Yeonseo Jang, Hoeun Bae, Hoeun Bae, SuHyeon Oh, Gyeongju Yu, Hyun Bae, Hyun Bae, Minh Quan Nguyen, Raghvendra Mall, Minjie Fu, Aritra Ghosh, Jihye Lee, Suhyun Kim, Seyun Shin, Nabukenya Mariam, Cheong Seok, Daesik Kim, SangJoon Lee, Si Ming Man, Rajendra Karki
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.