Objective To conjointly analyze the differentially expressed miRNAs in peripheral blood of patients with high altitude sickness and their upstream transcription factors and downstream mRNAs based on the GEO database, so as to explore potential pathogenesis of high altitude sickness based on molecular level. Methods　(1) Expression profile chip of miRNAs (GSE90500 data set) and mRNAs expression profile chip (GSE29977 data set) related to high altitude sickness were obtained from the GEO database, and then the limma package of R language 3.6 software was used to screen differentially expressed miRNAs and mRNAs. (2) Downstream target genes (mRNAs) and upstream transcription factors of differentially expressed miRNAs were predicted by employing the FunRich software, and functional enrichment analysis was performed on upstream transcription factors. The R language 3.6 software, DAVID database were used to perform functional and pathway enrichment analyses on downstream target genes, respectively. (3) The intersection was obtained between differentially expressed mRNAs and downstream target genes of differentially expressed miRNAs in GSE29977 data set, and regulatory axis of miRNA⁃mRNA was screed according to the expression relation of miRNAs with its target genes. Results　(1) A total of 14 differentially expressed miRNAs, and their 385 downstream target genes and 123 upstream transcription factors were screened. Differentially expressed miRNAs were mainly enriched in transcription factors, containing EGR1, RREB1, MYF5, and MEF2A. (2) Upstream transcription factors were mainly involved in biological processes of signal transduction, regulation of nucleic acid metabolism, fatty acid metabolism, glycometabolism, cytokine and chemokine mediated signaling pathways and cell cycle, etc. Downstream target genes were mainly enriched in biological processes in terms of transcriptional regulation, cardiomyocyte proliferation, angiogenesis, and chromatin remodeling, etc., and in signaling pathways with respect to PD⁃L1 expression and PD⁃1 immune checkpoint pathway, cell senescence, MTOR signaling pathway, MAPK signaling pathway, and PI3K/AKT signaling pathway, etc. (3) A total of 433 differentially expressed mRNAs were screened, and 5 core mRNAs related to high altitude sickness were obtained after acquiring the intersection with downstream target genes of differentially expressed miRNAs, as well as regulatory axis of hsa⁃miR⁃155⁃5p⁃MYO1D was established. Conclusion There are multiple differentially expressed miRNAs in high altitude sickness, their upstream transcription factors EGR1, RREB1, MYF5, and MEF2A may be the core factors involved in regulating downstream target genes transcription. Upstream transcription factors and downstream target genes of differentially expressed miRNAs may be jointly involved in the occurrence and development of high altitude sickness through regulating biological processes of gene transcription, cell proliferation and apoptosis, and inflammatory processes, etc. The regulatory relation between hsa⁃miR⁃155⁃5p and downstream target gene MYO1D may play an important role in the occurrence and development of high altitude sickness.

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