggesting uptake through Lf-binding site-mediated endocytosis. Cytotoxicity assays further indicated that Lf-conjugation improved the antiproliferative efficacy of TAX-loaded NPs relative to non-functionalized formulations, particularly in GB cells. Moreover, combination studies with TMZ showed that the developed NPs were able to sensitize GB cells to treatment with this alkylating agent. In sum, this work supports the potential of the developed Lf-decorated TAX-loaded PLGA NPs as a nanoplatform for targeted delivery against GB. Full article

Background: Neuroinflammation is recognized as a key contributor to Parkinson’s disease (PD), but the relationships between inflammatory signaling, immune-state alterations, and cell-type-specific transcriptional programs remain unclear. Methods: Public transcriptomic datasets, including GSE20141 (discovery cohort) and the substantia nigra subset of GSE114517 (external validation cohort), were analyzed. Genes identified by exploratory differential-expression screening in the discovery cohort were intersected with predefined inflammation- and chemokine-related gene sets to define a candidate space for downstream prioritization. Protein–protein interaction, Gene Ontology, KEGG, and immune-signature analyses were performed, followed by machine learning-based feature prioritization using Elastic Net, support vector machine-recursive feature elimination, and random forest. Prioritized candidates were further evaluated by cross-platform validation, single-nucleus transcriptomic mapping, and a hypothesis-generating in silico perturbation analysis in PD astrocytes. Results: Seventeen genes were retained at the intersection of PD-related differentially expressed genes and inflammation-/chemokine-associated gene sets. These candidates formed a response module enriched in mitochondrial organization, oxidative phosphorylation, and mitophagy pathways. Immune-signature analysis suggested an altered transcriptome-derived immune landscape in PD, with changes in NK cell-related signatures and significant correlations between immune-state scores and the candidate genes. Machine learning-based prioritization yielded five shared candidates, of which only CCL2 and PAK6 showed same-direction support with nominal significance in the external validation cohort. Single-nucleus transcriptomic analysis localized CCL2 predominantly to astrocytes, whereas PAK6 was more strongly associated with neuronal populations, particularly OTX2-positive ventral midbrain neurons. In silico perturbation analysis further predicted that CCL2 suppression in PD astrocytes may be associated with translational- and ribosome-related regulatory programs. Conclusions: CCL2 and PAK6 emerged as prioritized candidate biomarkers associated with PD-related inflammatory and chemokine-linked transcriptional alterations in the substantia nigra. More broadly, this study provides a multi-layered framework for candidate prioritization, cross-platform validation, and cell-type-level contextualization in PD neuroinflammation. Because the study is computational and the perturbation analysis is predictive, orthogonal experimental validation will be required to determine whether CCL2 and PAK6 are biomarkers of disease-associated transcriptional states, functional contributors to PD pathogenesis, or both. Full article

Although transplantation of induced oligodendrocyte progenitor cells (iOPCs) is a promising strategy for white matter injury, the therapeutic efficacy of in vitro-generated iOPCs remains limited due to insufficient differentiation potential. Here, we aimed to identify key transcription factors and small-molecule drugs to optimize iOPC quality. Through transcriptome sequencing and bioinformatics analysis, we identified the transcription factor SOX10, which is differentially expressed between endogenous fetal OPCs and exogenous iOPCs. We established lentivirus-mediated SOX10 overexpression in neural stem cells (NSCs) before iOPC induction and performed cellular assays and multi-omics analysis. Early SOX10 overexpression reduced cell migration but promoted maturation into oligodendrocytes and suppressed astrocyte differentiation. Multi-omics analyses revealed that SOX10 overexpression is associated with the extensive redistribution of SOX10 chromatin binding and enrichment of regulatory programs linked to oligodendroglial differentiation, including the activation of the key signaling downstream transcription factors JUN/FOS. Moreover, TSA, Dabrafenib, and Fedratinib effectively upregulated SOX10 and improved iOPC differentiation. This study identifies SOX10 as a core upstream regulator governing the fate of iOPCs, providing a potential strategy for optimizing iOPC induction for future investigation of white matter injury therapy. Full article

Background: Intracerebral hemorrhage (ICH) is a devastating subtype of stroke, in which neuroinflammation and blood–brain barrier (BBB) disruption are secondary pathophysiological events that drive progressive brain injury. Histone lysine demethylase JMJD3 (Jumonji C domain-containing protein 3) is a master epigenetic switch governing inflammatory signaling; however, its participation in ICH-induced vascular disruption and its possible mechanism remain elusive. Objective: To examine the expression patterns of JMJD3 in the context of ICH and to evaluate the therapeutic potential of its specific inhibitor, GSK-J4, in attenuating neuroinflammation and BBB disruption in a murine ICH model. Methods: Hemin treatment of a mouse C8-D1A astrocytic cell line was used to develop an in vitro ICH model. The transcript level of the Jmjd3 gene and its correlation with pro-inflammatory signaling were analyzed with or without GSK-J4 pretreatment. ICH in vivo was created experimentally in adult male C57BL/6 mice through stereotactic striatal injection of collagenase IV, and the mice were randomly assigned to sham, ICH + vehicle, and ICH + GSK-J4 (30 mg/kg intraperitoneally (i.p.), every other day starting three days before ICH) groups. At three days post-ICH, ipsilateral brain tissues were collected to detect JMJD3 cellular localization, pro-inflammatory mediator levels, tight junction protein expression, BBB ultrastructure, and hematoma volume. White matter integrity and neuronal recovery were assessed on day 7, and sensorimotor function was assessed longitudinally on days 1, 3, 5, 7, and 14. Results: Jmjd3 gene transcription was upregulated in hemin-treated astrocytes and correlated positively with IL-6 pro-inflammatory signaling activation. In vivo, the co-localization of JMJD3 with the astrocytic identifier glial fibrillary acidic protein (GFAP) was markedly increased in the area adjacent to the hematoma at three days post-ICH. GSK-J4 administration significantly suppressed the pro-inflammatory signaling cascade by decreasing the levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase-9 (MMP-9), enhanced brain vascular structural and functional integrity by upregulating tight junction proteins zonula occludens protein-1 (ZO-1) and claudin-5, improved BBB ultrastructural integrity, and decreased hematoma volume at three days post-ICH. Furthermore, GSK-J4 administration promoted white matter integrity (increased myelin basic protein [MBP] expression) and neuronal recovery (increased neuron-specific nuclear protein [NeuN] expression) at seven days post-ICH and significantly improved the performance of ICH mice in sensorimotor behavioral tests. Conclusions: Astrocytic JMJD3 is upregulated following ICH and promotes neuroinflammation, which in turn mediates BBB disruption. Pharmacological inhibition of JMJD3 by GSK-J4 attenuates neuroinflammation and subsequent BBB damage, accelerates hematoma resolution, and promotes histological and functional recovery after ICH, likely by downregulating MMP-9 expression. These findings identify astrocytic JMJD3 as a novel epigenetic therapeutic target for acute ICH. Full article

Diabetic retinopathy (DR) is a common cause of vision loss in diabetes, and it often progresses without early symptoms. DR reflects injury of the retinal neurovascular unit (NVU), which includes neurons, Müller glia, astrocytes, endothelial cells, pericytes, and immune cells. Chronic hyperglycemia drives oxidative stress, advanced glycation end products–receptor for advanced glycation end products (AGE–RAGE) signaling, mitochondrial injury, and low-grade inflammation. These changes disrupt endothelial junctions, promote leukostasis, weaken pericyte support, increase basement membrane thickening, and lead to capillary dropout and hypoxia. Hypoxia-related signaling increases anti-vascular endothelial growth factor (VEGF) activity, which raises vascular leakage and supports neovascular disease. Glial stress and microglial activation add cytokines and reactive oxygen species, and neural dysfunction can appear early and can weaken neurovascular coupling. Modern diabetes care changes the short-term risk landscape because potent therapies can lower HbA1c quickly. Large and rapid HbA1c reductions can trigger early worsening of diabetic retinopathy (EWDR), mainly in patients with high baseline HbA1c and moderate-to-severe baseline DR. Semaglutide’s retinopathy complication signal in SUSTAIN-6 fits an EWDR-like pattern that tracks with rapid glycemic improvement in vulnerable eyes. In parallel, surgery adds acute stress, inflammation, glucose swings, hemodynamic shifts, and medication interruptions. These factors can worsen microvascular instability during recovery. Current perioperative guidelines and regulatory recommendations describe glucose targets and medication safety considerations, including preoperative interruption of SGLT2 inhibitors to reduce euglycemic ketoacidosis risk; however, the retina-specific implications of these measures remain indirect. This review summarizes current evidence linking NVU biology, EWDR risk, and perioperative diabetes-related factors. It discusses how these factors may interact in patients with diabetes and how they may influence retinal outcomes. The review is intended to synthesize current evidence and mechanistic interpretations rather than to provide formal clinical practice recommendations. Full article

In 1988, two seminal studies were published almost simultaneously in the same scientific journal. Both spurred the field of brain energy metabolism research in new directions, culminating in a long-lasting debate that appeared to split its practitioners into two factions that seem unwilling to agree on what metabolic processes are fueling the active brain with adenosine triphosphate (ATP). The first study used rat hippocampal slices to demonstrate the ability of lactate to support neuronal function as the sole oxidative mitochondrial substrate. The second study demonstrated that upon brain stimulation, glucose consumption is not accompanied by respective oxygen consumption, but a non-oxidative glucose utilization or what has become known as “aerobic glycolysis”. Consequently, for almost four decades, researchers in this field have been divided between those who profess that brain activity is supported by oxidative lactate metabolism and those who insist that non-oxidative glucose metabolism supports it. Hypotheses for both concepts were offered, “The Astrocyte Neuron Lactate Shuttle Hypothesis” and “The Efficiency Tradeoff Hypothesis,” respectively. To bridge the gap between the two groups, a recent editorial, authored by over twenty leading investigators, was published. The editorial received two separate responses from investigators who supported the non-oxidative glucose consumption as the main process supporting neural activity, signaling that the gap between the two groups remained. The present perspective highlights the principal disagreements that divide this utmost important field of research. It argues that the main reason for these disagreements is rooted in the assumption that pyruvate is the end-product of aerobic glycolysis, even when many among those who adhere to this assumption accept that in the active brain glycolysis is the main provider of the necessary ATP and the end-product is lactate under aerobic conditions. The consideration of a paradigm shift, according to which lactate is the real end-product of glycolysis, independent of the presence or absence of oxygen, could bridge the great divide between those who separate glycolysis into two outcomes and those who profess that there is only one, prefix-less glycolytic pathway that always ends with the production of lactate. Full article

Aneurysmal subarachnoid hemorrhage (SAH) remains a devastating cerebrovascular disorder with high morbidity and mortality, despite advances in aneurysm securing and neurocritical care. Clinical outcomes are determined by early brain injury (EBI), delayed cerebral ischemia (DCI), hydrocephalus, and long-term cognitive impairment, extending beyond the traditional focus on large-vessel vasospasm alone. Emerging evidence identifies the dysfunction of the glymphatic system and meningeal lymphatic pathway, the brain’s primary clearance pathways, as a central and unifying mechanism linking acute hemorrhagic injury to delayed and chronic neurological sequelae. Following SAH, acute intracranial pressure elevation, subarachnoid blood clot burden, loss of arterial pulsatility, venous congestion, astrocytic aquaporin-4 perivascular depolarization, and neuroinflammation converge to suppress cerebrospinal fluid–interstitial fluid exchange and outflow in glymphatic system and subsequent meningeal lymphatic drainage. Persistent clearance failure promotes the retention of blood breakdown products, inflammatory mediators, and metabolic waste, amplifying microvascular dysfunction, cortical spreading depolarizations, blood–brain barrier disruption, and secondary ischemic injury. Importantly, accumulating data highlight venous pathology and meningeal lymphatic impairment as critical, yet underappreciated, contributors to delayed injury and post-SAH hydrocephalus. In this review, we synthesize the current knowledge of the physiological organization of glymphatic and meningeal lymphatic systems, delineate the mechanistic and molecular drivers of their dysfunction after SAH, and discuss clinical implications for EBI, DCI, hydrocephalus, and long-term cognitive outcomes. We further outline future directions, including translational imaging, biomarker development, and therapeutic strategies targeting clearance pathways, to advance disease-modifying approaches in SAH. Full article