Hepatoprotective effects of natural polysaccharides: molecular mechanisms, structure–activity relationships, sources, applications in functional foods, and prospects

Natural polysaccharides from plants, fungi, algae, microorganisms, and animals have attracted increasing interest as food-derived candidates for liver protection. This critical review integrates preparation identity, structural attributes, mechanistic evidence, disease-model specificity, and translational readiness rather than treating these dimensions independently. Available preclinical evidence suggests that hepatoprotective phenotypes may emerge from interconnected redox, inflammatory, metabolic, gut–liver-axis, immune, and regulated-cell-death processes; however, many pathway assignments remain associative, and comparatively few studies use inhibitors, genetic perturbation, rescue experiments, microbiota depletion, or transplantation to establish causality. Reported structure–activity relationships are strongly preparation- and context-dependent. Molecular weight, monosaccharide composition, glycosidic linkage, branching, higher-order conformation, and chemical modification may contribute jointly to bioactivity, but cross-study heterogeneity in extraction, purification, purity, dose, route, and experimental model precludes a universal “optimal” structural rule. Translation is further constrained by the lack of standardized quality-control criteria, uncertain oral absorption and biodistribution, incomplete dose–response and long-term safety characterization, and the scarcity of controlled human trials. We therefore propose a structure–mechanism–model–efficacy framework and identify priorities for preparation standardization, causal mechanistic validation, pharmacokinetic and gut-metabolite studies, clinically feasible dosing, and well-controlled human trials. This evidence-calibrated framework may support the development of natural polysaccharides as functional-food ingredients and, where clinical evidence permits, potential adjunctive interventions for liver disorders.