Nrf2 Deficiency Exacerbates Methamphetamine-Induced Neuronal Apoptosis and Cognitive Dysfunction in Male Mice.

Intracerebral hemorrhage (ICH) is a serious neurological disease with high mortality, accounting for 10%–15% of all stroke subtypes (). This condition has a sudden onset and progresses rapidly, with up to 70% of cases associated with a history of hypertension (). Long term hypertension not only directly damages the cerebral vascular endothelium, increases vascular fragility, induces vascular rupture, hematoma, and neurological damage, but also exacerbates target organ damage through immune inflammatory mechanisms (immune cell activation, pro-inflammatory cytokine release, etc.), ultimately leading to cognitive impairment, affecting memory, attention, and executive function, and severely reducing patient independence (; ). At present, the methods for treating cerebral hemorrhage include blood pressure management, surgical intervention, and coagulation reversal (; ). Therapeutic options for cognitive decline after hypertensive intracerebral hemorrhage are still constrained, and specific biomarkers for early detection and risk assessment are lacking. Therefore, identifying biomarkers that can effectively identify CI in HCH is particularly important for the treatment of HCHwCI. RNA sequencing (RNA-Seq) enables comprehensive transcriptome analysis and has proven invaluable in identifying disease biomarkers and therapeutic targets. In neuroscience, RNA-Seq technology has been effectively employed to examine transcriptional alterations in neurological conditions like Alzheimer’s disease and stroke, greatly enhancing the identification of disease biomarkers and therapeutic target screening (). For instance, Peripheral blood RNA-Seq in intracerebral hemorrhage patients demonstrated the pivotal involvement of inflammatory responses, oxidative stress, and vascular dysfunction in disease development (). Although no direct transcriptome sequencing studies on human HCHwCI have been reported to date, an RNA-Seq study in hypertensive mice demonstrated that the combination of hypertension and stroke induces abnormal changes in differentially expressed genes associated with neuroinflammation in the brain. These molecular-level alterations were directly correlated with worsening cognitive impairment (), demonstrating that RNA-Seq can reveal key molecular pathways and pathological processes underlying cognitive dysfunction (). This holds significant implications for screening biomarkers for HCHwCI, elucidating disease mechanisms, and guiding therapeutic strategies. This study identified biomarkers associated with CI in HCH based on transcriptome sequencing data from clinical patients, through differential expression analysis, PPI screening, and expression validation. Furthermore, gene set enrichment analysis, subcellular localization, chromosomal mapping, and GeneMANIA analysis were performed based on these biomarkers. To investigate underlying mechanisms and therapeutic implications, regulatory network analysis and drug target prediction were conducted. Finally, biomarkers were validated via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to assess key gene expression.