Food-Derived Polygonatum cyrtonema Hua polysaccharide PCP1: Targeting Gut Microbiota-Derived SCFAs to Inhibit Ferroptosis in Alcoholic Liver Disease

This study investigates the therapeutic potential and mechanisms of Polygonatum cyrtonema Hua polysaccharide (PCP1) in the treatment of alcohol-induced liver disease (ALD), with a focus on the gut-liver axis. The therapeutic effects of PCP1 were assessed using biochemical, histological, and 16S rRNA sequencing analyses. To elucidate the underlying mechanism, a comprehensive series of in vivo and in vitro experiments were employed, including antibiotic-induced microbiota depletion, fecal microbiota transplantation (FMT), direct in vivo SCFA supplementation, and direct SCFA application to hepatocytes. The results revealed that PCP1 significantly reduced elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, mitigated hepatic lipid accumulation and histological damage, and inhibited ferroptosis mechanistically through the upregulation of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Additionally, PCP1 induced a notable shift in the gut microbiota composition, increasing fecal  levels of acetate and propionate. Importantly, antibiotic-induced depletion of gut microbiota abolished the hepatoprotective effects of PCP1, while FMT successfully restored them. Furthermore, the mediating role of SCFAs was confirmed both in vivo and in vitro, as direct supplementation of acetate and propionate rescued liver injury in microbiota-depleted mice, while they also directly suppressed ethanol-induced ferroptosis in AML-12 hepatocytes. This study provides compelling evidence that PCP1 exerts its hepatoprotective effects through the gut microbiota-SCFA-ferroptosis axis, positioning PCP1 as a promising microbiota-targeted therapeutic for ALD. As a food-derived macromolecule, PCP1 demonstrates considerable prebiotic potential for functional food development.