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Sci. Adv., Apr 10 2026, 12 (15) eaea3979 | https://doi.org/10.1126/sciadv.aea3979 Innate immune sensing of dietary alcohol ignites inflammation to drive alcohol-related disease

Yeonseo Jang^1†, Hoeun Bae^1†, SuHyeon Oh^2,3†, Gyeongju Yu^2†, Hyun Bae¹, Minh Quan Nguyen¹, Raghvendra Mall⁴, Minjie Fu¹, Aritra Ghosh⁵, Jihye Lee², Suhyun Kim², Seyun Shin², Nabukenya Mariam⁶, Cheong Seok⁶, Daesik Kim⁶, SangJoon Lee^2*, Si Ming Man^5*, Rajendra Karki^1,7*

¹Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
²Department of Biological Science, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea.
³Center for Study of Emerging and Re-emerging Viruses, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon, Republic of Korea.
⁴Biotechnology Research Center, Technology Innovation Institute, Abu Dhabi, 9639, United Arab Emirates.
⁵Division of Immunology and Infectious Diseases, The John Curtin School of Medical Research, The Australian National University, Canberra, 2601, Australia.
⁶Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
⁷Institute of Molecular Biology and Genetics (IMBG), Seoul National University, Seoul, Republic of Korea.

*Corresponding authors: S.L.; S.M.M.; R.K.
^†These authors contributed equally to this work.

Abstract

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.

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