Oral iron sulfide prevents acute alcohol intoxication by initiating the endogenous multienzymatic antioxidant defense system

Acute alcohol intoxication could cause multiorgan damage, including nervous, digestive, and cardiovascular systems, and in particular, irreversible damage to the brain and liver. Emerging studies have revealed that the endogenous multienzymatic antioxidant defense system (MEAODS) plays a central role in preventing oxidative stress and other toxicological compounds produced by alcohol. However, few available drugs could quickly regulate MEAODS. Herein, we report a nanosized iron sulfide (nFeS) that can rapidly release polysulfide species in gastric juice. The released hydrogen polysulfide activates the Keap1/Nrf2 pathway via S-persulfidation of cysteine residues in Keap1, which promotes the expression of antioxidant enzymes and glutathione synthesis–related enzymes, thus potentiating MEAODS. Results indicate that the activated MEAODS not only alleviates oxidative stress and inflammation in the brain and liver but also mitigates movement dysfunction after only 2.5 hours of oral nFeS treatment. Collectively, this study provides a MEAODS-regulated strategy with nFeS and may aid the prevention of acute alcoholic injury.