👤 Rena Lu

This study aims to elucidate the role of Enterococcusin the progression from inflammatory bowel disease to colorectal cancer (CRC), with a focus on identifying key metabolites and host genes regulated by Enterococcusand their influence on CRC development. Using the database gutMGene, gutMDisorder and MACdb, we mined the key metabolites and human genes. We acquired the activated genes (panel 1) and inhibited genes (panel 2), and metabolite associated genes (MAGs, panel 3). Subsequent analyses included protein-protein interaction (PPI) network construction, functional enrichment, differential expression and survival analysis in CRC, and immune infiltration assessment. We screened 12 activated genes (Panel1: Show less

Cancer-associated fibroblasts (CAFs) drive immunosuppression in hepatocellular carcinoma (HCC). However, their metabolic regulation remains poorly defined. We investigated the role of nicotinamide N-methyltransferase (NNMT) in CAFs. High NNMT expression in CAF tissues was confirmed by western blotting and immunofluorescence staining. Primary CAFs from HCC patients, single-cell RNA-seq (GSE149614), patient-derived organoids (PDOs), and fibroblast-specific NNMT-knockout mice were integrated by metabolomic analyses. NNMT in CAFs binds EZH2 and impedes its nuclear translocation, thereby reducing H3K27me3 enrichment at the promoter of angiopoietin-like 4 (ANGPTL4) to increase ANGPTL4 secretion. Secreted ANGPTL4 engages GLUT1 in HCC cells, activating aerobic glycolysis and increasing histone H3K18la levels. This epigenetic reprogramming transcriptionally upregulates PD-L1 expression, thereby facilitating tumor immune evasion. Additionally, CAF-derived ANGPTL4 promotes angiogenesis in HCC. Therapeutically, targeting the NNMT-ANGPTL4 axis restored CD8 We identified an NNMT-ANGPTL4-driven metabolic-epigenetic cascade in CAFs that induces PD-L1-mediated immune evasion, providing a therapeutic strategy to overcome resistance to immunotherapy in patients with HCC. Show less

Bone angiogenesis is important for bone formation and regeneration after bone injury. Endothelial-derived angiogenic factors are key signal transducers in the bone microenvironment and maintain vascular-osteogenic coupling during bone regeneration. CGRP, a bone sensory neuron-derived peptide, contributes to bone formation, but the potential mechanism by which it improves bone regeneration via angiogenesis is unclear. Here, we demonstrate that CGRP may contribute to bone repair in the elderly, as human CGRP levels are inversely proportional to age and proportional to bone mass in clinical data and bulk transcriptome data. Based on single-cell RNA sequencing data and experimental analyses, CGRP is found to promote the angiogenesis of human microvascular endothelial cell line-1 in vitro through the FAK-AKT-VEGF pathway. CGRP gene deletion in mice reduced bone vascular density and bone mass, and delayed angiogenesis and bone regeneration at the bone defect site. Recombinant CGRP restored bone repair after defect introduction. It also promoted Angptl4 secretion by bone vascular endothelial cells, thereby driving osteogenic differentiation of bone marrow mesenchymal stem cells and enhancing bone regeneration after bone injury. Treatment with recombinant Angptl4 enhanced bone healing in a mouse bone defect model. These integrated analysis reveal the important role and mechanism of CGRP in vascular-mediated osteogenesis, suggesting a novel therapeutic strategy for promoting bone regeneration. Show less

Exosomes are crucial mediators of intercellular communication. As a key component of milk, milk-derived exosomes are abundant in genetic cargo, particularly microRNAs (miRNAs), indicating their potential role in regulating mammary gland physiology. Therefore, this study aimed to investigate the specificity of miRNAs in milk-derived exosomes and their regulatory roles in lipid synthesis in bovine mammary epithelial cells (BMECs). Based on 17,838 DHI records showing a significantly higher milk fat percentage (MFP) in late lactation (4.24% ± 1.07%), 10 high- (5.96% ± 0.26%, HMF) and 10 low-MFP (1.68% ± 0.23%, LMF) cows were selected during this stage for milk-derived exosome isolation and miRNA profiling. Exosomes isolated via differential ultracentrifugation were verified as 50-150 nm vesicles expressing CD9, CD81, and TSG101. miRNA sequencing identified 1,320 differentially expressed miRNAs (496 upregulated and 824 downregulated) between the HMF_EXO and LMF_EXO groups. Uptake assays confirmed that BMECs internalized these exosomes, and qRT-PCR validation showed that miR-423-5p and miR-125b were significantly upregulated and downregulated in HMF_EXO- and LMF_EXO-treated BMECs, respectively. Functionally, exosomal miR-423-5p promoted intracellular lipid accumulation and TG synthesis in BMECs by targeting APOA5, whereas miR-125b inhibited lipolysis and fatty acid oxidation by repressing SLC27A1. This study demonstrates that milk-derived exosomal miRNAs represent a novel mechanism for regulating milk fat synthesis. Specifically, miR-423-5p and miR-125b directly modulated lipid metabolism in BMECs via the miR-423-5p/APOA5 and miR-125b/SLC27A1 pathways. These findings provide new insights into the molecular regulation of milk fat synthesis and highlight the importance of exosome-mediated intercellular communication in the lactating mammary gland. Show less

To investigate changes in serum lipid profile parameters combined with tumor markers in gastric cancer (GC) patients and their value in GC screening. A total of 100 patients diagnosed with GC at Renji Hospital (West) between May and September 2025 were consecutively enrolled as the GC group (54 cases in stage Ⅰ/Ⅱ and 46 cases in stage Ⅲ/Ⅳ). Additionally, 100 age- and sex-matched healthy individuals undergoing routine physical examinations were included as the healthy control (HC) group. The serum levels of nine lipid indicators (high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC], triglycerides [TG], small and dense low-density lipoprotein cholesterol [sdLDL-C], apolipoprotein [Apo] A1, ApoB, ApoC2, and ApoC3) and five tumor markers (carcinoembryonic antigen [CEA], carbohydrate antigen [CA] 19-9, CA50, CA242, and CA72-4) were measured using an automatic biochemical analyzer and an electrochemiluminescence instrument. Intergroup differences were analyzed using the Mann-Whitney Compared with the HC group, the GC group showed significantly lower levels of ApoA1, ApoC3, TC, HDL-C, LDL-C, and sdLDL-C ( The combined panel of ApoA1, ApoC3, HDL-C, LDL-C, TC, sdLDL-C, CEA, CA50 and age offers a potential auxiliary tool for detecting gastric cancer. Show less

ApoB (apolipoprotein B)-containing lipoproteins are causal risk factors for atherosclerotic coronary artery disease (CAD). Since human cathelicidin LL-37 binds to ApoB-100 in this pathological context, we investigated whether the circulating LL-37-ApoB-100 complex could serve as a biomarker for CAD. We performed surface plasmon resonance and protein-protein docking to demonstrate the direct LL-37-ApoB-100 interaction. We developed a specific polyclonal antibody against the complex and measured its levels in human atherosclerotic plaques and plasma, as well as in We identified that LL-37 directly interacted with multiple distinct binding sites on ApoB-100. Plasma levels of LL-37-ApoB-100 complex were significantly elevated in human patients with atherosclerosis. Consistently, levels of this complex were positively correlated with atherosclerotic plaque area in Circulating LL-37-ApoB-100 levels are strongly associated with angiographically documented CAD, highlighting LL-37-ApoB-100 as an independent predictor for CAD. Show less

Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III, reduces triglycerides by ~60% and remnant cholesterol by ~70%, has a neutral effect on LDL cholesterol (LDL-C), and reduces apolipoprotein B (apoB) by ~15% in moderate hypertriglyceridemia. We investigated the effect of olezarsen on coronary plaque in adults with largely moderate hypertriglyceridemia. We conducted a coronary computed tomography angiography (CCTA) study within Essence-TIMI 73b, a randomized, placebo-controlled trial of olezarsen vs. placebo that enrolled patients between November 2022 and February 2024. Inclusion criteria were triglycerides ≥150 mg/dL (2.26 mmol/L), presence or high risk for cardiovascular disease, and non-calcified plaque on baseline CCTA. The primary endpoint was percent change from baseline to 12 months in non-calcified plaque volume (NCPV). Of 468 participants (349 olezarsen, 119 placebo), the median age was 63 years (IQR 56-70); 31% were women, and 97% received lipid-lowering therapy. Median baseline triglycerides were 249 mg/dL (IQR 197-331), and remnant cholesterol was 53 mg/dL (IQR 38-76). Median baseline NCPV was 125.3 mm Despite substantial triglyceride and remnant cholesterol lowering, treatment with olezarsen for 12 months on top of standard-of-care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia did not affect noncalcified coronary plaque volume. Show less

Residual cardiovascular risk persists in statin-treated patients with coronary artery disease (CAD), even when low-density lipoprotein cholesterol (LDL-C) targets are met. Excess apolipoprotein B (apoB), defined as measured apoB minus LDL-C-predicted apoB, may capture atherogenic particle burden beyond LDL-C, but its prognostic value for long-term mortality in secondary prevention remains uncertain. We conducted a pooled analysis of two nationwide Chinese cohorts (CIN-II and RED-CARPET) comprising 68,616 statin-treated CAD patients. Excess apoB was calculated using an internal reference population (triglycerides ≤ 1.0 mmol/L). Associations with all-cause and cardiovascular mortality were assessed using multivariable Cox models, with adjustment for clinical covariates including nutritional status. External validation was performed in 13,702 participants from the UK Biobank. Over a median follow-up of 5.2 years, 10,835 deaths occurred (5,090 cardiovascular). Each 1-standard deviation (15.4 mg/dL) increase in excess apoB was associated with a 12% higher risk of all-cause mortality (adjusted hazard ratio [aHR] 1.12, 95% CI 1.06-1.18) and a 24% higher risk of cardiovascular mortality (aHR 1.24, 95% CI 1.15-1.34). Patients in the highest excess apoB quartile (≥ 11.5 mg/dL) had significantly worse survival. Notably, these associations persisted consistently across all achieved LDL-C strata (< 2.0 to > 4.0 mmol/L). These findings were robustly confirmed in the external validation cohort. Excess apoB is an independent predictor of long-term mortality in statin-treated CAD patients, even among those with well-controlled LDL-C. Its incorporation into risk assessment could improve prognostic stratification and guide personalized management in secondary prevention. CIN-II: ClinicalTrials.gov, NCT05050877 (Retrospectively registered, 21 September 2021); RED-CARPET: Chinese Clinical Trial Registry, ChiCTR2000039901 (Prospectively registered, 14 November 2020). The UK Biobank study is covered by generic ethical approval from the NHS National Research Ethics Service (Ref: 99231). Show less

The comparative roles of triglyceride-rich lipoproteins (TRLs) and low-density lipoproteins (LDLs) in abdominal aortic aneurysm (AAA) pathogenesis are unclear. To evaluate the putative causal role of TRLs in AAA, quantify the relative effect on AAA risk ("aneurysmogenicity") of TRL vs LDL particles, and prioritize lipid-lowering drug targets for AAA prevention and treatment. We performed summary-level and individual-level Mendelian randomization (MR) analyses. Genetic variants were selected from 383,983 UK Biobank participants and ranked into 10 sets of variants where set 1 predominantly affected LDL cholesterol (LDL-C) and set 10 predominantly affected TRL cholesterol (TRL-C; and with mixed effects for intermediate variant sets). AAA outcome data were obtained from AAAgen (37,214 cases), FinnGen (4,439 cases), and the VA Million Veteran Program (MVP; 23,848 cases). Multivariable MR was used to assess the independent roles of LDL-C and TRL-C in AAA. For each set of variants, MR or logistic regression was used to estimate AAA odds ratios (ORs) per 10 mg/dL higher apolipoprotein B (apoB). Interaction analyses were conducted between a statin-like LDL-C-lowering variant set (set 3) and a TRL-C-lowering variant set (set 10). Drug-target MR was performed to evaluate lipid-lowering targets relevant to LDL-C- and TRL-C-lowering. Genetically predicted LDL-C and TRL-C concentrations were each associated independently with genetic liability for AAA after mutual adjustment, with 3.0 to 5.5 times stronger associations for TRL-C compared to LDL-C on a per-cholesterol basis. In AAAgen, the AAA OR per 10 mg/dL increased apoB concentrations were 1.10 (95% CI, 1.05-1.14) for variant set 1 (LDL-C-predominant) and 1.89 (95% CI, 1.69-2.11) for variant set 10 (TRL-C-predominant). Using the ratio of log(OR) per 10 mg/dL apoB for set 10 versus set 1 as a conservative estimate of relative aneurysmogenicity, TRLs were approximately 3.2 to 6.9 times more aneurysmogenic than LDLs across the three studies. No evidence of interaction was observed between LDLs and TRLs, indicating additive contribution to AAA risk. Drug-target MR supported strong protective associations for genetically proxied inhibition of TRL-pathway targets, particularly TRLs are at least threefold more aneurysmogenic than LDLs on a per-particle basis. Therapeutic strategies targeting TRL-C -especially via Show less

In recent years, non-traditional lipid indices have emerged as significant predictors for cardiovascular events following emergency percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). However, the relationship of residual lipoprotein-cholesterol (RLP-C) and atherogenic index of plasma (AIP) with in-hospital outcomes, especially their predictive value for major adverse cardiovascular and cerebrovascular events (MACCEs) after PCI in STEMI patients, remains underexplored and warrants further investigation. This retrospective cohort study included 526 STEMI patients who underwent emergency PCI between January 2023 and August 2024. We collected baseline demographic, clinical, and laboratory data. RLP-C and AIP were calculated from lipid profiles obtained before PCI. Independent predictors of in-hospital MACCEs were identified using multivariate logistic regression, and model discrimination was evaluated using receiver operating characteristic (ROC) curve analysis. Among 526 STEMI patients receiving PCI, 92 (17.49%) developed in-hospital MACCEs. Multivariate analysis identified RLP-C (OR = 3.97, 95%CI: 1.71–9.21; RLP-C and AIP are independent predictors of in-hospital MACCEs following PCI in STEMI patients. Combined assessment of these indices improves risk stratification and may facilitate early targeted interventions to improve outcomes. The online version contains supplementary material available at 10.1186/s12872-026-05555-9. Show less

To elucidate the molecular basis of intramuscular fat (IMF) variation in yellow-feathered broilers, we selected 10 high-IMF (HF) and 10 low-IMF (LF) breast muscle samples from a total of 214 samples, after z-score filtering for LC-MS lipidomics and RNA-seq analyses. Lipidomics identified 94 differentially expressed lipids (DELs; 83 upregulated, 11 downregulated in HF), predominantly triglycerides (TGs, 20.2%), phosphatidylethanolamines (PEs, 15.3%), phosphatidylcholines (PCs, 12.1%), and sphingomyelins (SMs, 8.4%). LION/web enrichment indicated an unsaturated lipid-rich phenotype, characterized by fatty acids containing ≥ 2 double bonds and membrane structural components. RNA-seq revealed 423 differentially expressed genes (DEGs; 312 upregulated, 111 downregulated in HF), enriched in plasma membrane, cell periphery, retinol metabolism, and steroid hormone biosynthesis pathways. RT-qPCR validation of nine lipid metabolism-related DEGs confirmed the RNA-seq trends. Cross-omics Pearson correlation between these DEGs and the top 20 DELs identified PLIN1, SCD, and APOB as central regulatory hubs strongly associated with multiple polyunsaturated TGs and PCs. Functional overlap across omics layers suggests coordinated membrane remodeling and unsaturated lipid deposition in HF breast muscle, providing a data-driven framework for future mechanistic validation and breeding strategies. Show less

The gut microbiota is a diverse and abundant microbial community in animals; it plays a key role in nutrient absorption and immune defense and is an important factor affecting chicken health and growth performance. Understanding the composition of chicken gut microbiota and its influencing factors can provide a theoretical foundation for maintaining the diversity and microecological balance of beneficial microbial communities in the chicken intestinal tract. This review aimed to explore the recent advancements in understanding the non-genetic e.g. environmental and host genetic factors that influence the chicken gut microbiome, focusing on the gut microbial composition including host genetic kinship, heritability, microbial quantitative loci, and candidate genes. Studies on host genetic factors have identified several genes associated with gut microbial composition including lipid droplet associated hydrolase (LDAH) and apolipoprotein B (APOB) associated with Staphylococcus; TOX high mobility group box family member 2 (TOX2) significant locus linked to Veillonella, and reelin (RELN), lumican (LUM), and S-phase cyclin A associated protein in the ER (SCAPER) associated with intestinal microbial abundance. These factors are involved in host growth, development, and immune system regulation, collectively indicating that host genes play a significant role in regulating chicken gut microbiota. Furthermore, a comprehensive exploration of both non-genetic and host genetic factors could provide a solid foundation and practical strategies for improving chicken health and production performance by regulating the gut microbiota. Show less

Sepsis is a syndrome caused by the host's inflammatory response to an infection with an unknown mechanism. This study aimed to identify differentially expressed genes (DEGs) potentially involved in the development and recovery of tracheal injury from septic shock. Nine New Zealand white rabbits were randomized to control (CON), septic shock model (SS), and septic shock norepinephrine treatment (SSNE) groups (each group n = 3). The SS and SSNE groups were injected with lipopolysaccharide to induce septic shock. The SSNE group was administered Ringer lactate with norepinephrine to maintain normal blood pressure. All animals underwent cuffed endotracheal intubation for 2 h. The injured tracheal segment was harvested. RNA sequencing was performed to identify the DEGs, followed by bioinformatics analysis, and pathological staining (both HE and Masson) was performed for pathological evaluation. Bioinformatics analysis included principal component analysis (PCA), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) network construction. Key findings were validated by qRT-PCR and immunohistochemistry. We obtained 124 upregulated and 28 downregulated DEGs in SS vs. CON groups, along with 60 upregulated and 178 downregulated DEGs in SSNE vs. SS groups. The pathological score showed that trachea tissue in the SS group had the highest score. The protein-protein interaction (PPI) prediction identified APOB and CD36 as the hub genes. The molecular experiments further confirmed that at mRNA and protein levels, APOB was significantly upregulated, while CD36 was significantly downregulated. Subsequent qRT-PCR and immunohistochemical analyses confirmed that APOB expression was significantly upregulated while CD36 was downregulated in the septic shock group, a trend partially reversed by norepinephrine treatment. Our study results suggest that APOB and CD36 may be involved in the pathogenesis of tracheal injury recovery in septic shock patients treated with NE. Not applicable. Show less

The triglyceride-glucose (TyG) index, an insulin resistance marker linked to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), underscores the redox imbalance-mediated crosstalk between MASLD and cardiovascular-liver-metabolic health (CLMH), although its causal mechanisms and molecular drivers remain unresolved. We employed a multi-omics framework to integrate Mendelian randomization (MR) and transcriptome-wide association studies (TWAS). MR leveraged 192 genome-wide significant single-nucleotide polymorphisms for TyG from the UK Biobank, employing inverse-variance weighted (IVW) and generalized summary-data MR (GSMR). Transcriptomic integration utilized four approaches: Multi-marker Analysis of GenoMic Annotation for gene-set enrichment; Joint-Tissue Imputation PrediXcan (JTI-PrediXcan) for tissue-specific expression; Sparse Multi-Tissue Imputation Xcan (SMulTiXcan) for cross-tissue meta-analysis; and Fine-mapping of Causal Gene Sets (FOCUS) for Bayesian fine-mapping. Comorbid genes were validated using Functional Summary-based Imputation (FUSION) and prioritized based on the Polygenic Priority Score (PoPS). Single-cell spatial transcriptomics (sc-ST) in embryonic mice (E16.5) mapped tissue-specific expression via genetically informed spatial mapping (gsMap). The MR analysis demonstrated a causal effect of TyG on MASLD risk [IVW: odds ratio (OR) = 1.58, 95% CI = 1.04-2.38, P = 0.030; GSMR: OR = 1.43, 95% CI = 1.27-1.61, P = 5.20 × 10 -9 ]. TWAS identified 12 comorbid genes (C2orf16/SPATA31H1, FNDC4, GCKR, GMIP, HAPLN4, LPAR2, MAU2, MEF2B, NDUFA13, NRBP1, TM6SF2, and ZNF513). Independent validation using the FUSION framework confirmed nine TyG-MASLD comorbid genes with genome-wide significant false discovery rate-adjusted associations. Notably, TM6SF2 (TyG-PoPS = 7.2491) and GCKR (TyG-PoPS = 6.7102) showed strong positive associations in TyG, whereas NDUFA13 exhibited negative scores in MASLD (PoPS = -0.5028). Spatial mapping revealed conserved enrichment of APOA1, APOB, and APOC4 (sc-ST, P < 0.001) in murine liver and vascular tissues. Organ-specific analysis showed significant MASLD signals including the liver (sc-ST, P = 6.43 × 10 -5 ), adrenal gland (Cauchy P = 0.0064), and connective tissue (sc-ST, P = 3.29 × 10 -5 ). This study establishes TyG as a causal MASLD driver mediated by redox-sensitive hubs and evolutionarily conserved apolipoproteins, linking hepatic lipid peroxidation to systemic metabolic dysregulation. Targeting these pathways may mitigate dual hepatic-cardiovascular risks, advancing precision therapies for CLMH. Show less

Dysregulation of low-density lipoprotein (LDL) cholesterol is strongly correlated with the risk of metabolic dysfunction-associated steatotic liver disease. Endogenous molecules targeting LDL clearance play crucial roles in the progression of liver steatosis. Human cathelicidin LL-37 can form complexes with lipoproteins, but whether these complexes regulate lipoprotein-driven cholesterol metabolism is not clear. Here, we find that cathelicidin LL-37 binds to LDL via apolipoprotein (Apo)B-100 domains, enhancing the solubility of ApoB-100 and inhibiting the modifications and aggregation of LDL. LL-37-LDL interaction promotes LDL uptake through LDL receptor (LDLR) both in hepatocytes and macrophages. This interaction also promotes LDL cholesterol clearance by facilitating cholesterol excretion and cholesterol efflux. In Apoe Show less

Schizophrenia is frequently comorbid with dyslipidemia and hyperglycemia. However, whether metabolic-modifying agents aggravate schizophrenia progression remains unclear. We perform a drug-target genetic association study in two independent Han Chinese schizophrenia cohorts (N = 2,111/292 for discovery/validation). Leveraging metabolic genome-wide association studies, we generate genetic risk scores (GRSs) for lipid-modifying and hypoglycemic targets. Those with higher APOC3 (inhibited by volanesorsen/olezarsen) GRS exhibit attenuated triglycerides and improvement in negative symptoms assessed by Positive and Negative Syndrome Scale (PANSS) (β = 1.23, 95% confidence interval [CI]: 0.30-2.16). Higher GCK (activated by dorzagliatin) GRS is associated with decreased glucose and less improvement across PANSS total (β = -1.70, 95% CI: -2.91-0.50), positive, negative, general subscales. Causal associations of GCK are replicated in independent validation. The effects of APOC3 and GCK on negative symptom recovery are robust in hyperlipidemic/diabetic subgroups. Genetically proxied proteomics analysis provides further functional validation for the identified target-outcome associations. Our findings suggest volanesorsen/olezarsen as potential adjunctive candidates; dorzagliatin warrants prudence in schizophrenia with metabolic disturbance. Show less

Vascular calcification (VC) is prevalent in patients with chronic renal failure (CRF), and it is closely related to the morbidity and mortality of cardiovascular diseases; however, no medical treatments are available for this condition. Recent clinical studies have shown that plasma apolipoprotein C3 (ApoC3) levels are positively correlated with VC. However, whether ApoC3 is involved in VC remains unclear. Sections of calcified renal arteries from CRF patients were immunostained to measure calcium deposition and ApoC3 expression. VC was induced in ApoC3 transgenic (Tg) and knockout (KO) mice by both 5/6 nephrectomy and vitamin D ApoC3 expression levels were increased in calcified arteries from mice and patients with CRF. ApoC3 overexpression exacerbated calcium deposition in the calcified aortas from Tg mice in vivo, and in calcified aortic rings of Tg mice ex vivo and VSMCs infected by adenovirus of ApoC3 in vitro. Consistently with these findings, ApoC3 deficiency alleviated these effects. Furthermore, ApoC3 overexpression increased ferroptosis in calcified aortas and VSMCs, whereas ApoC3 deficiency suppressed ferroptosis. Further investigation revealed that ApoC3 inhibited the AMPK/NRF2 signaling pathway through toll-like receptor 2 (TLR2) in calcified VSMCs, downregulated the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), subsequently increased lipid peroxidation and promoted ferroptosis, ultimately exacerbating calcification in the VSMCs. Furthermore, we found that knockdown of ApoC3 by siRNA remarkably attenuated calcification of renal arterial rings in humans. We demonstrated that ApoC3 exacerbated VC and increased the osteogenic transdifferentiation in VSMCs by increasing ferroptosis. ApoC3 might be a potential target for VC treatment. Show less

Vascular smooth muscle cell (VSMC) phenotype switching plays a significant role in the pathogenesis of atherosclerosis (AS). However, the subtypes of VSMC transdifferentiation and their impact on AS progression and atherosclerotic plaque instability remains unclear. We reanalysed scRNA-seq datasets of GSE155513 and GSE253903 and performed single-sample gene set enrichment analysis (ssGSEA) in three transcriptome datasets from unstable plaques to determine the major subtypes contributing the most to plaque instability. Using high-dimensional weighted gene co-expression network analysis (hdWGCNA), we identified hub genes in macrophage (MP)-like smooth muscle cells (SMCs) of unstable plaques. We conducted cell communication analysis according to tensin1 (TNS1) gene levels in VSMCs. TNS1 expression was analysed in human AS plaques. Finally, an AS model was established in VSMC-specific Tns1 knockout ApoE MP-like SMC was identified as the key subtype for plaque instability. hdWGCNA analysis for MP-like SMC identified blue module as the key gene module involved in unstable plaques. Decreased TNS1 expression in VSMCs was positively correlated with the down-regulation of contractile VSMC marker genes, SRF and MYCOD genes, negatively correlated with the up-regulation of CD68 and KLF4 genes, and activated VCAM, PDGF, THBS and CXCL signalling pathways. TNS1 mRNA expression levels were lower in human atherosclerotic arteries than in healthy arteries, and even lower in unstable plaques than in early and stable plaques. TNS1 protein levels in VSMCs were lower in human atherosclerotic plaques than in healthy arteries, and even lower in advanced plaques than in early plaques. VSMC-specific Tns1 gene deficiency aggravated AS progression and enhanced plaque instability with increased MP-like SMC transdifferentiation. The reduction of TNS1 gene in VSMCs might drive contractile VSMC transdifferentiation into MP-like SMC, the major subtype contributing to plaque instability. In vivo experimental results confirmed the role of Tns1 gene in contractile VSMC transdifferentiation into MP-like SMC and plaque instability. Show less

Atherosclerotic cardiovascular disease remains the leading cause of global mortality, with hypercholesterolemia serving as a critical driver of atherogenesis. Although current lipid-lowering therapies substantially improve circulating lipid profiles, strategies that provide more durable, safe, and efficient control of lipid metabolism are still needed. Epigenome editing offers a promising approach for long-lasting repression of disease-modifying genes without altering the underlying DNA sequence. Here, we develop CRISPRoff platforms delivered by adeno-associated virus or lipid nanoparticle to epigenetically silence hepatic Hmgcr or Pcsk9 in vivo. In both C57BL/6J wild-type and ApoE Show less

Scavenger receptor B3/differentiation cluster 36 (SCARB3/CD36) has been established as a fatty acid transporter and genetic deficiency of CD36 in mice models shows decreased uptake of oxidized low-density lipoprotein (oxLDL) and reduced atherosclerosis. The present study proposes CD36 as a drug target inhibited by leonurine to alleviate inflammation and prohibit unstable atherosclerotic plaques. We showed that the anti-atherosclerotic effects of leonurine were dependent on CD36 in a mice model of arterial atherosclerosis induced by tandem stenosis surgery fed with Western diet (TS + WD) established in both wild type (WT) and Cd36 Show less

Macrophages play central roles in the initiation and growth of atherosclerosis (AS). This study aimed to investigate the role of ENC1 in macrophage oxidative stress during AS and its mechanism. An animal model of AS was constructed by feeding ApoE KO mice with a high-cholesterol diet, and an in vitro AS model was induced on mouse macrophages RAW 264.7 using oxLDL. Macrophage-specific adeno-associated viruses containing the F4/80 promoter were used to interfere with RBM47 and ENC1 expression in vivo, and lentiviral infection of RAW 264.7 was applied in vitro. RBM47 improved the stability of ENC1 by binding to the AU-rich elements, which curbed NRF2 synthesis and nuclear translocation. Exogenous inhibition of ENC1 or RBM47 suppressed aortic oxidative stress in mice with AS, reduced lipid and cholesterol uptake, and strengthened cellular scavenging activity against oxidative stress in RAW 264.7 cells. The NRF2 inhibitor ML385 reversed the above benefits from the knockdown of ENC1 in RAW 264.7 cells, and combined overexpression of ENC1 reversed these benefits from the knockdown of RBM47 in vitro and in vivo. This study provides new evidence that ENC1 is a contributor to AS progression, and targeting ENC1 in macrophages may serve as a potential therapy. Show less

This study aims to investigate the effects of mulberry anthocyanin (MA) in high-fat and high-cholesterol (HFHC) diet-fed ApoE-/- mice. ApoE-/- mice were randomly divided into control (ACON), mulberry fruit anthocyanin extract (MFAE), cyanidin-3-glucoside (C3G) group 1 (C3GT), and C3G group 2 (C3GP). After 7 weeks of HFHC diet feeding and following 2-3 weeks of treatment, samples were collected and analyzed. The C3GT group significantly decreased low-density lipoprotein (7.3 ± 1.5 mmol/L) and interleukin-1β (355.4 ± 41.7 pg./mL) levels. Moreover, the MFAE (636.3 ± 90.7 pg./mL), C3GT (611.5 ± 65.4 pg./mL), and C3GP (757.5 ± 47.6 pg./mL) significantly increased glutathione peroxidase (GSH-PX) levels compared with those in the ACON group. The MA treatments significantly increased the number of MA treatment may attenuate AS-associated risk factors by decreasing inflammatory factor-related gut microbial genera. The mechanism may be related to regulating liver glutamine, ATP, and related metabolic pathways. Show less

Rheumatoid arthritis (RA) is a chronic inflammatory joint disorder in which macrophages play crucial roles. Given macrophage heterogeneity, novel biomarkers are needed for timely diagnosis and severity assessment. This study aimed to identify macrophage-specific hub genes in RA and investigate their biological functions. Bulk and single-cell RNA-seq datasets were downloaded from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) in RA synovial macrophages were identified from the GSE97779 dataset using the Limma R package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to determine the biological processes and pathways associated with the DEGs, followed by Gene Set Enrichment Analysis (GSEA) for further validation. Hub genes were identified using the STRING database and Cytoscape. Based on the single‑cell dataset GSE192504, cell clusters were annotated with Seurat to determine macrophage‑specific hub genes, whose associated biological processes were explored via gene set variation analysis (GSVA). Further sub‑clustering revealed distinct macrophage subtypes. Finally, immunofluorescence staining was performed to identify molecular markers of macrophage subtypes, while RT-qPCR and ELISA were used to validate the mRNA and protein expression of macrophage-specific hub genes in in vitro experiments. We identified 334 DEGs enriched in immune-related pathways. Ten hub genes ( Show less

Endothelial cells under oxidative stress and inflammation are vital contributors to the progression of atherosclerosis. Although Orientin possesses antioxidant and anti-inflammatory activities, the effects of Orientin on oxidized low-density lipoprotein and high glucose (ox-LDL/HG)-triggered endothelial cell injury and diabetes-accelerated atherosclerosis remain unclear. ApoE 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

Pharmacological activation of brain Retinoid X Receptors (RXRs) enhances cognition and facilitates amyloid-beta (Aβ) clearance in Alzheimer's disease (AD) mouse models, partly by upregulating apolipoprotein E ( Show less

Diabetic foot ulcers (DFU) are a severe complication of diabetes. Although dysregulated M2 macrophage polarization is recognized as a key driver of chronic inflammation in DFU, the molecular checkpoints that can be therapeutically targeted to restore M2 bias remain poorly defined. Here, we aimed to determine whether the RNA-binding protein TAF15 acts as a post-transcriptional stabilizer of the M2-promoting CEBPB/APOE/PTX3 axis, thereby accelerating DFU healing. First, we confirmed that APOE positively regulates PTX3, which supports M2 polarization and the proliferation and migration of HDF. CEBPB transcriptionally activated APOE and promoted M2 macrophage polarization. TAF15 stabilized CEBPB mRNA and affected HDF cell proliferation and migration by promoting M2 macrophage polarization. Additionally, TAF15 overexpression partially counteracted the disruption of M2 macrophage polarization caused by APOE silencing and facilitated DFU wound healing. Collectively, our findings establish TAF15-driven stabilization of CEBPB mRNA as a target point that sequentially activates APOE/PTX3 signaling to enforce M2 polarization and accelerate DFU closure. This study provides a preclinical rationale for the development of TAF15-targeted oligonucleotides or small-molecule strategies to reprogram wound macrophages and improve DFU outcomes in patients with diabetes. 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