ZBP1 identified as key innate immune sensor driving alcohol-related inflammatory cell death and liver injury

Alcohol-related disease (ARD) presents significant health challenges, yet the precise innate immune sensors detecting toxic alcohol signals remain poorly understood. Current understanding points to multiple host and environmental factors, but a critical gap exists in identifying the specific molecular mechanisms by which alcohol triggers damaging inflammation. This research focuses on how alcohol interacts with immune signaling to drive inflammatory cell death and tissue damage, particularly in the liver.

Researchers investigated the interplay between ethanol and interferon signaling in driving inflammation and liver injury using both human samples and mouse models. They stimulated cells and animals with combined ethanol and interferon, observing outcomes related to inflammatory cell death, cytokine release, and liver pathology. The study focused on identifying specific pattern recognition receptors involved in this response. Key assays likely included those to detect pyroptosis, apoptosis, necroptosis, cytokine levels (e.g., ELISA), and markers of liver injury.

Z-DNA binding protein 1 (ZBP1) was identified as a key innate immune sensor mediating pyroptosis, apoptosis, and necroptosis in response to combined ethanol and interferon stimulation. This mechanism involves interferon elevating ZBP1 expression, while ethanol simultaneously suppressed adenosine deaminase acting on RNA 1 (ADAR1) expression. The convergence of interferon and ethanol activated JNK signaling, which subsequently promoted Z-RNA formation. This Z-RNA then directly triggered ZBP1, leading to the observed inflammatory cell death and liver pathology. These findings were consistent across both human and mouse models, demonstrating a conserved mechanism by which alcohol and interferon synergize to induce ZBP1-dependent inflammation.