Poria cocos polysaccharides improve alcoholic liver disease by interfering with ferroptosis through NRF2 regulation.

ABSTRACT

The active ingredient in Poria cocos, a parasitic plant belonging to the family Polyporaceae, is Poria cocos polysaccharide (PCP). PCP exhibits liver protection and anti-inflammatory effects, although its effect on alcoholic liver disease (ALD) remains unstudied. This study investigated the mechanism of PCP in improving ALD by regulating the Nrf2 signaling pathway. After daily intragastric administration of high-grade liquor for 4 hours, each drug group received PCPs or the ferroptosis inhibitor ferrostatin-1. The Nrf2 inhibitor ML385 (100 mg/kg/day) group was intraperitoneally injected, after which PCP (100 mg/kg/day) was administered by gavage. Samples were collected after 6 weeks for liver function and blood lipid analysis using an automatic biochemical analyzer. In the alcoholic liver injury cell model established with 150 mM alcohol, the drug group was pretreated with PCP, Fer-1, and ML385, and subsequent results were analyzed. The results revealed that PCP intervention significantly reduced liver function and blood lipid levels in alcohol-fed rats, along with decreased lipid deposition. PCP notably enhanced Nrf2 signaling expression, regulated oxidative stress levels, inhibited NF-κß, and its downstream inflammatory signaling pathways. Furthermore, PCP upregulated FTH1 protein expression and reduced intracellular Fe2+, suggesting an improvement in ferroptosis. In vitro studies yielded similar results, indicating that PCP can reduce intracellular ferroptosis by regulating oxidative stress and improve alcoholic liver injury by inhibiting the production of inflammatory factors.