Innate immune sensing of dietary alcohol ignites inflammation to drive alcohol-related disease

Abstract

Alcohol consumption has short- and long-term impacts on physical and mental health. Although multiple host and environmental factors contribute to alcohol-related diseases, the innate immune sensors that detect toxic signals from alcohol remain poorly defined. Here, we show that alcohol cooperates with sterile- or infection-induced interferon signaling to drive inflammatory cell death, cytokine release, and liver injury in humans and mice. We identified the pattern recognition receptor ZBP1 as a key innate immune sensor mediating pyroptosis, apoptosis, and necroptosis in response to combined ethanol and interferon stimulation. While interferon elevated ZBP1, ethanol suppressed ADAR1 expression. Together, interferon and ethanol activated JNK signaling to promote Z-RNA formation, triggering ZBP1. These findings reveal a mechanism by which alcohol and interferon converge to induce ZBP1-dependent inflammatory cell death and liver pathology, providing mechanistic insight and highlighting potential therapeutic targets for alcohol-related disease.