Background. Breast-cancer-related depression (BCRD) is associated with an increased mortality rate among breast cancer (BC) survivors. Luteolin has many pharmacological effects, particularly in the treatment of BC. In this study, we aimed to explore the anti-BCRD activity of luteolin and its underlying functional mechanism. Methods. A BCRD mouse model was induced by injecting 4T1 cells and corticosterone (COR). Behavioral test, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, Nissl staining, immunofluorescence, reverse-transcription quantitative PCR (RT-qPCR), and western blotting were used to study the effect of luteolin in mice with BCRD in vivo. A COR-induced neuron injury model was established in HT-22 cells in vitro. The role of miR-124-3p in the anti-BCRD effects of luteolin was studied using a miR-124-3p inhibitor. Results. Luteolin significantly reduced the size and weight of the tumor, increased the mice entry frequency in the symmetrical sector, and reduced the duration of immobility in the tail suspension and forced swimming tests of mice affected by BCRD. Simultaneously, apoptosis of hippocampal neurons was inhibited, and the number of Nissl bodies increased with luteolin treatment. In addition, luteolin resulted in the upregulation of miR-124-3p expression in the hippocampus and downregulated the expression of tumor necrosis factor-α (TNF-α) and TNF receptor-associated factor 6 (TRAF6), as well as lowered the phosphorylation levels of nuclear factor-kappa B (NF-κB) and IkappaB (IκB). Luteolin also inhibited pyroptosis of hippocampal neurons in mice affected by BCRD, as revealed by the low protein levels of NOD-like receptor protein 3 (NLRP3), caspase-1, gasdermin D-N (GSDMD-N), interleukin (IL)-1β, and IL-18. However, the miR-124-3p inhibitor significantly reversed the therapeutic effect of luteolin on COR-induced HT-22 cells. Conclusion. Our study demonstrated that the anti-BCRD function of luteolin was mediated by regulating the miR-124-3p/TNF-α/TRAF6-related pathway and inhibiting neuronal cell pyroptosis and subsequent inflammation. Therefore, luteolin may be a potential drug candidate in the treatments of BCRD.

Background: Major depressive disorder (MDD) leads to significant distress and disruption across social, occupational, and other functional domains. Although cerebrospinal fluid (CSF) biomarkers have been identified as potential indicators and therapeutic targets for depression, their causal relationship with MDD remains unclear. Methods: We analyzed publicly available CSF metabolomics and genotype data, quantifying 338 distinct metabolites. Among these, 296 were chemically validated and classified into eight major metabolic groups, while 38 remained undefined. To assess the genetic association with depression, we used summary statistics from a GWAS (F5_DEPRESSIO dataset, including 53,313 diagnosed cases and 394,756 controls from Finland). An integrated approach combining Mendelian randomization (MR), inverse variance weighting (IVW), and linkage disequilibrium score regression (LDSC) was applied to explore the causal impact of CSF metabolites on depression risk. Results: Our analysis identified 62 metabolites significantly associated with depression (p < 0.05). Sensitivity tests revealed heterogeneity in five metabolites: 5-hydroxyindoleacetic acid, X-19438, ethylmalonic acid, γ-glutamylglutamine, and β-alanine. A focused analysis on 14 metabolites further supported a potential causal link with depression. LDSC confirmed significant genetic heritability for metabolites such as creatinine, arginine succinate, N-acetylisourea, 3-amino-2-piperidone, and carboxyethyl-GABA. Systematic leave-one-out analyses demonstrated that these associations are driven by multiple interacting SNPs rather than a single variant. Conclusion: This study provides novel insights into the potential causal relationship between CSF metabolites and depression, highlighting 14 key metabolites with significant associations. The robustness of these findings is supported by MR and sensitivity analyses. Further longitudinal studies are warranted to confirm the clinical relevance of these CSF biomarkers in MDD.

Background: High mobility group A1 (HMGA1) has emerged as a key oncogenic factor in various cancers, but its specific role in liver hepatocellular carcinoma (LIHC) remains incompletely understood. This study aimed to investigate the expression pattern, biological functions, immune associations, clinical relevance, and therapeutic potential of HMGA1 in LIHC. Methods: We conducted a multi-omics analysis integrating transcriptomic, proteomic, and clinical data from TCGA, CPTAC, and HPA databases. Functional enrichment, immune infiltration profiling, and survival analyses were performed. In-vitro assays, including CCK-8, colony formation, β-galactosidase staining, and wound healing, were used to validate HMGA1’s biological functions in LIHC cells. Results: HMGA1 was significantly overexpressed in LIHC at both mRNA and protein levels (P<0.001). High HMGA1 expression correlated with advanced pathological stage, metastasis, and elevated AFP levels (all P<0.001). Kaplan-Meier analysis revealed that elevated HMGA1 predicted poor overall survival (OS) (HR=1.83, 95% CI: 1.12–2.99, P=0.014), disease-specific survival (DSS) (HR=2.12, 95% CI: 1.33–3.35, P=0.002), and progression-free interval (PFI) (HR=1.68, 95% CI: 1.14–2.48, P=0.009). Multivariate Cox analysis confirmed HMGA1 as an independent prognostic factor for OS (HR=1.75, 95% CI: 1.11–2.76, P=0.016). A nomogram incorporating HMGA1 and clinicopathological variables showed good predictive performance with a 3-year AUC of 0.723. Functionally, HMGA1 knockdown suppressed LIHC cell proliferation (38.9% reduction in HepG2 and 46.0% in Huh-7 at 48h), migration (44–59% inhibition at 24h), and colony formation (41.8–44.2% reduction), while significantly inducing cellular senescence (3.4–3.5-fold increase in β-gal+cells, P<0.001). GSEA and immune analysis indicated that HMGA1 may promote immune evasion and senescence bypass. Conclusion: HMGA1 serves as a robust prognostic biomarker and functional driver of malignant progression in LIHC. Its integration into prognostic models may enhance risk stratification and guide personalized therapeutic strategies. Nevertheless, further in-vivo validation and prospective clinical studies are required to establish its translational applicability.

Cerebral atherosclerosis has been linked in observational studies to changes in cerebrospinal fluid (CSF) metabolites, yet whether these associations reflect causal relationships is uncertain. Understanding such links could advance biomarker discovery and prevention strategies. We conducted a bidirectional Mendelian randomization analysis to evaluate potential causal associations between 338 CSF metabolites and the risk of cerebral atherosclerosis, using summary statistics from genome-wide association studies. The inverse variance weighted method was the primary approach, complemented by Mendelian randomization-Egger regression, Mendelian randomization-PRESSO outlier tests, Cochran’s Q test, and linkage disequilibrium score regression. Effect sizes were expressed as odds ratios (ORs) with 95% confidence intervals (CIs) and corresponding P -values. Twelve metabolites showed suggestive causal associations ( P < .05) with cerebral atherosclerosis. After accounting for pleiotropy and heterogeneity, 11 remained significant. Protective associations (OR < 1) included acetoacetate (OR: 0.78, 95% CI: 0.63–0.98, P = .030), 5-oxoproline (OR: 0.41, 95% CI: 0.17–0.98, P = .044), 3-hydroxyoctanoate (OR: 0.78, 95% CI: 0.63–0.98, P = .033), tartarate (OR: 0.64, 95% CI: 0.42–0.98, P = .039), and X-23739 (uncharacterized; OR: 0.74, 95% CI: 0.58–0.93, P = .011). Risk associations (OR > 1) included 3-methoxytyramine sulfate (OR: 1.38, 95% CI: 1.03–1.86, P = .032), carnitine (OR: 1.38, 95% CI: 1.03–1.86, P = .032), homoarginine (OR: 1.74, 95% CI: 1.02–2.98, P = .042), isovalerate (i5:0; OR: 1.21, 95% CI: 1.06–1.39, P = .006), ascorbic acid 3-sulfate (OR: 1.11, 95% CI: 1.01–1.22, P = .037), and creatinine (OR: 1.01, 95% CI: 1.0005–1.0185, P = .037). Sensitivity analyses showed no significant pleiotropy or heterogeneity, and no reverse causality for most associations. Linkage disequilibrium score regression identified a significant genetic correlation only for 3-hydroxyoctanoate. This study identifies several CSF metabolites that may be associated with the risk of cerebral atherosclerosis. While the results are robust across sensitivity analyses, they should be interpreted cautiously, and further validation in larger, longitudinal cohorts is warranted before inferring definitive causal roles.

Aim. To investigate the mechanism via which FKN/CX3CR1 signaling abnormalities mediate N-methyl-D-aspartic acid receptor (NMDA) overexcitation-induced hippocampal neuronal injury in diabetic rats complicated with depression (DD). Methods. Sixty rats were randomly divided into 5 groups. The depression-like behaviors of the rats were evaluated by open field test and Morris water maze. The pathological changes of hippocampus in DD rats were observed by HE staining. The blood levels of inflammatory factors (IL-1β, TNF-α, and IL-6) and neurotransmitters (D-serine and glutamic acid) were determined by enzyme-linked immunosorbent assay (ELISA). The expressions of BDNF, A1 receptor (A1R), A2 receptor (A2R), A3 receptor (A3R), calmodulin dependent kinase II (CaMKII), CX3CR1, CX3CL1 (FKN), NR2A, and NR2B proteins were detected by immunohistochemistry and Western-blotting. Results. Compared with the normal control group, blood glucose level increased significantly and body weight decreased in T2DM group and T2DMC group. In addition, the number of spontaneous activities significantly decreased and the capability of learning and memory was attenuated in T2DMC group and Chronic Stress group. The blood levels of IL-1β, TNF-α, IL-6, glutamate (Glu), and D-serine significantly increased in each model group. After intervention with CX3CR1 antibody, the expressions of BDNF, CaMK II, A1R, and A3R increased and those of A2R, CX3CR1, FKN, NR2A, and NR2B decreased. Conclusion. In the diabetic state, the binding of FKN to CX3CR1 increases, which regulates a variety of adenosine receptors. When it exerts its effect on neurons, the overactivation of NR results in neuronal injury and causes depression.