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

Alcohol consumption has short- and long-term impacts on physical and mental health. Although multiple host and environmental factors contribute to alcohol-related disease, 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 Z-DNA binding protein 1 (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 adenosine deaminase acting on RNA 1 (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.