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. 

A research team, affiliated with UNIST has uncovered a novel molecular pathway explaining why alcohol consumption can lead to severe liver damage, particularly when individuals are already battling infections, such as cold and influenza.

Led by Professor SangJoon Lee from the Department of Biological Sciences at UNIST, alongside Professors Rajendra Karki of Seoul National University and Si Ming Man of the Australian National University, the research sheds light on how alcohol interacts with the immune system to accelerate liver cell death and exacerbate liver disease. 

The team discovered that, in the presence of interferon—a key immune signaling molecule produced during infections—alcohol triggers an inflammatory cascade within liver cells. Specifically, alcohol increases the level of Z-RAN, an abnormal form of RNA, which is detected by the pattern recognition receptor Z-DNA binding protein 1 (ZBP1). This activation initiates inflammatory cell death, contributing to liver damage.

Under normal circumstances, the protein ADAR1 suppresses Z-RNA formation, preventing unwarranted immune activation. However, the study revealed that alcohol impairs ADAR1 production, allowing Z-RNA to accumulate and activate ZBP1. This process involves the JNK signaling pathway, which was validated through animal experiments showing that inhibiting ZBP1 or blocking JNK signaling significantly reduced liver injury—even in the presence of alcohol and interferon.

Professor Lee explained, "While the direct toxicity of alcohol on liver cells has long been recognized, our findings highlight an immune-mediated pathway that exacerbates liver damage during illness. This discovery opens new possibilities for targeted therapies, such as ZBP1 inhibitors, to treat alcohol-related liver diseases."

The findings of this research were published in Science Advances on April 10, 2026. The study was supported by the National Research Foundation of Korea (NRF), the Korea Drug Development Find (KDDF), the Institute for Basic Science (IBS), the Circle Foundation, and Yuhan Corporation. It has also been supported through the Global Physician-Scientist Training Program and the ARPHA-H Project from the Korea Health Industry Development Institute (KHIDI) under the Ministry of Health and Welfare (MOHW). 

Journal Reference

Yeonseo Jang, Hoeun Bae, SuHyeon Oh, et al ., “Innate immune sensing of dietary alcohol ignites inflammation to drive alcohol-related disease,” Adv. Sci ., (2026).