Secondary injury after spinal cord injury (SCI) develops through intertwined oxidative, metabolic and inflammatory processes that engage several programmes of regulated cell death. Ferroptosis and pyroptosis are both implicated in experimental SCI, but their relationship across cellular compartments and injury phases remains incompletely understood. Ferroptotic injury is prominent in neurons, oligodendrocyte-lineage cells and vascular endothelium. Inflammasome-gasdermin signalling is concentrated mainly in microglia and infiltrating myeloid cells. Their partial cellular separation raises the possibility that coupling occurs through shared lesion stress and communication between neighbouring populations. This review examines how metabolic, redox and inflammatory disturbances shape ferroptosis-pyroptosis coupling across cells and over time, and distinguishes common upstream regulation from direct cross-pathway control. The emerging picture is one of context-dependent metabolic-inflammatory coupling, with the strength and direction of interaction likely to vary across lesion compartments and injury phases. Clinical translation will depend on identifying where and when each pathway is active and on developing biomarkers and treatment strategies matched to lesion biology.

The ABCC9 gene and its cognate protein SUR2 play important roles in neurovascular coupling and are implicated in hippocampal sclerosis of aging (HS-Aging). However, prior studies have not focused on human brain SUR2 expression or SUR2 in glial cells. Here we analyzed cell type-specific ABCC9/SUR2 expression patterns, and correlation with known genetic risk variants, using multiple data sets and a novel antiserum. Existing single-nucleus RNA sequencing data sets and new spatial transcriptomics data indicated that SUR2 transcripts were expressed primarily in human brain pericytes, astrocytes, smooth muscle cells, and endothelial cells. Evaluation of Sur2 expression in a sample of mice brains showed similar results except Sur2 was not detected in the mice astrocytes. In a SUR2-enriched subcluster of human astrocytes, the pattern of transcript expression suggested responsiveness to thyroid hormone signaling: SUR2-correlated gene products were enriched for thyroid hormone-sensitive transcripts and SLCO1C1, the astrocyte thyroid hormone importer, was the transcript with the strongest correlation with SUR2 expression. Cells in the SUR2 + astrocyte cluster tended to have been derived from individuals lacking severe Alzheimer's disease pathology. An ABCC9 single nucleotide variant (rs1914361, also a HS-Aging risk allele) was associated with increased SUR2 expression in astrocytes, but not other cell types. SUR2 mRNA splicing differed between cell types; astrocytes preferentially expressed the SUR2B variant. A novel SUR2 antiserum immunolabeled blood vessel walls and some astrocyte-morphology cells in human brain. Overall, human brain SUR2 expression was enriched among different cell types of the gliovascular unit. A SUR2-enriched, possibly-homeostatic astrocyte subcluster suggested connections to thyroid hormone signaling.

Oxidative stress (OS) is critically implicated in the onset and progression of neurodegenerative diseases (NDDs), yet its genetic determinants remain insufficiently elucidated. This study aims to delineate the putative causal relationships between OS-related genes (OSRGs) and NDDs, along with the potential regulatory and pathogenic mechanisms. Summary-data-based Mendelian randomization (SMR) was conducted to explore the putative causal associations of 936 OSRGs with NDDs, integrating genome-wide association studies (GWAS) data and expression quantitative trait loci (eQTL) data, using a multi-cohort design with blood eQTLs for discovery and replication, followed by brain eQTL validation. Subsequently, colocalization analysis was used to verify putative causal inferences in SMR. In addition, DNA methylation regulation and pathway enrichment analyses were applied to explore potential regulatory and pathogenic mechanisms. Genetically predicted levels of 15 genes were found to be significantly associated with the risk of NDDs. Higher genetically predicted expression of ACE and TP53INP1 was associated with decreased Alzheimer's disease risk, whereas higher TSFM expression was associated with increased multiple sclerosis risk; these associations were consistently supported by replication cohort and brain eQTL validation for ACE and TSFM, while TP53INP1 showed brain-level consistency without replication. Among 15 genes, the expression levels of ACE, TP53INP1, and other 5 genes were regulated by DNA methylation. Pathway enrichment analysis showed specific enrichment in autophagy-apoptosis and mitochondrial pathways. These findings provide genetic evidence supporting a putative causal role of OSRGs on NDDs, offering mechanistic insights and potential therapeutic targets, and substantially advance the pathobiological understanding of NDDs.

Cuproptosis, a copper-dependent form of regulated cell death acting through lipoylated tricarboxylic acid (TCA) cycle proteins, has been proposed as a molecular link between type 2 diabetes and Alzheimer's disease. We asked whether cuproptosis effector genes are dysregulated in a cell-type-specific manner in the human Alzheimer's disease cortex, and whether any such signal survives controls for neuronal composition and disease specificity. Single-nucleus data from 21 prefrontal cortex donors were aggregated to donor-level pseudobulk within each cell type. Four independent bulk cohorts, each contributing one observation per donor, entered a random-effects meta-analysis. Adjustment for estimated neuronal content, competitive and expression-matched null gene-set testing, and comparison against Huntington's disease and vascular dementia were applied as controls. The donor was the unit of replication throughout. No gene-cell-type pair survived correction across the 75 prespecified tests; PDHA1 in inhibitory neurons showed the largest nominal reduction (- 0.418, q = 0.829). In donor-level meta-analysis PDHA1 was lower in Alzheimer's disease in all four cohorts (- 0.457, 95% CI - 0.712 to - 0.201, I[2 ]= 0%) but did not survive correction (q = 0.086). A post hoc lipoylation/pyruvate dehydrogenase/TCA module did reach the adjusted threshold (- 0.245, 95% CI - 0.363 to - 0.127, q = 0.035), whereas the copper modules pooled to zero and moved in opposite directions across cohorts. Comparable reductions occurred in Huntington's disease and vascular dementia, and the disease-control contrasts were not significant. These transcriptional associations do not demonstrate cuproptosis, are not specific to Alzheimer's disease, and are hypothesis-generating only.

Mitochondrial dysfunction is linked to sleep disorders in previous report, but the potential roles of specific genes remain unclear. This study aimed to dissect different subtype-specific genetic associations and their underlying mechanisms. A multi-omics Summary-data-based Mendelian Randomization (SMR) approach was performed to identify potential causal links between mitochondrial function-related genes and sleep disorders. We integrated GWAS data from FinnGen database (the discovery set), independent GWAS datasets (covering different sleep-disorder subtypes and used for validation), and cis-QTLs (including mQTLs, eQTLs, and pQTLs) to perform systematic exploration. Specially, we performed targeted validation of tissue-specific effects, leveraging gene expression data from disease-relevant brain regions within the GTEx database. Our SMR analysis identified mitochondrial function-related genes potentially modulating sleep disorders across biological layers, initially identifying 102 genes at the methylation level, 48 at the gene expression level, and 6 at the protein abundance level. Integrative analysis subsequently prioritized DCXR and ACADVL and revealed their distinct, subtype-specific associations. DCXR exhibited a protective role in sleep apnea while ACADVL showed a paradoxical risk conferring role in daytime sleepiness. In addition, the analysis identified an epigenetic regulatory mechanism for DCXR in which its expression and protein levels are modulated by DNA methylation. Finally, validation in brain-hypothalamus tissue confirmed DCXR as a significant potential protective factor (OR = 0.929, 95% CI: 0.887-0.973, P_HEIDI = 0.999, FDR = 0.2449). Our findings implicate key mitochondrial genes, particularly DCXR and ACADVL, in the pathophysiology of specific sleep disorder subtypes, highlighting potential avenues for precision medicine. Clinical trial number: Not applicable.

Platelet-derived growth factor subunit B (PDGFB) is a key regulator of vascular remodeling, angiogenesis, and blood-brain barrier integrity. Although elevated PDGFB levels have been reported after ischemic injury, whether stroke liability itself causally influences circulating PDGFB levels remains unclear. We performed a two-sample Mendelian randomization (MR) analysis to assess the causal effects of genetically predicted all stroke, ischemic stroke, and cardioembolic stroke on plasma PDGFB concentrations. Genetic instruments were obtained from large-scale GIGASTROKE genome-wide association studies, and outcome data were derived from a proteomics GWAS. Instruments were then filtered by removing variants associated with established cardiovascular risk factors in a phenome-wide screen and outliers identified by RadialMR. The inverse variance-weighted (IVW) method was used as the primary analysis, complemented by weighted median, weighted mode, and MR-Egger approaches. Sensitivity analyses included Cochran's Q statistics, MR-Egger intercept tests, single-SNP analyses, leave-one-out analyses, and MR-PRESSO. IVW analysis demonstrated a significant positive causal association between genetic liability to all stroke and plasma PDGFB levels (β = 0.209, SE = 0.062, 95% CI 0.088 to 0.331, p = 7.3 × 10[-4]). A similar association was observed for ischemic stroke (β = 0.155, SE = 0.059, 95% CI 0.039 to 0.270, p = 0.009), with directionally consistent results across sensitivity analyses. MR-Egger regression for ischemic stroke initially suggested pleiotropy.After removal of a radial-MR outlier (rs2289252), the intercept was attenuated and no longer statistically significant (- 0.0190, p = 0.282). In contrast, no evidence of a causal association was found between cardioembolic stroke liability and plasma PDGFB levels across all MR methods (β = - 0.078, SE = 0.087, 95% CI - 0.248 to 0.092, p = 0.368). These findings provide genetic evidence that liability to stroke, particularly ischemic stroke, is causally associated with increased circulating PDGFB levels, whereas cardioembolic stroke does not show such an effect. This suggests that elevated PDGFB reflects vascular responses specific to ischemic stroke rather than a general consequence of all stroke subtypes.

Mental and behavioural disorders substantially impair everyday functioning, yet the biological mechanisms through which the gut microbiome may contribute to psychiatric vulnerability remain insufficiently characterized. We jointly analysed genome-wide association study data for 473 gut microbial taxa, approximately 1,400 circulating metabolites, and seven mental and behavioural disorders, including schizophrenia, obsessive-compulsive disorder, post-traumatic stress disorder, attention-deficit/hyperactivity disorder, chronic depression, bulimia nervosa, and hypersomnia. Mendelian randomization was used to estimate genetically proxied associations among these traits, and two-step MR was used to evaluate candidate statistical mediation by circulating metabolites. We identified FDR-supported associations for eight microbial taxa across four disorders: UBA8904, Dorea, and Ruminococcus A sp000432335 with ADHD; Pseudomonas aeruginosa, Bifidobacterium kashiwanohense, and CAG-273 sp003534295 with chronic depression; Syntrophorhabdia with bulimia nervosa; and Aneurinibacillales with hypersomnia. Twelve circulating metabolites were statistically consistent with partial mediation of candidate microbiota-disorder associations. Glycocholate glucuronide (1) accounted for an estimated 5.95% of the Syntrophorhabdia-bulimia nervosa association, whereas 5-dodecenoate (12:1n7) was consistent with mediation of 8.28% of the inverse association between CAG-273 sp003534295 and chronic depression. Target enrichment prioritized lipid metabolism and neuroactive ligand-receptor interaction pathways for further study. The inverse association between genetically predicted 5-dodecenoate and depression was reproduced in an independent depression GWAS. These findings nominate candidate microbiota-metabolite pathways for mechanistic investigation; however, residual horizontal pleiotropy and linkage-disequilibrium-related confounding cannot be excluded, and the results should not be interpreted as definitive causal evidence.

Traumatic brain injury (TBI) is associated with complex transcriptional disturbances involving cortical suppression, neuroimmune responses, and altered neuroactive signaling. Although repetitive transcranial magnetic stimulation (rTMS) and acupuncture-related stimulation have been investigated as neuromodulatory strategies after brain injury, the transcriptomic features associated with combined rTMS and press-tack needle (PTN) stimulation remain incompletely understood. In this study, RNA sequencing was performed on prefrontal cortex tissue from Sham rats, TBI rats, and TBI rats treated with combined rTMS + PTN. Differentially expressed genes (DEGs), functional enrichment, pathway-gene interaction networks, protein-protein interaction networks, and gene set enrichment analysis (GSEA) were used to explore transcriptional alterations associated with TBI and combined intervention. TBI induced marked transcriptional changes in the prefrontal cortex, including genes enriched in neuroactive ligand-receptor interaction, calcium signaling, and injury-related pathways. Combined rTMS + PTN stimulation was associated with additional transcriptional remodeling, particularly involving immune-inflammatory pathways such as NF-κB signaling, IL-17 signaling, cytokine-cytokine receptor interaction, and Toll-like receptor signaling. Intersection analysis identified 55 shared TBI-associated and intervention-responsive genes as a candidate signature. Further PPI and GSEA analyses suggested that Nts/Ntsr1, Egr1, Drd1, and related neuroactive signaling molecules may participate in the transcriptional response to combined stimulation after TBI. These findings provide an exploratory RNA-seq-based framework for understanding NTSR1-associated neuroimmune and neuroactive molecular signatures after TBI. Targeted qRT-PCR assessment of selected neuroactive candidate genes, including Ntsrl, Egrl, and Drd1, provided complementary evidence of group-dependent expression differences in an independent animal cohort. Further protein-level and functional validation will be required to determine the causal relationships among these candidate molecules.

Postoperative delirium (POD) and Alzheimer's disease (AD) are increasingly recognized as related neurocognitive conditions, but the aging-associated cell states that may connect them remain poorly defined. Here, we integrated two brain transcriptomic discovery datasets analyzed at single-cell/single-nucleus resolution, including a POD-related cohort (GSE291019) and an AD cohort (GSE129308), together with two independent peripheral-blood bulk transcriptomic datasets (GSE163943 and GSE63060), to identify aging-associated cellular programs and prioritize convergent molecular candidates. Across 184,168 high-quality cells, inhibitory neurons showed the most consistent aging-associated perturbation across the POD- and AD-related datasets. Re-clustering further identified three inhibitory-neuron subtypes, Inh_Neurons2, Inh_Neurons3, and Inh_Neurons5, with relatively high aging-related gene activity and preferential localization to later pseudotime states. Cross-platform integration of aging-associated inhibitory-neuron genes with a shared bulk DEG set identified four convergent candidates: RGL2, AKT1, SYK, and TNFSF13B. Among them, RGL2 emerged as the leading candidate, with the strongest downstream support concentrated in AD-related analyses. In two-sample Mendelian randomization, genetically predicted higher RGL2 expression was associated with increased AD risk, whereas the estimate for the delirium genome-wide association study proxy used for POD-related analyses was not significant. Pathway analyses further linked higher RGL2 expression to complement/coagulation and innate immune-inflammatory programs in AD-related analyses. These findings suggest a model in which POD and AD may partially intersect through aging-vulnerable inhibitory-neuron states and identify RGL2 as a prioritized candidate for downstream mechanistic investigation.

Obsessive-compulsive disorder (OCD) is linked to cortico-striato-thalamo-cortical circuit dysfunction, but molecular programs within striatal circuit nodes remain incompletely characterized. We tested whether translation, mitochondrial bioenergetics, and proteostasis show a coordinated transcriptomic signature in the OCD caudate. We reanalyzed postmortem caudate RNA-sequencing data from GSE262138 after retaining OCD cases and unaffected controls (OCD n = 27; control n = 85). Gene-level models adjusted for RNA integrity number and sex. Ranked gene statistics were used for pathway enrichment, module testing, expression-matched random-gene comparisons, sensitivity analyses, marker-score adjustment, and comparison with published OCD striatal literature. The caudate gene-level landscape showed a broad ranked-expression pattern. Pathway analysis identified recurrent lower expression of translation/ribosome, mitochondrial oxidative phosphorylation, electron-transport, and proteostasis-related terms across annotation systems. Translation/ribosome, mitochondrial/OXPHOS, and proteostasis modules showed lower average shifts relative to expression-matched random gene sets, and the direction remained consistent across sensitivity analyses. OCD caudate transcriptomic variation shows a pathway-level signature centered on translational, bioenergetic, and proteostatic programs. The results connect public postmortem caudate expression data with CSTC circuit biology and provide a focused molecular view of OCD-associated caudate dysfunction.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects over 12 million people worldwide. A central pathological feature is the accumulation of aggregated alpha-synuclein (αS) in Lewy bodies and Lewy neurites. Engineered αS variants such as 3K (E35K+E46K+E61K) and KLK (KTKEGV→KLKEGV in 6 repeats) have been shown to enhance membrane binding and aggregation propensity, contributing to cellular toxicity. To further investigate the impact of 3K and KLK on αS biology, we developed a sensitive assay in a human neuroblastoma model to assess expression levels and cytotoxicity. Relative to wild-type αS, the 3K mutant exhibited reduced steady-state expression and increased toxicity, consistent with prior reports. In contrast, the KLK mutant showed no marked change in protein expression but induced significantly higher toxicity, more than the 3K variant. Furthermore, stearoyl-CoA desaturase (SCD) inhibition partially rescued the toxicity of 3K and KLK αS, with 3K showing greater restoration of cell growth than KLK, validating the sensitivity of our live-cell assay to detect pharmacological responses. These findings underscore the utility of our assay in dissecting disease-relevant mechanisms and highlight the potential of engineered αS variants to model pathogenic features of PD. This platform offers a versatile tool for evaluating therapeutic strategies targeting αS aggregation and toxicity in PD and related synucleinopathies.

Post-stroke Broca-type motor aphasia is characterized by impaired oral expression and naming function (Cătălin Jianu 2022). Single standardized speech rehabilitation requires a long period for neural remodeling and carries a high risk of long-term deterioration of language function. Jin's tongue triple acupuncture is a targeted tongue acupuncture therapy, which is widely adopted as an adjuvant aphasia intervention in multiple rehabilitation departments nationwide. Existing relevant clinical studies have limitations including small sample sizes, single outcome indicators, lack of stratified efficacy comparison, absence of biomarker detection, and merely qualitative safety description.We performed a 1:1 propensity score-matched retrospective cohort analysis to quantify intergroup disparities in language function, peripheral neuroinflammatory mediators, and graded acupuncture-related adverse reactions. We further clarified the target population and therapeutic boundaries of Jin's tongue triple acupuncture while avoiding overestimation of its clinical efficacy. We retrospectively retrieved consecutive inpatient rehabilitation medical records of stroke patients admitted to the Department of Rehabilitation Medicine, Jingzhou First People's Hospital from March 2025 to March 2026. Sample size calculation was performed based on effective rates reported in previous similar studies. Of the 614 initially screened patients, 188 were excluded according to predefined inclusion and exclusion criteria. The remaining 426 eligible patients were divided into a combined group (Jin's tongue triple acupuncture + standardized speech rehabilitation, n = 221) and a control group (standardized speech rehabilitation alone). To balance baseline confounding variables, 1:1 nearest-neighbor propensity score matching with a caliper of 0.05 was conducted; baseline covariates were regarded as balanced when the standardized mean difference (SMD) was less than 0.1. Primary outcomes covered the total score and four subscores (spontaneous speech, naming, repetition, auditory comprehension) of the Aphasia Battery of Chinese (ABC). Secondary outcomes referred to serum concentrations of BDNF, CGRP, ET-1, IL-1β and TNF-α measured via ELISA. Stratified subgroup analyses were carried out in accordance with aphasia severity, stroke subtype, age and type 2 diabetes status. All acupuncture-associated adverse reactions were counted by grading standards. Statistical analyses were completed with SPSS 26.0; propensity score matching was performed via the MatchIt package of R 4.2, and conditional logistic regression was conducted using the clogit function from the survival package Table 1. A total of 182 pairs of samples with balanced baseline data were obtained after matching. After continuous 30-day complete intervention, all ABC subscale scores were significantly improved compared with baseline in both groups. The total ABC score, spontaneous speech score and naming score in the combined group were significantly higher than those in the control group (all P < 0.001). No statistically significant intergroup differences were observed in repetition and auditory comprehension (P > 0.05, Table 2). serological detection revealed statistically significant yet moderate-magnitude changes in the expression levels of peripheral neurotrophic factors and inflammatory mediators in the combined group after intervention (all P < 0.001, Table 3). Stratified analysis revealed that Jin's tongue triple acupuncture yielded definite clinical benefits only in patients with mild and moderate motor aphasia Fig. 4. Patients with ischemic stroke, aged ≤ 65 years and without type 2 diabetes exhibited better intervention responses Fig. 5. The total incidence of acupuncture-related adverse events was 6.59%, all presenting as self-resolving mild reactions without moderate or severe complications Fig. 6. Propensity-matched real-world clinical data demonstrated that adjuvant Jin's tongue triple acupuncture selectively enhanced spontaneous speech and naming performance among subacute stroke survivors with mild-to-moderate ischemic Broca aphasia. The therapy also modulated circulating levels of peripheral neurotrophic factors and inflammatory mediators. This acupuncture therapy appeared to produce limited expressive language improvements in patients with severe aphasia and extensive bilateral cortical lesions; older age, hemorrhagic stroke, and type 2 diabetes might be associated with attenuated rehabilitation responses based on exploratory subgroup analyses. Formal interaction testing is needed to verify whether these factors significantly modify therapeutic efficacy. Mild acupuncture adverse reactions had low incidence and strong self-healing property, yet clear boundaries existed for applicable populations. Individualized rehabilitation protocols should be formulated according to stratified results to reasonably control rehabilitation expectations.

Migraine may involve neuroimmune-related mechanisms, but migraine-associated peripheral immune-cell states remain incompletely defined. We aimed to characterize peripheral blood immune remodeling in migraine at single-cell resolution. We reanalyzed PBMC single-cell RNA-sequencing dataset GSE269117, using migraine and vestibular migraine samples as the migraine group and healthy controls as controls. After quality control, we performed major immune-cell annotation, CD4 T-cell subclustering, pseudobulk differential-expression analysis, pathway enrichment, pseudotime reconstruction, CellChat-based communication analysis, transcription-factor activity inference and AL589693.1-focused state analysis. A total of 31,514 PBMCs from 15 retained biological samples were analyzed and annotated into six major immune-cell populations. Major lineage proportions showed no broad sample-level differences between groups, whereas sample-level analysis of 7,647 CD4 T cells indicated a redistribution of CD4 T-cell states. At the sample level, migraine samples showed enrichment of non-cytotoxic-like CD4 T cells and depletion of cytotoxic-like CD4 T cells compared with controls. CD4 pseudobulk and enrichment analyses highlighted inflammatory, estrogen-response, calcium-responsive and cAMP-related programs, with relative depletion of oxidative phosphorylation, MYC targets and translation-related pathways. Pseudotime analysis supported a shift toward earlier or less cytotoxic CD4 states. CellChat inferred fewer total interactions in migraine than in controls, especially cytotoxic-like CD4-related interactions. AL589693.1 emerged as a migraine-associated transcript, and its no-self signature marked a non-cytotoxic-skewed CD4 state that partially contributed to the CD4 imbalance. Peripheral CD4 T-cell state remodeling may represent an important feature of migraine-associated immune alterations, with AL589693.1-positive CD4 states as candidate markers for future validation.

Acute ischemic stroke is a major cause of death and disability, and post-stroke cognitive impairment remains a major clinical challenge. Cardioembolic stroke (CES), often associated with atrial fibrillation, is closely linked to cognitive decline. Increasing evidence suggests that vascular dysfunction contributes to both vascular cognitive impairment and Alzheimer's disease (AD), but the shared molecular basis remains unclear. This study aimed to identify shared molecular signatures and candidate biomarkers linking CES and AD. Gene expression datasets were obtained from the Gene Expression Omnibus database. Differentially expressed genes were identified using limma, and disease-related gene modules were constructed using weighted gene co-expression network analysis. Functional enrichment analyses were performed to explore shared pathways. Three machine learning algorithms-LASSO, SVM-RFE, and random forest-were used to prioritize candidate genes. Receiver operating characteristic analysis, nomogram modeling, single-gene gene set enrichment analysis, and external validation were performed to evaluate the potential relevance of the identified gene. Seven overlapping genes were identified between CES and AD. Among them, SCRIB was consistently selected by the integrated feature-selection workflow and showed moderate diagnostic performance in both internal datasets. Supportive validation was observed in an independent AD dataset and in an atrial fibrillation-related surrogate validation cohort. SCRIB may represent a shared transcriptomic biomarker candidate linking CES and AD. These findings provide preliminary transcriptomic evidence for a potential molecular link between cerebrovascular pathology and neurodegeneration, but further mechanistic and clinical validation is required.

In the face of rising global rates of age-related cognitive decline, identifying accessible, non-pharmacological interventions is a critical public health priority. This narrative review synthesizes contemporary evidence to elucidate the molecular and systemic mechanisms by which voluntary exercise enhances hippocampal-dependent memory. We detail how physical activity initiates a coordinated cascade, beginning with the release of systemic factors like FNDC5/irisin, lactate, and IGF-1. These signals converge to robustly upregulate hippocampal brain-derived neurotrophic factor (BDNF) and its TrkB receptor, activating a master regulatory network that promotes neuronal survival, synaptogenesis, and adult neurogenesis. Furthermore, exercise induces a protective hippocampal milieu characterized by reduced neuroinflammation, enhanced antioxidant defenses, optimized monoaminergic neurotransmission, and improved glymphatic clearance of metabolic waste. Translational human evidence confirms these mechanisms, demonstrating that regular aerobic exercise increases hippocampal volume, strengthens functional connectivity, and elevates serum BDNF, correlating with measurable improvements in episodic and spatial memory across populations from healthy older adults to those with mild cognitive impairment. The review concludes by bridging this mechanistic insight to therapeutic applications, discussing optimal exercise prescriptions, the synergy of exercise with pharmacological and other lifestyle interventions, and the future potential of "exercise mimetics." Ultimately, this synthesis posits voluntary exercise as a potent, plasticity-enhancing therapy whose decoded molecular blueprint provides a scientific foundation for strategies aimed at preserving cognitive resilience throughout the lifespan.