Natural polysaccharides as multifunctional regulators of energy metabolism: mechanisms, structure-activity relationships, and cross-disease applications

Dysregulated energy metabolism is a common pathological feature of various chronic diseases, including metabolic syndrome, neurodegenerative disorders, cancers, and cardiovascular diseases. Natural polysaccharides, known for their structural diversity, biocompatibility, and safety, have emerged as promising modulators for metabolic disorders due to their multi-target regulatory capabilities. Despite extensive research on their immunomodulatory functions, there is a gap in understanding their direct and systematic mechanisms in regulating energy metabolism across diseases. This review systematically explores three key mechanisms by which natural polysaccharides regulate energy homeostasis: (1) direct modulation of cellular energy pathways, enhancing glucose uptake, lipid metabolism, and mitochondrial function; (2) indirect regulation via the gut microbiota-metabolism axis, with microbial metabolites like short-chain fatty acids; and (3) reshaping the metabolic microenvironment through immunometabolic coupling, including macrophage polarization to alleviate metabolic inflammation. Additionally, the structure-activity relationship of polysaccharides is analyzed, linking molecular features like molecular weight, monosaccharide composition, glycosidic bonds, and branching with their metabolic effects. Finally, this review provides an overview of recent advances in natural polysaccharides' potential applications for metabolic diseases, neurodegeneration, cancer, aging, and more, offering a solid foundation for their clinical translation as novel metabolic modulators.