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Tc17 cells (IL-17 The percentage of Tc17 cells, monocytes and IL-1β Higher populations of Tc17 cells, IL-1β The present results show that suppressing IL-1β expression by preventing CD80 [Figure: see text] The online version contains supplementary material available at 10.1186/s12964-026-02785-4. Show less

Following spinal cord injury (SCI), neuroinflammation driven by lipid-laden macrophage foam cells is a key pathology, yet how these cells manage their lipid homeostasis is unclear. We delineate a neuroprotective axis in which macrophages deploy apolipoprotein E (APOE) to transfer intracellular lipids to neighboring cells, especially fibroblasts. Genetic ablation of The online version contains supplementary material available at 10.1186/s12974-026-03756-9. Show less

The apolipoprotein E ε4 (APOE ε4) allele, a major genetic risk factor for Alzheimer's disease, is associated with early atrophy in the precuneus and posterior cingulate cortex. Whether physical activity can mitigate this atrophy in high-risk APOE ε4 carriers remains unclear. This study aimed to determine whether physical activity can reduce such neurodegenerative changes in older adults carrying this allele. This 10-year longitudinal study included 295 community-dwelling older adults (154 men and 141 women; age ≥65 years). Baseline physical activity was measured using accelerometers and analyzed according to activity intensity. Participants were categorized as APOE ε4 carriers or non-carriers. Volumes of the precuneus and posterior cingulate cortex were assessed using longitudinal magnetic resonance imaging. Sex-stratified linear mixed models examined the interaction between physical activity and APOE ε4 status on brain volume changes, adjusting for relevant covariates. The moderate-to-vigorous physical activity (MVPA) × APOE ε4 × year effect in women's left precuneus was significant unadjusted but not after false discovery rate (FDR; 16 models) and exploratory. Left precuneus volume declined significantly over 10 years regardless of MVPA level or APOE ε4 genotype (each p < 0.0001). However, among APOE ε4 carriers, greater time spent in MVPA slowed the rate of volume decline. No similar effect was observed in men. Higher habitual MVPA may be associated with slower left precuneus decline in APOE ε4-positive women. As this exploratory three‑way effect was FDR‑nonsignificant, targeted replication is needed to clarify the role of everyday activity in genetically vulnerable groups. Show less

Alzheimer disease (AD) pathology may begin decades before symptoms. Genetic factors, such as APOE ε4 carrier status and polygenic risk scores (PRS), influence AD risk, but their roles in cognitive decline among Asian populations remain unclear. To evaluate whether APOE ε4 carrier status and a non-APOE polygenic risk score (PRS_ADnapoe) are associated with age-related cognitive decline in community-dwelling older adults in Taiwan. This prospective cohort study used data from 2 assessment waves of the Healthy Aging Longitudinal Study in Taiwan, spanning 2009 to 2019. Participants were aged 55 years and older and had both genetic data and Mini-Mental State Examination (MMSE) scores. Data analyses were conducted from August to December 2025. APOE ε4 carrier status (noncarrier, heterozygote, homozygote) and PRS_ADnapoe score, derived from genome-wide association summary statistics excluding APOE variants. The primary outcome was change in MMSE scores, which were assessed cross-sectionally and longitudinally, modeled with mixed-effects regression accounting for age-related effects and covariates including sex, education, smoking, and population structure. Among 4392 participants (mean [SD] age, 68.2 [7.8] years; 2359 [53.7%] women), 723 (16.5%) were APOE ε4 heterozygotes and 33 (0.8%) were APOE ε4 homozygotes. Over a mean (SD) follow-up of 6.3 (0.9) years, the mean (SD) annual MMSE decline was -0.2 (0.5). APOE ε4 carriage was associated with a significantly steeper quadratic age-associated decline in MMSE scores compared with noncarriers (estimate, -0.005; SE, 0.001; P = .001). This association was strongest among homozygotes (estimate, -0.017; SE, 0.008; P = .03), with MMSE trajectories diverging after approximately age 70 years. In contrast, PRS_ADnapoe scores were not associated with MMSE decline. Sensitivity analyses restricted to participants with 2-wave data and adjusted with inverse probability of censoring weighting confirmed these findings. In this cohort study of middle-aged and older adults in Taiwan, APOE ε4 carriage, particularly homozygosity, was associated with accelerated age-related cognitive decline detectable after age 70 years, whereas non-APOE polygenic risk was not associated with cognitive decline over the current follow-up. These results highlight the potential utility of early genetic risk awareness and support consideration of targeted preventive strategies for APOE ε4 carriers. Show less

Research suggests varying effects of fatty acids on cognitive function and brain structure in neurocognitive disorders, but inconsistent findings call for further investigation and advanced neuroimaging techniques. This study investigated the relationship between serum fatty acid levels (omega-3 PUFAs, omega-6 PUFAs, omega-6:omega-3 ratio, MUFAs, and SFAs) and temporal lobe volume in cognitively normal (CN) individuals, those with mild cognitive impairment (MCI), and those with Alzheimer's disease (AD). The results indicated that, as expected, there was a significant difference in temporal lobe volumes (p < 0.001), with the AD group showing more pronounced reductions in volume compared to both the CN and MCI groups. Unexpectedly, higher plasma omega-3 PUFA levels were associated with reduced temporal lobe volume (β = - 0.31, p = 0.021), and a lower omega-6:omega-3 ratio was also associated with diminished temporal lobe volume (β = 0.26, p = 0.039), both observed only in the AD group, after adjustment for age, gender, education, and APOE ε4 allele status as potential confounders. No significant associations were observed for any lipids with temporal lobe volumes in the CN or MCI groups. Interestingly, the only significant association observed between fatty acids and cognitive function was in the CN group, where higher MUFAs and SFAs were both associated with worse cognitive scores. In short, higher omega-3 PUFA levels and a lower omega-6:omega-3 ratio were associated with reduced temporal lobe volume in Alzheimer's patients not using fatty acid supplements. Notably, this observational cross-sectional study cannot establish causality and should be interpreted cautiously, as the findings may be influenced by residual confounding, non-fasting sampling, potential reverse causality, lack of detailed dietary and longitudinal data, and methodological constraints including limited lipid characterization and region-specific morphometric analysis. Further research is needed to confirm these findings and investigate potential mechanisms. Show less

Determining apolipoprotein E (APOE) ε4 allele status, a key genetic risk factor for Alzheimer's disease (AD), requires molecular genotyping infrastructure not widely accessible beyond specialized centers. A fully automated high-throughput apoE E4 proteotyping immunoassay was evaluated for clinical performance (460 participants across three cohorts) and analytical validity. Concordance with polymerase chain reaction (PCR)-based genotyping and measures of analytical validity were reported. The apoE E4 immunoassay demonstrated 99.6% (95% confidence interval [CI]: 98.4% to 99.9%) concordance with PCR-based APOE ε4 genotype results across the pooled clinical cohort; 100.0% (95% CI: 97.1% to 100.0%) in those with AD (N = 127) and 99.4% (95% CI: 97.8% to 99.8%) in those without AD (333). The assay met analytical validity criteria for E4 isoform specificity, interference, precision, and stability. The apoE E4 immunoassay demonstrated high concordance with PCR-based genotyping and robust analytical validity, offering an accessible alternative for APOE ε4 zygosity assessment. A novel high-throughput plasma-based proteotyping immunoassay for APOE ε4 zygosity classification was developed and evaluated for clinical performance and analytical validity. The apoE E4 immunoassay demonstrated high concordance (99.6%) with PCR-based APOE ε4 genotyping across a diverse international cohort, and a robust analytical profile. An apoE E4 immunoassay may offer a more cost-effective and accessible alternative to DNA genotyping approaches currently used for AD risk evaluation and anti-amyloid treatment decisions. Show less

Alzheimer's disease (AD) is increasingly recognized as a disorder of innate immune dysregulation within the central nervous system. The triggering receptor expressed on myeloid cells 2 (TREM2), a microglial immunoreceptor, has emerged as a pivotal genetic risk factor for late-onset AD, underscoring the critical role of neuroimmune interactions in disease pathogenesis. This review synthesizes recent advances concerning TREM2's modulation of core microglial functions, including phagocytosis, inflammatory signaling, cellular metabolism, and survival, processes that are essential for responding to amyloid-β plaques and neuronal damage. We highlight the TREM2-APOE pathway as a central mechanism driving the disease-associated microglia (DAM) phenotype and examine how loss-of-function mutations such as Show less

Growing evidence suggests that both ApoE genotype and metabolic disturbances including insulin resistance (IR) and obesity constitute risk factors for Alzheimer's disease (AD). However, large-scale studies investigating whether ApoE genotype interacts with metabolic abnormalities to indirectly impair cognitive function in AD remain scarce. This cross-sectional study aimed to explore the associations between ApoE genotype, metabolic disturbances [IR assessed by triglyceride-glucose (TyG) index and body mass index (BMI)], and cognitive function in AD patients. We analyzed 1,162 clinically diagnosed probable AD patients from the Cognitive Impairment Clinic at Tianjin Huanhu Hospital. Participants were categorized by ApoE ε4 carrier status. Metabolic parameters were evaluated using the TyG index and BMI. Mediation effect models were employed to assess the relationships between ApoE genotype, metabolic indices, and cognitive function. ApoE ε4 carriers exhibited significantly lower BMI ( ApoE ε4 carriers demonstrate a distinct metabolic profile characterized by lower BMI and elevated TyG index, associated with poorer cognitive performance. Our findings suggest that ApoE ε4 may indirectly influence AD cognition through metabolic pathways, highlighting early interventions targeting ApoE-related metabolic dysregulation as potential strategies to delay AD progression. Show less

In recent years, lecanemab received regulatory approval from several regulatory agencies. The safety profile, particularly the risk of amyloid-related imaging abnormalities (ARIA), necessitates post-marketing surveillance. From a public health perspective, generating robust real-world evidence (RWE) is essential. This study aims to inform policy and clinical decision-makers by analyzing prescribing information, literature evidence, and the FDA Adverse Events Reporting System (FAERS) pharmacovigilance reports. This study employed a mixed-method approach. First, prescribing information for lecanemab was collected and compared across four regulatory agencies. Second, a systematic literature review was conducted in MEDLINE and Embase to identify RWE studies reporting adverse events (AEs), symptoms, or management strategies in patients treated with lecanemab. Finally, post-marketing safety data from the FAERS database were analyzed. Four regulatory agencies have approved lecanemab through different pathways, each requiring confirmation of amyloid pathology and careful assessment of ARIA risk, particularly in Apolipoprotein E (ApoE) ε4 homozygotes. Notable differences exist across agencies regarding indications, contraindications, monitoring protocols, and criteria for treatment suspension, resumption, or discontinuation. All authorities mandate post-marketing programs to ensure ongoing monitoring of safety and effectiveness. A bibliographic search identified 26 studies. Nine cohort studies included between 19 and 407 participants and reported follow-up periods ranging from 6 to 14 months; in a few studies, lecanemab was administered to individuals with moderate or severe AD. As expected, infusion-related reactions (IRRs) and ARIA were the most frequent adverse events, predominantly occurring within the first seven infusions. Some studies reported preliminary efficacy outcomes, although attrition bias may have affected these findings. Seventeen case reports described nineteen individuals aged 57–82, with most AEs arising between the 3rd and 7th infusion and primarily consisting of ARIA; serious events such as stroke, seizures, and two fatalities were also noted. In most cases, lecanemab was paused or permanently discontinued. Analysis of the FAERS database identified 1,286 reports revealing 2,627 AEs, of which 30% were classified as serious, including forty-six deaths. The most reported AEs were headache, ARIA-E, ARIA-H, and chills. ARIA-E and ARIA-H have similar demographics, onset timing, and severity profiles. This study highlights the complexity of lecanemab’s safety profile and the variability in regulatory prescribing recommendations. While ARIA, especially in ApoE ε4 homozygotes, remains the most frequent adverse event, its severity ranges from mild to, in rare cases, severe or fatal. These findings underscore the need for robust post-marketing surveillance and harmonized recommendations to ensure safe and effective clinical use. The online version contains supplementary material available at 10.1007/s10072-026-08829-4. Show less

The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer's disease (sAD), yet its cell-autonomous effects remain poorly understood. While young, asymptomatic APOE4 carriers exhibit abnormal brain metabolism, the mechanistic link between mitochondrial dysfunction and lysosomal-autophagic failure remains unclear. In this study, we conducted a comprehensive analysis of primary human fibroblasts from APOE3 controls, APOE4, and sAD donors to assess mitochondrial bioenergetics, oxidative stress, autophagy, and lysosomal function. APOE4 fibroblasts displayed increased mitochondrial content-associated markers (PGC1α, mtDNA) accompanied by reduced respiratory capacity, elevated proton leak, and excessive mitochondrial ROS. In parallel, APOE4 fibroblasts showed impaired autophagic flux and reduced LC3-TOMM20 colocalization, indicating defective mitophagy. Lysosomal proteolytic activity, assessed using DQ-BSA, was significantly reduced and remained unresponsive under to starvation, in contrast to the partial recovery observed in sAD cells. Pharmacological targeting of mitochondrial ROS with site-specific inhibitors revealed that complex III-derived ROS is the predominant driver of redox stress in APOE4 fibroblasts, while complex I contributes primarily in sAD. Notably, selective inhibition of complex III-derived ROS with S3QEL restored lysosomal degradation, autophagic flux, and mitochondrial respiration in APOE4 cells. Together, these findings demonstrate that mitochondrial oxidative stress disrupts the mitochondria-lysosome axis in an APOE4-specific manner, revealing early and mechanistically distinct vulnerabilities that may precede neurodegeneration. Our results challenge the notion that APOE4 merely amplifies AD pathology and instead identity site-specific redox signaling as a promising target for allele-informed interventions. Show less

The identification of plasma biomarkers for the diagnosis of Alzheimer's disease (AD) has been a longstanding research priority; however, few plasma biomarkers have yet been implemented in routine clinical practice. This study enrolled 141 participants, including 71 patients with AD, 44 individuals with mild cognitive impairment, and 28 cognitively healthy controls (HC). A total of 16 plasma inflammatory proteins were quantified using multiplex liquid-chip assays, and APOE genotyping was performed. The diagnostic utility of plasma proteins was assessed using the least absolute shrinkage and selection operator (LASSO) with nested cross-validation. Patients with AD exhibited marked alterations in plasma inflammatory profiles, with elevated levels of IFN-γ, IL-33, and IL-18, and reduced levels of IL-7 and CCL11. Integrating inflammatory markers with clinical variables and APOE genotype substantially improved discrimination between AD and HC, increasing the area under the ROC curve from 0.863 to 0.953. Among all biomarkers, IFN-γ emerged as the most informative predictor and was significantly elevated in AD patients carrying the APOE ϵ4 allele. Analyses of single-nucleus RNA sequencing data further revealed pronounced enrichment of IFN-γ signaling in APOE4/4 AD-associated lipid droplet-accumulating microglia (LDAM), defined by high ACSL1 expression. Notably, IFN-γ stimulation enhanced ACSL1 expression in ApoE4-overexpressing HMC3 microglial cells. These findings provide a new perspective on the involvement of plasma inflammatory markers for AD diagnosis, and suggest a novel link between IFN-γ and APOE ϵ4-associated AD risk through modulating the ACSL1-driven pathogenic LDAM phenotype. Show less

Our previous study demonstrated that a 6-month combined physical and cognitive training program improved mismatch negativity (MMN)—an event-related potential reflecting the brain’s automatic detection of environmental changes—in older adults with subjective cognitive decline (SCD). However, not all individuals benefited equally from the intervention. Identifying baseline predictors of intervention outcomes could enable the prediction of individual responsiveness and support the development of personalized, stratified intervention strategies to promote brain health in this at-risk population. This study aimed to identify baseline predictors of response to a 6-month combined cognitive and physical training program among older adults with SCD. We conducted a secondary analysis of a cluster-randomized trial involving 33 older adults with SCD who participated in twice-weekly integrated training sessions. MMN was assessed for the analytic sample ( Regression analysis indicated that APOE ε4 non-carriers showed significantly greater improvement in MMN amplitude (β = ‒0.449, APOE ε4 carrier status and baseline physical activity levels may be associated with the effectiveness of multidomain interventions in older adults with SCD. The online version contains supplementary material available at 10.1186/s12877-026-07270-8. Show less

Clarifying relationships between amyloid, tau, and cognition is crucial to understanding dementia risk, but has been mainly performed in non-Hispanic White (NHW) participants. It is unknown whether findings are generalizable to other ethnoracial groups. We evaluated relationships between amyloid-β (Aβ) positivity, apolipoprotein E allele (APOE) ε4, tau-positron emission tomography (PET) Black (β = 0.28, p < 0.001) and Hispanic (β = 0.34, p < 0.001) participants had higher medial temporal lobe (MTL) tau than NHW participants; however, findings were attenuated when accounting for choroid plexus off-target binding. Hispanic participants showed higher tau in lateral temporal regions compared to NHW and Black participants; however, reducing meningeal off-target binding through erosion demonstrated similar lateral temporal tau across groups. Factors other than amyloid and tau may impact cognition in Black participants. PI2620 off-target ethnoracial differences should be investigated. Show less

Parkinson's disease (PD) is a prevalent neurodegenerative disorder predominantly affecting individuals over 60. Its motor symptoms stem from the deterioration of dopaminergic neurons within the substantia nigra. Despite aging being a significant risk factor, the specific mechanisms linking aging and PD pathology remain unclear. Leveraging advancements in single-cell genomics, this study utilizes single-nucleus multiome sequencing to capture transcriptomic and epigenetic profiles from 40,125 cells across the lifespan of the mouse substantia nigra. Our analysis pinpoints age-associated changes at a cell type-specific level, revealing a subset of genes that increasingly express with age and are enriched in PD-related pathways, notably in oligodendrocytes at late aging stages. Integration with five public PD single-cell RNA-seq data sets highlights 85 genes consistently differentially expressed with aging and PD. Key genes such as Show less

Alzheimer disease (AD) is a progressive neurodegenerative disorder that predominantly affects the aging population. Anti-amyloid β (anti-Aβ) therapies, such as lecanemab, have been developed to slow disease progression. However, their use is occasionally associated with amyloid-related imaging abnormalities (ARIA), posing prominent clinical challenges. It has been shown that apolipoprotein E ( This retrospective study evaluated patients with AD who underwent A total of 85 patients were included in the study with rare genotypes excluded from analysis (3 patients). Among the common genotypes, e3/e4 was the most prevalent (55%). Statistical analysis revealed significant association between In this cohort of patients with AD being evaluated for lecanemab therapy, a significant association was identified between Show less

Apolipoproteins (APOs) are essentially structural and functional components of lipoproteins, which are composed of 22 members and their effects on certain types of cancer have been studied. However, their roles in endometrial cancer (EC), which is one of the most common malignant tumors in gynecology were unclear and rarely investigated. We investigated the expression levels of APOs genes in EC. Furthermore, we explored the roles of APOs in prognostic value, and immune infiltrates in EC patients by using different bioinformatics databases. Nine APO genes (APOC1, APOC2, APOC4, APOD, APOE, APOL3, APOL4, APOLD1, and APOO) were found differently expressed between EC and control tissues by the GEPIA2. However, APOC4 was not included in the subsequent analysis due to its low expression in EC tissues. Moreover, mRNA expression levels of APOs were found correlated with the clinicopathological characteristics of EC, including stage, grade, molecular subgroups, p53 mutant conditions, PTEN mutant conditions, and expression levels of ESR1 and ESR2. Meanwhile higher expression levels of APOs were significantly correlated with better (APOD, APOL3) or poorer (APOC1, APOE, APOLD1) OS. ssGSEA showed 7 TILs in EC which differed significantly from those in adjacent noncancerous tissues were correlated with prognosis of EC patients. The expression levels of both APOD and APOE were positively correlated with all 7 TILs. Finally, western blotting showed that 17β-estradiol (E2) increased APOE protein expression level and reduced APOD protein expression level. Furthermore, APOE was identified to promote the cell migration by scratch assay. The expression of APOs may be a promising prognostic biomarker and is associated with immune invasion as a potential target for endometrial cancer. Show less

Atherosclerotic cardiovascular diseases (ASCVDs) remain the primary cause of morbidity and mortality. Macrophages are involved in the progression and regression of atherosclerosis, and macrophage amino acid metabolism is important during this process. Here, we identified that the expression of cystine/glutamate antiporter Slc7a11 was upregulated by oxidized low-density lipoprotein, and specifically enhanced in the macrophages of atherosclerotic plaques. Macrophage-specific Show less

Endoplasmic reticulum (ER) stress during overnutrition causes leptin resistance in obese animals and humans. ER stress induces the activation of the unfolded protein response, which disrupts the leptin signaling pathway, accelerating atherosclerosis development and its complications. Indole-3-carbinol (I3C) improves metabolic dysfunction in diet-induced obesity; however, its role in protecting against ER stress-induced hyperleptinemia remains unclear. Herein, we explored whether dietary I3C alleviates ER stress in apolipoprotein E-deficient (apoE ApoE I3C supplementation (0.05%) resulted in reduced adipose tissue weight and plasma leptin levels compared with those in WD-fed apoE I3C may serve as a feasible compound for preventing atherosclerosis and its associated complications. Show less

Apolipoprotein E (APOE), particularly the ϵ4 allele, is a well-established susceptibility gene for dementias. However, its role in other neurological diseases and injuries remains unclear. This study aims to evaluate APOE as a risk factor for nervous system conditions beyond dementias. A systematic review was conducted from inception to May 2025 across six databases: PubMed, Embase, CINAHL, APA PsycInfo, Web of Science and Cochrane. Studies were included if they employed clinical research methodologies, involved adult participants, completed APOE genotyping and examined APOE as a susceptibility gene in nervous system injuries other than dementias. Thirty-three studies met inclusion criteria, encompassing stroke ( While the APOE genotype may influence susceptibility in intracerebral hemorrhage and chronic traumatic encephalopathy, further research is needed to clarify its broader role and underlying mechanisms in non-dementia nervous system diseases and injuries. Show less

Atherosclerotic macrophages predominantly exhibit a pro-inflammatory phenotype, driving chronic inflammatory and accelerating atherosclerotic progression. Interferon regulatory factor 5 (IRF5) is highly expressed in lesional macrophages within advanced atherosclerotic plaques, where it promotes the secretion of pro-inflammatory cytokines. However, current approaches lack an effective therapeutic strategy to specifically silence this gene in lesional macrophages for atherosclerosis treatment. This study aims to develop and evaluate a dual-targeted, siRNA-based nanotherapeutic platform that selectively acts on atherosclerosis-promoting genes in plaque macrophages, offering a potential strategy for treating atherosclerosis by reprogramming lesional macrophages. Here we designed and developed dual-targeted liposome-based nano-immunotherapeutics encapsulating small interfering RNA (siRNA) against IRF5 (siIRF5) to reprogram macrophage phenotypes within advanced plaques. In high-fat diet-fed Show less

Mitochondrial dysfunction is a hallmark of neurodegenerative diseases, where respiratory defects and downstream bioenergetic failures arise from impaired mitophagy or the accumulation of damaged mitochondria. Mitophagy is a mitochondrial quality-control pathway in which mitochondria tagged with ubiquitin phosphorylated at Serine 65 (pS65-Ub) are targeted for degradation via the autophagy-lysosome system. We previously identified a significant genome-wide association between apolipoprotein E ε4 [APOE ε4] with pS65-Ub levels in the hippocampus of Lewy body disease (LBD). However, the relationship between genetic background in the mitochondrial genome and the PINK1-PRKN pathway biomarker pS65-Ub remains to be elucidated. In this study, we examined whether mitochondrial DNA (mtDNA) variation contributes to changes in pS65-Ub level in 514 neuropathologically confirmed LBD brains, with replication in an independent cohort of 384 LBD brains. No individual mtDNA haplogroup was significantly associated with pS65-Ub levels after correction for multiple testing (P < 0.005 considered significant); mtDNA haplogroup V exhibited a nominally significant (P < 0.05) association, but this association was not observed in an independent replication series. Our data reveal an overall lack of direct evidence linking mtDNA variations to mitophagy marker pS65-Ub levels in LBD, suggesting that mitochondrial damage is unlikely to be explained by major mtDNA determinants alone and may instead reflect cumulative and multilayered perturbations of mitochondrial function. Single cell analyses combined with larger replication cohorts integrating multi-omics datasets will be essential to validate these findings and to advance the discovery of biomarkers for mitochondrial dysfunction in neurodegeneration. Show less

Cervical cancer (CC) is the most common gynecological malignancy and is strongly linked to human papillomavirus (HPV) infection. Currently, immune checkpoint blockade therapy has shown limited clinical benefits for CC, highlighting the need to find more effective therapeutic targets. LILRB4, a member of the leukocyte immunoglobulin-like receptor superfamily, is considered a key mediator of cancer immunosuppression. However, its role in the CC immune microenvironment remains unclear. Here, LILRB4 expression was upregulated in CC tissues, and high expression levels were positively associated with advanced disease and immunosuppressive genes in tumors. In an immunocompetent mouse model, LILRB4 expression in CC tumors increased with tumor growth, whereas blocking LILRB4 reduced tumor growth. Flow cytometry analysis revealed that blockade of LILRB4 reduced CD8 Show less

The neural precursor cell expressed developmentally down-regulated protein 1 (NEDD1) is implicated in tumorigenesis, but its role in hepatocellular carcinoma (HCC) remains unclear. This study aims to explore the oncogenic role, regulatory mechanisms, and tumor microenvironment interactions of NEDD1 in HCC. Multi-omics analyses were performed using public datasets (TCGA, GEO) and in-house clinical samples. These included expression and survival analysis, epigenetic (DNA methylation) and post-translational (phosphorylation) profiling, functional pathway enrichment, and drug sensitivity prediction. Functional validation was conducted via NEDD1 knockdown in HCC cells and a subcutaneous xenograft model. The co-expression and spatial distribution of NEDD1 and its predicted partner MZT2B were investigated using single-cell (GSE140228) and spatial transcriptomic (HRA000437) datasets. NEDD1 was significantly overexpressed in HCC tissues and correlated with poor prognosis. Its overexpression was potentially linked to promoter hypomethylation and aberrant phosphorylation. NEDD1 knockdown suppressed HCC cell proliferation, migration, and tumor growth in vivo. Notably, NEDD1 expression positively correlated with immune checkpoint molecules (PD-1, CTLA-4), and low NEDD1 expression was associated with better predicted response to immunotherapy. Single-cell and spatial transcriptomics revealed that NEDD1 and MZT2B co-expression was highly enriched in specific macrophage subsets (e.g., APOE+) and exhibited cell context-dependent heterogeneity, suggesting they may constitute a dynamic functional module within the HCC microenvironment. This multi-omics study suggests NEDD1 as a potential prognostic biomarker and therapeutic target in HCC. We propose a novel model wherein the NEDD1-MZT2B module may operate in both tumor cells and immunosuppressive macrophages, potentially influencing disease progression and immunotherapy response. Show less

Medial temporal lobe amnestic syndrome (MTLA) is classically considered a hallmark of Alzheimer's disease (AD). However, emerging evidence suggests etiological heterogeneity, challenging the assumption that MTLA universally reflects AD pathology. To determine the prevalence of amyloid pathology in isolated MTLA, identify phenotypic and genetic risk factors, and characterize associated network vulnerabilities in amnestic mild cognitive impairment (aMCI). This retrospective observational study analyzed 55 patients with isolated MTLA at the aMCI stage. Participants underwent neuropsychological testing, cerebrospinal fluid (CSF) biomarker analysis, amyloid PET, and 18FDG-PET. Patients were stratified by amyloid status (positive/negative) and compared for APOE genotype, clinical features, and metabolic patterns. Statistical analyses included the Kruskal-Wallis test for non-parametric group comparisons and chi-square tests for categorical genetic associations. Amyloid pathology was observed in only 67% (37/55) of MTLA patients, dissociating the syndrome from AD in one-third of cases. Amyloid-positive patients demonstrated a significantly higher APOE ɛ4 carrier rate compared to amyloid-negative peers (χ MTLA syndrome is not homogeneous on the biological level and amyloid pathology and APOE ɛ4 genotype stratify patients into distinct subgroups. Amyloid-positive cases demonstrate inferotemporal hypometabolism, suggesting AD-related network vulnerability. By contrast, amyloid-negative MTLA group shows no systemic brain network vulnerabilities, likely due to its heterogeneous etiological origins. These findings advocate for a precision medicine framework integrating biomarkers to guide therapeutic strategies, moving beyond syndromic diagnoses to target underlying mechanisms. Show less

Accumulating evidence suggested that bile acids play a significant role in modulating metabolic and inflammatory diseases. In this study, we investigated the roles of the farnesoid X receptor (FXR) and its endogenous antagonist hyodeoxycholic acid (HDCA) in the development of atherosclerosis (AS). We found that serum HDCA was significantly reduced in patients with AS, and systemic HDCA therapy attenuated plaque burden in vivo. Adoptive transfer of HDCA-treated Foxp3+ Tregs into ApoE-deficient recipients reduced lesion growth, whereas FXR-deficient Tregs failed to confer benefit. HDCA enhanced Treg migration and accumulation within plaques and reprogrammed Treg metabolism by antagonizing FXR and modulating PD-1/mTORC1 signaling. This shift relieved CPT1a-driven fatty acid oxidation bias, increased glycolysis and ATP production, and improved migratory capacity and effector function. We further identify ZNF671 as a transcriptional inhibitor of Treg migration that is mitigated by HDCA-dependent metabolic switching. Collectively, HDCA reduced FXR-mediated metabolic constraints while activating glycolytic and migratory programs in Tregs, thereby improving lipid handling and immune regulation within the plaque microenvironment. These findings position the HDCA-FXR-PD-1/mTORC1 axis as a novel immunometabolic target for AS. Show less

Vitiligo pathogenesis involves progressive melanocyte loss and keratinocyte dysfunction, which are driven primarily by oxidative stress resulting from excessive ROS accumulation. We engineered a temporally controlled hydrogel microneedle system that integrates ginseng-derived exosomes (G-Exos) with biomimetic polydopamine nanoparticles (PDA@PEGs) to concurrently target the pathogenic triad of vitiligo, including oxidative stress, inflammation, and melanocyte deficiency. This system employs methacrylated hyaluronic acid (HAMA) hydrogel microneedles for rapid PDA@PEG release while utilizing glyceryl monostearate micelles to achieve matrix metalloproteinase-9 (MMP-9)-responsive G-Exo release at inflammatory foci, enabling intelligent spatiotemporal control. Functionally, G-Exos help restore redox homeostasis and suppress inflammation through bioactive constituents, thereby protecting melanocytes and enhancing keratinocyte proliferation. Moreover, PDA@PEG promotes repigmentation through the dual mechanisms of exogenous melanin deposition and endogenous melanogenesis stimulation. In murine models, this strategy achieves significant repigmentation within 3 weeks by activating follicular stem cells, upregulating melanogenic markers (Tyr/Mc1r), increasing antioxidant defense (ApoE), and suppressing inflammatory signaling (IL-17). This natural-biomimetic hybrid design leverages biocompatible materials to co-target multiple pathological axes, offering a novel self-adaptive approach for microenvironmental rehabilitation in vitiligo. Show less

Globally, Alzheimer's disease (AD) is the leading cause of dementia. Key symptoms include extracellular amyloid β (Aβ) accumulation, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, and BBB disruption. Integrative solutions are needed because conventional medicines merely relieve symptoms and cannot stop disease progression. Low-density lipoprotein receptor-related protein 1 (LRP1) plays a crucial role in Aβ efflux, tau control, neuroinflammatory signaling, and neurovascular unit maintenance, making it a promising but unexplored therapeutic target. In AD and aging, LRP1 deficiency worsens clearance, vascular impairment, and neurodegeneration. Ligand-functionalized nanocarriers, antibodies, and gene manipulation show preclinical promise, but lower receptor expression, systemic off-target effects, and BBB penetration are challenges. Recent advances suggest innovative strategies, such as upregulating hepatic LRP1 for peripheral Aβ storage, modulating cofactors like ANKS1A (ankyrin repeat and SAM domain containing protein 1A) for receptor trafficking, using engineered nanoparticles or extracellular vesicles as Aβ decoys, preventing negative apolipoprotein E: ApoE4 and LRP1 interactions, and promoting neuroprotective pathways through LRP1 modulation. Endothelial-targeted gene therapy and dual transport rebalancing, which increases LRP1-mediated efflux and decreases RAGE-driven influx, are complementary. These precision strategies reposition LRP1 as a multifaceted therapeutic gateway rather than a clearance receptor, combining biomarker-driven patient stratification with next-generation delivery systems to transform AD disease-modifying therapies. Show less

Perinatal brain injury remains a major cause of neonatal morbidity and lifelong neurological disability. Despite advances in neonatal care, the molecular determinants that modulate vulnerability and recovery in the immature brain remain poorly defined. Genetic variation is increasingly recognized as a contributor to the heterogeneous susceptibility observed among affected infants. Among the genes implicated in neurodevelopmental outcomes, apolipoprotein E (ApoE) has emerged as a key regulator of lipid metabolism, neuroinflammatory signaling, and neuronal repair in the central nervous system. This systematic review examines clinical studies linking APOE genotype to the occurrence, severity, and outcome of perinatal brain injury, including intraventricular hemorrhage, hypoxic–ischemic encephalopathy, and perinatal stroke, and integrates these findings with a narrative synthesis of experimental and mechanistic literature. Available human data remain limited and heterogeneous. While some studies suggest that the ε2 and ε4 alleles may be associated with increased susceptibility to severe injury and poorer outcomes, findings are inconsistent and require independent replication. Preclinical studies further demonstrate that ApoE modulates glial activation, lipid and cholesterol transport, blood–brain barrier integrity, and neuronal survival following hypoxic–ischemic and inflammatory insults. Isoform-specific effects, especially associated with ApoE4, appear to exacerbate neuroinflammatory and vascular dysfunction. However, despite converging evidence from animal models and adult neurological disease, ApoE-dependent mechanisms in the developing brain remain insufficiently explored. Overall, this review highlights APOE genotype as a plausible contributor to vulnerability following perinatal brain injury and underscores the need for large, well-characterized neonatal cohorts and developmentally appropriate mechanistic studies to inform future neuroprotective strategies. The online version contains supplementary material available at 10.1186/s40348-026-00223-6. Show less

This study aims to systematically investigate the multi-target mechanisms of cobalamin in the treatment of ischemic stroke using network pharmacology and molecular docking approaches. We screened databases to identify the targets of cobalamin and performed intersected with with ischemic stroke-related targets to construct a “drug-target-disease” interaction network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to identify key biological processes and signaling pathways. Additionally, molecular docking simulations were performed to assess the binding affinity between cobalamin and hub proteins. Molecular dynamics (MD) simulations were used to assess the stability of the protein–ligand complexes over a 500 ns simulation period. Additionally, ADME (Absorption, Distribution, Metabolism, Excretion) and blood–brain barrier (BBB) permeability predictions were made using ADMETlab 3.0 and admetSAR 3.0. A total of 95 therapeutic targets of cobalamin for ischemic stroke were identified. Network analysis and molecular docking highlighted eight core targets—ALB, TIMP1, PLG, FN1, AGT, SERPINE1, APOE, and SPP1—with high binding affinities to cobalamin. GO analysis suggested that cobalamin regulates inflammatory responses, post-translational modifications, complement binding, and lipoprotein particle binding. KEGG analysis identified complement and coagulation cascades, the PI3K/AKT pathway, and inflammation-related signaling as central to its therapeutic effects. Molecular docking showed strong binding to ALB and TIMP1, which was further confirmed by MD simulations, with minimal conformational changes. The PLG-cobalamin complex exhibited more fluctuations. ADME analysis revealed low passive permeability, particularly across the blood–brain barrier, but moderate distribution and high plasma protein binding. This study provides evidence that cobalamin may offer neuroprotective effects in ischemic stroke by interacting with key target proteins involved in coagulation, inflammation, and lipid metabolism. The findings highlight the potential of cobalamin as a therapeutic agent, although its limited ability to cross the blood–brain barrier may restrict its oral use. Further experimental validation and development of suitable delivery methods are needed to fully realize cobalamin’s potential in stroke therapy. The online version contains supplementary material available at 10.1038/s41598-026-41564-6. Show less