Immunomodulatory, Antifatigue, and Hypoxia Tolerance Effects of Polygonatum cirrhifolium Polysaccharides: Structural Characterization and MAPK/NF‐κB Pathway Insights

ABSTRACT Polygonatum cirrhifolium (Wall.) Royle is an important medicinal plant used in traditional Tibetan medicine for enhancing vitality, improving immunity, alleviating fatigue, and promoting adaptation to high‐altitude environments. However, the pharmacological activities and underlying mechanisms of its polysaccharides remain largely unexplored. Polygonatum cirrhifolium polysaccharides (PCP) were extracted, purified, and structurally characterized. Their immunomodulatory activity was evaluated in cyclophosphamide‐induced immunosuppressed mice, while anti‐fatigue and hypoxia tolerance effects were assessed using weight‐loaded swimming and normobaric hypoxia models, respectively. The involvement of the MAPK/NF‐κB signaling pathway was further investigated by Western blotting. The purified PCP exhibited a triple‐helix structure. Administration of PCP restored thymus and spleen indices, enhanced phagocytic activity, improved both humoral and cellular immune responses. PCP also activated the MAPK/NF‐κB signaling pathway through increased phosphorylation of ERK, JNK, p38, and NF‐κB p65, together with upregulated MyD88 expression. In addition, PCP significantly extended exhaustive swimming time, preserved glycogen reserves, reduced blood urea nitrogen levels, and enhanced hypoxia tolerance by elevating superoxide dismutase and catalase activities. This study provides the first comprehensive evidence that PCP possesses significant immunomodulatory, anti‐fatigue, and hypoxia‐tolerance effects. The findings suggest that the MAPK/NF‐κB signaling pathway may be involved in its immunomodulatory actions and that PCP could be a promising candidate for enhancing physical performance and promoting health in hypoxic environments.