👤 Zhao Yan

Apolipoprotein E (ApoE) serves as a critical molecular nexus between Alzheimer's disease (AD) and atherosclerosis, two age-associated inflammatory disorders that share vascular pathology, amyloid-beta (Aβ) deposition, and lipid dysregulation. Atractylenolide I (AI), a promising therapeutic candidate derived from Show less

The repeated failure of amyloid therapies highlights a core misunderstanding of Alzheimer's disease (AD) origins. A new metabolic paradigm now positions impaired brain metabolism-not protein accumulation-as the central, early driver. Key evidence shows cerebral glucose hypometabolism emerges decades before symptoms, linked to brain insulin resistance ("type 3 diabetes") and mitochondrial dysfunction. The APOE ε4 allele worsens lipid defects thereby, accelerating the progression of AD pathology. These disruptions-alongside gut-brain axis issues-create a self-reinforcing cycle that fuels amyloid β (Aβ), tau, neuroinflammation, and synaptic loss. This framework integrates with the neuron-centric model, explaining disease heterogeneity and the inadequacy of single-target drugs. This review particularly highlights the metabolic perspective in AD, underscoring the need for a radical therapeutic shift: from late stage protein clearance strategies to early, multimodal interventions that restore metabolic homeostasis and disrupt the entire pathogenic continuum. Show less

To investigate the controversial association between exogenous hormone use (EHU) and dementia, with a focus on subtype-specific risks. This prospective cohort study followed 273,069 women in the UK Biobank over 3,802,608 person-years, identifying 4,710 dementia cases. Cox models assessed use of oral contraceptive (OC) and hormone replacement therapy (HRT) in relation to all-cause dementia, Alzheimer's disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD) across treatment durations. Subgroup analyses were stratified by age, ethnicity, APOE status, education, income, and reproductive factors. A systematic review was conducted to synthesize existing evidence. In the cohort study, OC use was associated with reduced risks of all-cause dementia (HR 0.90, 95%CI 0.84-0.95), AD (HR 0.87, 95%CI 0.79-0.95), and VaD (HR 0.81, 95%CI 0.70-0.93), particularly after 4-14 years of use. HRT showed no significant association with increased dementia risk. Synthesized results largely corroborated these findings: OC use was associated with reduced risks of dementia (HR 0.90, 95%CI 0.89-0.92); and although four European studies reported a moderately increased AD risk after post-menopausal HRT use, neither cohort-based studies (HR 0.98, 95%CI 0.90-1.06) nor traditional case-control studies (OR 1.00, 95%CI 0.90-1.11) found an association between HRT and dementia. Our combined evidence does not support an increased risk of dementia associated with OC use; similarly, no clear association was observed between HRT and increased dementia risk. Clinical decisions on EHU should be individualized, balancing overall benefits against potential risks. Show less

Vascular stiffness and aging are critical contributors to cardiovascular diseases. Whether betulinic acid (BA), a natural triterpenoid, alleviates vascular aging remains unclear. Mouse aortic smooth muscle cells (MASMCs) with oleic acid (OA)-induced lipotoxic senescence were treated with BA (30 μM). Transcriptomic analysis and functional assays were conducted. Show less

Retinal detachment (RD) is a prevalent ocular disorder that leads to photoreceptor death and irreversible visual impairment. Following RD, microglia—the resident immune cells of the retina—become activated and participate in regulating inflammatory responses and tissue repair processes. A distinct microglial subtype, disease-associated microglia (DAM) emerges in stressed neuronal microenvironments. However, its specific contribution to photoreceptor degeneration remains poorly understood. Apolipoprotein E (ApoE), a major lipoprotein predominantly expressed in brain and ocular myeloid cells, has been implicated in modulating neurodegeneration within the central nervous system through influencing DAM activation. In this study, we employed an experimental mouse model of RD and observed upregulation of ApoE and DAM-related markers at three days following RD induction. Genetic deletion of ApoE significantly attenuated photoreceptor loss and suppressed neuroinflammatory responses after RD, accompanied by reduced DAM activation. Furthermore, modulation of the ApoE-Galectin-3 axis reduced TUNEL-positive cells and inhibited TLR4-dependent inflammatory cascades post-RD. Using humanized ApoE allele mice, we further elucidated that the ApoE4 isoform significantly downregulated DAM-associated markers (including Galectin-3, Spp-1 and Gpnmb), promoted photoreceptor survival, and attenuated retinal inflammation. In contrast, ApoE2 and ApoE3 conferred no protection benefit compared to wild-type mice after RD. Our findings indicate that ApoE-mediated DAM activation exacerbates photoreceptor degeneration after RD insult. Both ApoE deficiency and ApoE4 expression potentially mitigated RD-induced photoreceptor death and ameliorated neuroinflammatory pathways via suppression of DAM activation. Collectively, our study highlights ApoE4 as a promising therapeutic target for modulating microglial cells to promote neuronal survival in photoreceptor degeneration conditions. The online version contains supplementary material available at 10.1186/s12974-026-03762-x. 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

Abdominal aortic aneurysm (AAA) is a fatal cardiovascular disease with no effective drug treatment currently available. The aberrant expression levels of microRNAs (miRNAs or miRs) contribute to AAA pathogenesis. In the present study, miRNA microarray analysis was performed to screen for differentially expressed miRNAs in the aortas of AAA mice compared with those in control mice, and to clarify the role and mechanism of miRNA‑378a‑5p (miR‑378a‑5p) in the AAA development. A comprehensive miRNA microarray analysis was conducted to screen for differentially expressed miRNAs in the aortas of AAA mice and control mice. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was used to detect the expression levels of miR‑378a‑5p in the serum and aortas of patients with AAA and mice. To clarify the role of miR‑378a‑5p in the AAA development Show less

Periodontitis is linked to dyslipidaemia, but the mechanism still requires further investigation. This study aimed to investigate the periodontitis-dyslipidaemia interplay, comparing the impact of periodontitis-associated versus healthy salivary microbiota on systemic lipid metabolism in mice via the oral-gut axis. NHANES analysis established epidemiological link. ApoE-/- mice received salivary microbiota from periodontally healthy (A-PH) or severe periodontitis (A-SP) donors. Serum lipids and gut microbiota were assessed; correlations between microbial shifts and lipid changes were evaluated. NHANES confirmed significant association between self-reported physician-diagnosed bone loss around teeth and hypercholesterolemia (OR=1.266). A-SP mice exhibited higher TC, LDL and non-HDL compared with A-PH group. Gut dysbiosis featured increased proinflammatory genera ( Collectively, building upon the NHANES link, our findings demonstrate that the salivary microbiome from periodontitis patients, compared to that from healthy individuals, disrupts systemic lipid metabolism and induces gut dysbiosis in mice. The correlation between specific gut microbial shifts and atherogenic lipid profiles provides experimental support for the mediating role of the oral‒gut axis in linking periodontitis to hyperlipidaemia. Show less

COG133, a peptide fragment derived from apolipoprotein E (ApoE) corresponding to residues 133-149, has demonstrated significant anti-inflammatory and neuroprotective activity. However, its precise anti-inflammatory mechanisms and its potential to ameliorate depression-like behaviors remain incompletely understood. This study investigated the effects of COG133 in mouse models of depression induced by lipopolysaccharide (LPS), chronic social defeat stress (CSDS), and corticosterone (CORT), as well as in LPS-stimulated BV-2 microglial cells. We found that COG133 treatment significantly alleviated depression-like phenotypes and suppressed hippocampal neuroinflammation by inhibiting microglial overactivation. Using RNA sequencing (RNA-seq) and biochemical validation, we identified the MKK3/6-p38-ATF2 signaling axis as a central mechanism underlying the anti-inflammatory effects of COG133. Pharmacological modulation of p38 MAPK further confirmed that this pathway is essential for COG133-mediated behavioral and cellular recovery. Together, these findings identify COG133 as a promising peptide candidate for the treatment of depression through modulation of the p38 MAPK-mediated neuroinflammation axis. Show less

The gradual decline of endothelial function and the intensification of inflammatory responses form the basis for the occurrence and development of age-related diseases such as atherosclerosis (AS). Mitochondrial dysfunction-manifested by excessive reactive oxygen species (ROS) production, reduced mitochondrial membrane potential, and impaired mitophagic flux-and sterile inflammation are hallmarks of aged vasculature. We investigated whether bolstering mitochondrial quality control via the novel cell-penetrating antioxidant PEP-1-Catalase (CAT) could mitigate these key features of vascular aging. To model age-associated vascular pathology, ApoE⁻/⁻ mice were fed a high-fat diet (HFD) and treated with PEP-1-CAT. Endothelial cell function, plaque burden, and inflammation were analyzed. In vitro, human endothelial cells (HUVECs) were subjected to inflammatory stress and treated with PEP-1-CAT, with or without modulators of mitophagy. We assessed mitochondrial ROS, membrane potential, NOD-like receptor protein 3 (NLRP3) inflammasome activation, and the PINK1-Parkin pathway. PEP-1-CAT treatment significantly ameliorated atherogenesis and improved features of plaque stability in mice. It suppressed vascular oxidative stress, restored mitochondrial membrane potential, enhanced mitophagic flux, and inhibited NLRP3-driven inflammation. In endothelial cells, PEP-1-CAT attenuated mitochondrial oxidative stress and dysfunction. Crucially, it activated the PINK1-Parkin pathway to promote mitophagy, which was essential for its anti-inflammatory effects, as mitophagy inhibition abrogated the suppression of the NLRP3 inflammasome. Our findings demonstrate that targeting mitochondrial health with PEP-1-CAT alleviates hallmarks of atherosclerotic vascular pathology, including endothelial dysfunction and inflammation, by enhancing mitophagy. This strategy of restoring mitochondrial quality control presents a promising therapeutic approach to delay atherosclerotic vascular pathology. Show less

Calcific aortic valve disease (CAVD) involves pathological mineralization, but the roles of chemokine signaling and ferroptosis remain unclear. This study investigated the regulatory function of C-C motif chemokine ligand 5 (CCL5) in CAVD progression via the chemokine pathway and ferroptosis. Bioinformatics analysis and single-cell RNA sequencing analysis were performed to identify hub genes and potential cell types. Human aortic valve interstitial cells (VICs) were treated with osteogenic medium (OM) to induce calcification. Apoe CCL5 was identified as a key hub gene in CAVD. Knockdown of CCL5 significantly attenuated OM-induced VICs calcification, osteogenic differentiation, oxidative stress, and ferroptosis. Similar protective effects were observed in vivo, with reduced valve thickening and calcification in Apoe CCL5 promoted CAVD progression by activating the chemokine signaling pathway to induce ferroptosis. Targeting CCL5 may offer a novel therapeutic strategy for CAVD. Show less

Diabetic kidney disease (DKD) is a major diabetic complication that often progresses to end-stage renal disease and causes high mortality. Early diagnosis is essential for effective prevention and treatment. To explore the underlying mechanisms of DKD and identify plasma biomarkers for early diagnosis. In this study, healthy adults and individuals with diabetes mellitus (classified into normal albuminuria (NA), microalbuminuria (MI), and macroalbuminuria (MA) groups) were recruited. Plasma samples were collected from all participants, and 12 subjects per group were then randomly selected as a discovery cohort for proteomic analysis. Proteomics identified 95 differentially expressed proteins (DEPs) among the groups. These DEPs associated pathways evolved in a stage-specific manner in which inflammation dominated the early NA/Ctrl stage, complement and coagulation cascades became the main drivers during MI/NA, and MA/MI exhibited newly emerged disturbances in oxidative detoxification, lysosomal function, and nitrogen metabolism alongside sustained complement and coagulation changes. Among them, the complement and coagulation cascades were closely related to DKD progression. Through hub protein analysis, five proteins (FGG, ITIH4, A2M, C3, and APOE) that showed consistent trends across disease stages were identified as potential diagnostic biomarkers for DKD. Our research provides new insights into the mechanisms and early diagnosis of DKD. Show less

Atherosclerosis (AS), the primary pathophysiological foundation of coronary artery disease (CAD), initiates through endothelial dysfunction that facilitates lipid deposition and plaque formation. Emerging evidence implicates dipeptidyl peptidase IV (DPP4) in vascular pathologies, yet its mechanistic role in AS-associated endothelial ferroptosis remains undefined. Multidisciplinary approaches were employed: 1) Bioinformatic analysis of public databases identified DPP4-ferroptosis-AS associations; 2) Clinical samples measured plasma DPP4 levels across CAD severity strata; 3) Atherogenic progression was compared between DPP4 Clinical samples analysis revealed a significant increase in plasma DPP4 levels in patients with severe coronary artery stenosis, with DPP4 enrichment observed at plaque. Animal studies demonstrated that DPP4 deficiency attenuated progression of AS and ferroptosis in murine models. Cellular experiments revealed ox-LDL upregulated DPP4 expression, concomitant with increased ferroptosis susceptibility and endothelial dysfunction. DPP4 inhibition preserved endothelial viability by blocking lipid peroxide accumulation. Mechanistically, mouse proteomics revealed that ferroptosis and autophagy pathways were associated with DPP4 in AS. DPP4 destabilized FTH1 via NCOA4-mediated ferritinophagy, proven by concordant rescue effects of chloroquine (autophagy inhibition) and saxagliptin (DPP4 inhibition) on FTH1 preservation. This study establishes endothelial DPP4 as a regulator of ferritinophagy-driven ferroptosis, inducing endothelial dysfunction in AS. Our findings propose targeting the DPP4-NCOA4-FTH1 axis as a promising strategy to preserve endothelial viability and halt early AS progression, with translational implications for repurposing DPP4 inhibitors in cardiovascular therapeutics. Show less

Congo Red (CR) is the histochemical staining sensor used to diagnose amyloid tissue deposition in current clinical practice. Its characteristic aryl azo linkage is generally considered to be chemically stable. Here, we discovered by serendipity that neutral borate buffer can activate the inert azo bond in CR to covalently modify amyloid proteins at ambient temperature. Such chemistry allowed us to develop a covalent amyloid sensor to image, enrich, and proteotype amyloid deposits in Alzheimer's disease (AD) tissue. We first pinpointed the boronic acid in borate buffer triggers such amyloid bioconjugation and found that ultraviolet-light-induced azo Show less

Lower-extremity arterial disease (LEAD) is a manifestation of atherosclerotic cardiovascular disease, affecting 230 million people worldwide with increasing prevalence. Medial arterial calcification (MAC) is common in LEAD patients and contributes to disease-related mortality. However, therapeutic strategies targeting femoral MAC are lacking, and its underlying mechanisms remain unclear. This study aimed to identify molecular drivers of femoral MAC in LEAD. Calcium deposits and pro-calcifying markers were analyzed in human patient samples using von Kossa staining, immunofluorescence, and gene expression analysis. Femorals showed significantly more calcification and pro-calcifying gene expression than carotids. Given MAC abundance in LEAD, we assessed medial calcification in Apoe-/- mice fed a WD for 4/21 weeks. Digital PCR revealed upregulation of Ddr1 and Bmp2 in femoral versus carotid arteries after 21 weeks of WD. DDR1 expression positively correlated with calcification in human femoral samples. In vitro experiments with mouse femoral vs. carotid vascular smooth muscle cells (VSMCs) confirmed a significantly higher prevalence of calcifying proteins (DDR1, BMP2, and RUNX2) in femoral VSMCs. Additionally, calcification analyses in murine and human VSMCs showed that DDR1 inhibition reduced, while DDR1 activation increased, calcium deposition. Transcriptomic analysis revealed elevated NF-κB expression in human femoral arteries, matching data in femoral VSMCs. DDR1 stimulation activated NF-κB, and its inhibition blocked DDR1-induced calcification. This study identifies DDR1 as a key driver of calcification in LEAD, operating through NF-κB activation and the expression of calcifying proteins. Targeting DDR1 may offer a novel therapeutic approach to prevent MAC in LEAD. Show less

Cognitive impairment is a significant health concern in aging populations, but the interplay between biological aging, lifestyle factors, and genetic susceptibility remains unclear. This study examined whether accelerated biological aging is associated with cognitive impairment, whether lifestyle modifies this association, and how genetic background influences these relationships in Chinese older adults. In this cross-sectional study (2022-2023), 7033 participants from southwestern China were included. Accelerated biological aging was calculated as the residual difference between biological age (based on 10 biomarkers) and chronological age. Lifestyle was assessed via a composite index (smoking, alcohol, physical activity, diet, sleep). Cognitive function was measured using the Chinese Mini-Mental State Examination (C-MMSE), and genetic risk was evaluated through polygenic scores and APOE ε4 status. Linear and logistic regression models assessed associations between accelerated aging and cognition. Accelerated biological aging was associated with lower MMSE scores ( β = -0.243, 95% CI: -0.354, -0.133) and higher cognitive impairment prevalence (OR = 1.098, 95% CI: 1.040, 1.158). An unhealthy lifestyle exacerbated cognitive impairment in biologically older individuals (RERI = 0.25). Those with both accelerated aging and unhealthy lifestyle had the lowest MMSE scores ( β = -1.424, 95% CI: -1.846, -1.003) and highest odds of cognitive impairment (OR = 1.467, 95% CI: 1.194, 1.803). These effects were consistent across all genetic background subgroups. Accelerated aging was associated with lower cognitive function, especially in individuals with unhealthy lifestyles, regardless of genetic susceptibility. This highlights lifestyle modification as a potential intervention target for aging-related cognitive impairment. Show less

Multiple sclerosis (MS) is a chronic neurodegenerative disorder for which dysregulated ferroptosis and necroptosis have demonstrated pathological associations but these lack causal validation in disease susceptibility. This study employed proteome-wide Mendelian randomization (MR) to investigate causal links between ferroptosis/necroptosis pathways, their upstream regulators, immune interactions, and MS risk. Transcriptomic validation utilized bulk RNA-seq and single-cell RNA-seq data. MR identified IFNA4 (OR = 0.24) and TNFAIP3 (OR = 2.0) as key causal ferroptosis/necroptosis-related proteins for MS risk. Analysis revealed 15 upstream regulators significantly associated with MS (FDR < 0.05; e.g., GZMA, CXCL3, APOE, CFB, CA6, KIR2DL2/3). Transcriptomic validation consistently identified ceruloplasmin (CP) as upregulated in MS microglia and lesions. Mediation analyses established two complete causal pathways: an IFNA4-mediated pathway wherein five upstream immune regulators (KIR2DL2, KIR2DL3, CFB, GZMA, and CA6) influence MS susceptibility through IFNA4 regulation, with all component effects statistically significant; and an APOE-driven pathway operating via TNFAIP3, demonstrating significant total effects and near-significant mediator-outcome effects on MS risk. While 59 immune traits were MS-associated, only TNFAIP3 showed a suggestive association with CD27⁺ memory B cells. This study establishes ferroptosis/necroptosis pathways as causal drivers of MS susceptibility, highlighting TNFAIP3, IFNA4, CP, and APOE as therapeutically actionable targets. Show less

Endometrial carcinoma (EC) is a common malignancy of the female reproductive system. Rab35 is widely recognized as an oncogenic driver and has been implicated in the progression of various malignant tumors. However, its regulatory mechanism and pathobiological roles in EC remain unclear. Rab35 expression in EC was systematically profiled via integrative analysis of clinical endometrial specimens and multi-omics databases (CPTAC and GEO). The association between clinical prognosis and Rab35 expression was examined using Kaplan-Meier analysis. Mechanistic investigations included transwell assays, western blotting, and immunofluorescence in Rab35-overexpressing and CRISPR/Cas9-mediated Rab35-knockout EC cells. A mouse xenograft tumor model was established to confirm the effects of Rab35 in vivo. The Rab35 content increased gradually from normal endometrium to atypical hyperplastic endometrium to EC. Moreover, the findings indicated that elevated Rab35 expression was significantly associated with advanced disease characteristics and poor overall survival in patients with EC. In addition, Rab35 enhanced the migratory and invasive nature of EC cells. The expression of Rab35 was inversely linked to that of the β-catenin destruction complex-related proteins Axin-1 and GSK3β, leading to the increased nuclear translocation of β-catenin in EC cells. Animal experiments further verified that Rab35 augmented EC progression by regulating the nuclear translocation of β-catenin. The study revealed that high expression of Rab35 was strongly correlated with EC progression and a poor clinical outcome. Furthermore, Rab35 promoted EC cell metastasis by accelerating the nuclear translocation of β-catenin. These findings suggest that Rab35 serves as a valuable biomarker and therapeutic target for EC. Show less

Alzheimer's disease (AD) represents the most prevalent form of neurodegenerative disorder, characterized by progressive cognitive impairments and a scarcity of effective treatments. Salvianolic acid A (SalA), a natural phytochemical endowed with antioxidative, antiapoptotic, and anti-inflammatory properties, emerges as a promising therapeutic candidate for AD. This study explored the therapeutic efficacy and underlying mechanisms of SalA in mitigating AD-related pathologies. Through integrative network pharmacology, molecular docking, and pathway enrichment analysis, p38 MAPK and NF-κB were identified as potential targets of SalA in the context of AD. SalA treatment inhibited the activation of the p38 MAPK/NF-κB pathway via targeting p38 MAPK, leading to decreased levels of IL-1α and IL-1β in lipopolysaccharide (LPS)-stimulated HMC3 cells. In an in vivo 3 × Tg-AD mouse model, SalA administration ameliorated cognitive decline associated with AD, decreased tau protein hyperphosphorylation in the hippocampus and cortex, and reduced amyloid-β (Aβ) accumulation and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) levels. Furthermore, SalA attenuated the activation of the p38 MAPK/NF-κB pathway and the expression of related inflammatory cytokines in the brains of 3 × Tg-AD mice. In conclusion, this study elucidates the promising ameliorative effects of SalA on improving AD pathology, primarily through the modulation of the p38 MAPK/NF-κB signaling pathway. Show less

Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) may contribute to Alzheimer's disease (AD) pathogenesis by promoting amyloid-β (Aβ) aggregation. ASC protein is mainly composed of the N-terminal pyrin domain (PYD) and the C-terminal caspase recruitment domain (CARD). This study aims to explore the different roles of the two domains of ASC in AD. The SH-SY5Y-APP695 cells were treated with ASC neutralizing antibodies against the N-terminal domain (anti-ASC N-terminal antibodies) or C-terminal domain(anti-ASC C-terminal antibodies). The cell apoptosis and Aβ production were detected. The eight-month-old APP/PS1 mice received lateral ventricle injections of anti-ASC N-terminal antibodies or anti-ASC C-terminal antibodies. The cognitive function and AD-like pathology of APP/PS1 mice were assessed. The anti-ASC N-terminal and C-terminal antibodies attenuated apoptosis and mitochondrial damage, and reduced Aβ production by inhibiting BACE1 in vitro. Furthermore, intracerebroventricular administration of anti-ASC N-terminal and C-terminal antibodies improved cognitive impairment and reduced Aβ deposition, tau hyperphosphorylation, and neuroinflammation in the APP/PS1 mice. The anti-ASC N-terminal and C-terminal antibodies may have neuroprotective effects, which are manifested as reducing cell apoptosis, improving cognitive function, and alleviating AD-like pathology in AD mice. Immunotherapies targeting ASC are promising for treating AD. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, and chronic neuroinflammation, leading to synaptic dysfunction and cognitive decline. Current diagnostic methods rely on clinical symptoms and limited biomarkers, while available treatments only provide symptomatic relief without halting disease progression. MicroRNAs (miRNAs), small non-coding RNAs of 19-22 nucleotides, have emerged as crucial regulators of gene expression through post-transcriptional mechanisms and show distinct dysregulation patterns in AD patients' blood, cerebrospinal fluid (CSF), and brain tissues. Key miRNAs such as miR-132, miR-146a, miR-34a, and miR-125b demonstrate consistent alterations in expression levels, correlating with disease progression and offering potential as non-invasive diagnostic tools. This review comprehensively examines the dual role of miRNAs as diagnostic biomarkers and therapeutic targets for AD. We also provide an analysis of specific miRNA signatures in different biofluids (plasma, serum, CSF) and brain regions that correlate with disease stages, highlighting their potential for early and non-invasive diagnosis. Therapeutically, miRNAs modulate multiple AD-related pathways, including neuroinflammation via NF-κB signaling, Aβ production through BACE1 inhibition, and tau phosphorylation via GSK3β regulation. miRNAs also influence synaptic plasticity, mitochondrial function, and autophagy, presenting multifaceted opportunities for intervention. However, challenges, including miRNA heterogeneity, stability, and targeted delivery, remain critical impediments. Advances in nanocarriers, exosomal miRNAs, and viral vectors show promise in overcoming these obstacles, enabling precise miRNA modulation. In addition, we underscore the need for standardized protocols, further validation in clinical cohorts, and the development of cost-effective detection methods to translate miRNA-based approaches into practical diagnostics and therapies. By integrating miRNA biomarkers with existing diagnostic tools and exploring combinatorial therapeutic strategies, researchers can harness the potential of miRNAs to revolutionize AD intervention, paving the way for early detection and effective treatment of this devastating disease. Show less

FURIN cleaves a subset of proproteins into functional mature fragments. Evidence suggests that FURIN is involved in brain development and the associated diseases, whereas the potential mechanisms remain incompletely understood. Here, we report that cerebral FURIN-deficient mice exhibit cognitive decline and neurodegeneration. Lipid droplets (LDs) that are preferentially accumulated in astrocytes correlate with an increase of the LD markers PLIN2 and PLIN3, and conversely a decreased level of autophagic proteins including ATG5, BECN1 and MAP1LC3/LC3 as well as LAMP1. Accordingly, silencing of Show less

Fatty acids are important as structural components, energy sources, and signaling mediators. While studies have extensively explored genetic regulation of fatty acids in serum and other bodily fluids, their regulation within adipose tissue, a crucial regulator of cardiovascular and metabolic health, remains unclear. Here, we investigated the genetic regulation of 18 fatty acids in subcutaneous adipose tissue from 569 female twins from TwinsUK. Using twin models, the heritability of fatty acids ranged from 5% to 59%, indicating a substantial genetic regulation of fatty acid levels within adipose tissue, which was also tissue specific in many cases. Genome-wide association studies identified 10 significant loci, in SCD, ADAMTSL1, ZBTB41, SNTB1, EXOC6B, ACSL3, LINC02055, MKRN2/TSEN2, FADS1, and HAPLN across 13 fatty acids or fatty acid product-to-precursor ratios. Using adipose gene expression and methylation, which were concurrently measured in these samples, we detected five fatty acid-associated signals that colocalized with expression quantitative trait locus (eQTL) and methylation quantitative trait locus (meQTL) signals, highlighting fatty acids that are regulated by molecular processes within adipose tissue. We explored links between polygenic scores of common metabolic traits and adipose fatty acid levels and identified associations between polygenic scores of BMI, body-fat distribution, and triglycerides and several fatty acids, indicating these risk scores impact local adipose tissue content. Overall, our results identified local genetic regulation of fatty acids within adipose tissue and highlighted their links with renal and cardio-metabolic health. Show less

Coronary artery disease (CAD) remains a leading cause of mortality worldwide, with substantial unmet therapeutic needs. This study aimed to identify and prioritize genetically supported therapeutic targets for CAD using Mendelian randomization (MR). We implemented a two-sample MR framework to infer the causal effects of blood druggable cis-expression quantitative trait loci (cis-eQTLs) on CAD. To consolidate MR findings, we applied Steiger filtering, Bayesian colocalization, and multiple sensitivity analyses. Mediation and phenomewide MR analyses were employed to investigate potential mechanisms and on-target effects of prioritized druggable genes. We identified 66 causal druggable genes associated with CAD in European populations (false discovery rate < 0.001). Among these, ERP29 (odds ratio [OR] = 1.311; 95% confidence interval [CI]: 1.176-1.460), MCL1 (OR = 0.877; 95% CI: 0.840-0.915), TNXB (OR = 1.183; 95% CI: 1.102-1.269), DAGLB, FES, and TRPM4 colocalized with CAD (posterior probability for colocalization > 0.8). The associations for ERP29, MCL1, and TNXB were replicated in an East Asian cohort. Protein-protein interaction network analysis highlighted MAPK3 and TNF as prioritized druggable targets at the protein level. Mediation analysis indicated that body mass index, triglycerides, blood pressure, and atrial fibrillation partially mediate the association between MAPK3 and CAD. Phenome-wide MR analysis further suggested additional beneficial effects of targeting MAPK3 and TNF on diabetes mellitus, obesity, hypertension, unstable angina, myocardial infarction, angina pectoris, coronary atherosclerosis, ischemic heart disease, and disorders of lipoid metabolism. This druggable genome-wide MR study not only corroborated the targets of FDA-approved CAD medications (e.g., FGFR1, MAPK3, NEU1) but also uncovered several novel genes, such as ERP29, MCL1, TNXB, DAGLB, FES, and TRPM4, implicating mechanisms related to blood pressure, lipid metabolism, and additional beneficial effects on endocrine/cardiometabolic traits and circulatory system disorders. Further exploration is imperative to explore their feasibility and generalizability. We identified circulating ERP29, MCL1, TNXB, DAGLB, FES, TRPM4, MAPK3, and TNF as promising, genetically supported druggable targets for CAD treatment. Notably, MAPK3 and TNF demonstrated strong protein-level interactions and close associations with cardiometabolic disorders. Show less

Alterations in the FGFR family act as oncogenic drivers for multiple pediatric and adult tumors, leading to the development and approval of several FGFR inhibitors. However, the on-target gatekeeper and "molecular brake" mutations confer clinically acquired resistance to the FDA-approved FGFR inhibitors, which presents a significant unmet medical need. Herein, we report the first novel macrocycle-based FGFR inhibitors targeting both wild-type and clinically acquired variants of the FGFR family. The representative compound Show less

Chemotherapy-induced myelosuppression (MYE) remains a major dose-limiting toxicity that severely compromises treatment efficacy and patient outcomes, while effective therapeutic agents are still lacking. This study aimed to evaluate the therapeutic effects of 20(S)-protopanaxadiol-human serum albumin nanoparticles (20(S)-PPD-HSA NPs) on cyclophosphamide-induced MYE and to elucidate the underlying mechanisms. 20(S)-PPD-HSA NPs were characterized by electron microscopy, particle size, zeta potential, drug loading, and encapsulation efficiency. A cyclophosphamide-induced MYE mouse model was established. Hematopoietic recovery was evaluated via blood counts, ELISA for granulocyte colony-stimulating factor (G-CSF), and flow cytometry for Lin The 20(S)-PPD-HSA NPs exhibited a uniform nanostructure and excellent drug delivery performance. In vivo, the 20(S)-PPD-HSA NPs significantly alleviated cyclophosphamide-induced hematopoietic dysfunction, restored the structure of bone marrow and spleen tissues, and markedly increased the number of LSK cells, with their therapeutic effect being independent of elevated G-CSF levels. Further studies demonstrated that the 20(S)-PPD-HSA NPs activated the FGFR1/ERK signaling pathway, an effect that was partially blocked by FGFR1 or ERK inhibitors. In vitro, 20(S)-PPD-HSA NPs promoted the proliferation of OP9 cells and murine splenic stromal cells, inhibited apoptosis, DNA damage, and cellular senescence, and upregulated SCF and SDF-1 expression via activation of the FGFR1/ERK pathway. Co-culture experiments further confirmed that the NPs improved the hematopoietic microenvironment and enhanced the stromal cells' hematopoietic support function. 20(S)-PPD-HSA NPs effectively enhanced medullary and extramedullary hematopoietic functions in cyclophosphamide-induced MYE mice by activating the FGFR1/ERK pathway, independent of increased G-CSF levels. These findings highlight 20(S)-PPD-HSA NPs as a promising therapeutic strategy for chemotherapy-induced myelosuppression. Show less

Oligodendrocytes (OLs) generate myelin sheaths around axons and maintain them to facilitate the propagation of action potentials and support neuronal metabolism and synaptic function. Previously, we have shown that Fibroblast Growth Factor Receptor-1 and -2 (FGFR1/2) signaling is required for oligodendrocyte precursor cell (OPC) expansion, promoting myelin growth during developmental myelination and maintaining myelin/axonal integrity in the spinal cord during adulthood. However, whether OL-lineage cells may affect neuronal synaptic functions and impact memory/learning during adulthood/aging remained largely unknown. Here, we showed that FGFR1/2 signaling in OPCs and OLs is required throughout adulthood and is critical for the long-term maintenance of synaptic activity and memory. Specifically, the lack of FGFR1/2 signaling within OL-lineage cells resulted in the impairment of long-term potentiation (LTP), a reduction in docked synaptic vesicles at the synaptic terminals, deficits in hippocampal-based memory and learning, and β-APP accumulation in older animals. Importantly, we found that there was no loss of OPCs or OLs, myelin degeneration, astrogliosis, microglial activation, or reduction in myelin thickness in the adult hippocampus of mutant mice. Furthermore, the tamoxifen-inducible loss of FGFR1/2 signaling during adulthood also impaired LTP. In addition, the conditional ablation of either FGFR1 or FGFR2 individually in the OL-lineage cells impaired LTP during adulthood, although at different levels. Thus, these observations bring up the possibility that FGFR1/2 signaling in OL-lineage cells may play a potentially novel, previously unrecognized role in OL-neuron communication for the maintenance of synaptic plasticity and memory functions in the normal adult/aging brain. Show less