Identification and validation of biomarkers associated with mitotic catastrophe in high-altitude hypoxia.

BACKGROUND

High-altitude hypoxia (HAH) can cause adverse reactions, such as tinnitus and barotrauma, but the role of mitotic catastrophe (MC) in HAH remains unreported. This study investigated MC-associated biomarkers in HAH.

METHODS

HAH-related datasets and MC-related genes (MC-RGs) were retrieved from public databases. Differentially expressed genes (DEGs) between the HAH and control groups were screened, and overlapping genes between DEGs and MC-RGs were defined as candidates. Biomarkers were identified using three machine learning methods, receiver operating characteristic curve analysis, and expression validation. A nomogram was constructed for diagnostic assessment. Functional enrichment, immune infiltration, regulatory network, and drug prediction analyses were performed, with biomarker expression verified by reverse transcription quantitative polymerase chain reaction (RT-qPCR).

RESULTS

DIAPH1 and MDM4 were confirmed as MC-associated biomarkers in HAH, and the nomogram displayed excellent diagnostic ability (area under the curve = 0.929). These biomarkers were coenriched in pathways such as oxidative phosphorylation. DIAPH1 was positively correlated with the infiltration of resting NK cells, whereas MDM4 was negatively correlated with that of M2 macrophages. A transcription factor-mRNA-miRNA network was established, with USF2 and GATA2 jointly targeting both biomarkers. Drugs such as rescinnamine targeted MDM4. RT-qPCR verified that USF2 and GATA2 were significantly downregulated in HAH (both P < 0.01), consistent with the bioinformatics results.

CONCLUSIONS

DIAPH1 and MDM4 are valid MC-associated biomarkers for HAH. This study provides novel insights into HAH prevention and treatment.