Methamphetamine is a potent and highly addictive neurotoxic psychostimulant that triggers a spectrum of adverse emotional responses during withdrawal. G-protein coupled receptor 55 (GPR55), a novel endocannabinoid receptor, is closely associated with mood regulation. Herein, we developed a murine model of methamphetamine-induced anxiety- and depressive-like behavior during abstinence which showed a decreased GPR55 expression in the hippocampus. Activation of GPR55 mitigated these behavioral symptoms, concomitantly ameliorating impairments in hippocampal neurogenesis and reducing neuroinflammation. These findings underscore the pivotal role of GPR55 in mediating the neuropsychological consequences of methamphetamine withdrawal, potentially via mechanisms involving the modulation of hippocampal neurogenesis and inflammation.

Atherosclerosis (AS) is a leading cause of cardiovascular disease and stroke. Although mitochondria’s role in AS is recognized, effective molecular targets are lacking. This study investigated mitochondria-associated signature biomarkers in AS, providing insights for mechanistic research and targeted therapy. AS-related transcripts were retrieved from public databases. Bioinformatics analyses (differential expression, machine learning, and expression verification) were integrated to screen biomarkers, and a nomogram was constructed. The functions, immune features, and single-cell expression (cellular landscape) of the identified biomarkers were analyzed. The L-lactate dehydrogenase B and SLC25A4 genes emerged as mitochondrial signature biomarkers in both tissues and blood samples from patients with AS. The nomogram exhibited robust performance in predicting the prevalence of AS. Notably, these biomarkers were significantly involved in pathways associated with the pathogenesis of AS, such as the Toll-like receptor pathway. Compared with the findings in control samples, 27 types of immune cells exhibited increased infiltration in AS samples, and the biomarkers generally displayed a strong negative correlation with these infiltrating immune cells. Nine cell types were annotated at the single-cell level, among which vascular smooth muscle cells (VSMCs) represented the key cell population, being characterized by high pyruvate metabolism activity. Furthermore, VSMCs were primarily engaged in cell–cell communication with macrophages. Additionally, the expression profiles of the biomarkers exhibited an inverted U-shaped dynamic pattern corresponding to the expression changes in VSMCs. This study identified two mitochondrial signature biomarkers, preliminarily revealed their potential roles in AS, provided new insights for targeted therapy research, and laid a foundation for unraveling mitochondria-related pathological mechanisms in AS.

Metabolic reprogramming is closely linked to tumor proliferation, invasion, and immune escape. Despite its central role in amino acid metabolism, the regulatory mechanisms of asparagine metabolism in hepatocellular carcinoma (HCC) progression remain poorly characterized. Rather than focusing on canonical metabolic genes, prognostic markers were identified from co-expression modules associated with asparagine metabolism signatures. Using the TCGA database and asparagine metabolism-related gene sets, a prognostic risk-scoring model was developed through differential expression analysis, univariate Cox regression, and the LASSO algorithm and externally validated with the GEO dataset (GSE14620). Survival analysis, ROC curve evaluation, nomogram construction, scRNA-seq, GSEA, and drug sensitivity analysis were performed to systematically delineate the molecular mechanisms by which asparagine metabolism drives HCC progression. A three-gene signature comprising BOP1, SAC3D1, and PDE2A effectively stratified patients into high- and low-risk groups. High-risk patients exhibited markedly poorer overall survival, enrichment in tumor proliferation-associated pathways, increased tumor purity, reduced immune cell infiltration, and a substantially higher TP53 mutation rate (38% vs. 13%). In contrast, the low-risk group showed enrichment in pathways linked to hepatoblastoma suppression and liver function, alongside improved predicted response to immunotherapy. Single-cell analysis identified NK cells and endothelial cells as central mediators of asparagine metabolism-driven HCC progression, with BOP1, SAC3D1, and PDE2A displaying dynamic expression patterns during differentiation. Furthermore, the high-risk group was predicted to be more sensitive to chemotherapeutics such as cyclophosphamide and 5-fluorouracil. These findings highlight a potential interplay between nitrogen metabolism and asparagine metabolism in HCC and suggest mechanisms by which these pathways may influence NK cell and endothelial cell function to promote disease progression. This study establishes a novel prognostic model and identifies potential chemotherapeutic vulnerabilities in high-risk patients, warranting further experimental and clinical validation.