Integrative Multi-Omics and Network Pharmacology Analyses Reveal Potential Mechanisms of Codonopsis pilosula in Mountain Sickness

Mountain sickness comprises a spectrum of high-altitude disorders associated with hypobaric hypoxia, including acute mountain sickness (AMS) and high-altitude pulmonary edema (HAPE). Although Codonopsis pilosula has been widely used in traditional medicine for conditions related to hypoxia, its molecular basis in mountain sickness remains poorly understood. Here, we integrated network pharmacology, transcriptomic analysis, machine-learning-based feature selection, single-cell RNA sequencing, and molecular docking to explore potential molecular associations between Codonopsis pilosula-related candidate targets and mountain sickness. We identified a set of Codonopsis pilosula-associated candidate targets enriched in biological processes related to hypoxia response, oxidative stress, inflammation, and vascular regulation. Integrated transcriptomic analyses across high-altitude exposure, AMS, and HAPE revealed convergent alterations in immune-related and oxygen transport-associated programs. Machine-learning analysis further provided internal computational prioritization of candidate genes associated with high-altitude exposure, with recurrent selection across complementary algorithms within the analyzed paired cohort. Single-cell transcriptomic analysis provided additional cellular context for these candidates, revealing distinct expression patterns across peripheral blood and lung cell populations. Molecular docking further identified potential interactions between selected Codonopsis pilosula compounds and candidate proteins, with MMP9, CA2, and BCL2 showing comparatively favorable predicted interactions. Together, these findings provide an exploratory framework for evaluating potential associations between Codonopsis pilosula-associated candidate targets and transcriptional and cellular responses to high-altitude hypoxia, and identify candidate molecular pathways and targets for further experimental investigation.