Insights into natural polysaccharides in alleviating drug-induced liver injury: Protective mechanisms and recent advances.

Drug-induced liver injury (DILI) remains a major clinical challenge because effective treatments are limited. Natural polysaccharides may alleviate DILI in preclinical models by reducing oxidative stress, inflammation, immune dysregulation, apoptosis, and gut-liver axis dysfunction. This review summarizes the mechanisms of DILI caused by representative hepatotoxic drugs and evaluates polysaccharides from medicinal plants, edible fungi, algae, marine organisms, and food sources. It focuses on structure-activity relationships involving molecular weight, monosaccharide composition, glycosidic linkages, branching, uronic acid content, chain conformation, and chemical modification. Key pathways include nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE), nuclear factor kappa B (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), apoptosis-related signaling, bile acid transport, and gut-liver axis regulation. Major barriers include low bioavailability, limited pharmacokinetic and safety data, unclear active forms in vivo, and insufficiently validated delivery systems. This review presents a DILI-centered structure-mechanism-activity framework for the rational development of natural polysaccharides as hepatoprotective agents.