Natural Polysaccharides in Health and Targeting TGF-β/Smad Signaling Therapy in Chronic Diseases

Abstract Chronic diseases including cardiovascular disorders, cancers, diabetes and organ fibrosis are major global causes of mortality. The transforming growth factor-β (TGF-β)/suppressor of mothers against decapentaplegic (Smad) cascade governs key physiological events spanning cell proliferation, differentiation, immune homeostasis and extracellular matrix remodeling. Natural polysaccharides (NPs) are bioactive macromolecules widely distributed across diverse living organisms. This review summarizes the TGF-β/Smad pathway, addresses NPs structure–activity relationships, and dissects tissue-specific regulatory mechanisms. It highlights modulation of TGF-β/Smad signaling by NPs via gut microbiota dysbiosis and metabolic disturbances under chronic injury. Targeting TGF-β/Smad with NPs represents a promising therapeutic strategy for related chronic diseases. This review also discusses research bottlenecks and translational strategies, integrating gut microbiota–metabolite crosstalk across multiorgan pathologies to advance mechanistic insights into NPs-driven tissue homeostasis restoration and support NPs-based targeted therapy development.