Context-dependent immunomodulation by Astragalus polysaccharides: Structural determinants, structure-activity relationships, mechanisms, and applications: A review.

Astragalus polysaccharides (APS), derived mainly from Astragalus membranaceus (Fisch.) Bunge and Astragalus membranaceus var. mongholicus (Bunge) P. K. Hsiao, have attracted considerable attention as plant-derived immunomodulatory macromolecules. Accumulating evidence suggests that APS-mediated immunomodulation is context-dependent rather than unidirectional. Raw-material characteristics, processing methods, extraction procedures, fractionation, and purification can generate APS fractions with different structural characteristics, including molecular weight distribution, monosaccharide composition, glycosidic linkages, branching patterns, chain conformation, solubility, and aggregation behavior. This review summarizes recent progress in APS structural characterization, structure-activity relationships, immunomodulatory effects, mechanisms of action, and immune-related applications. Under immunosuppressive conditions, APS may help restore impaired immune defenses, whereas during immune hyperactivation, APS may suppress excessive inflammatory responses and support immune homeostasis. Mechanistically, APS may modulate innate and adaptive immune responses, gut microbial composition and metabolite production, mucosal barrier function, and gut-organ communication. Toll-like receptor 4-associated nuclear factor-κB and mitogen-activated protein kinase pathways are among the most frequently reported mechanisms, whereas nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling, regulation of the NOD-like receptor family pyrin domain-containing 3 inflammasome, interleukin-22/signal transducer and activator of transcription 3 signaling, and microbiota-mediated pathways may contribute in specific settings. In addition, APS-based interventions have been investigated for supportive clinical care, vaccine adjuvants, veterinary use, functional foods, immune-support products, and pharmaceutical or topical formulations. By linking structural variation to immune effects, mechanistic pathways, and application contexts, this review provides a basis for the structural standardization of APS, quality control, activity optimization, and immune-related product development.