G9a-mediated cholesterol metabolism triggers cuproptosis to promote alcohol-related liver disease

Abstract Whether and how disrupted cholesterol homeostasis contributes to alcohol-related liver disease (ALD) remains elusive. Here, we report that cholesterol biosynthesis is enhanced in ALD livers, driven by a reduction in the H3K9me2 epigenetic landscape orchestrated by the G9a methyltransferase. The heightened cholesterol-associated cuproptotic features, a copper-dependent form of cell death particularly evident in the presence of alcohol, drive extensive liver damage and ALD progression. Notably, pharmacological interventions targeting cholesterol biosynthesis with statins or mitigating cuproptotic features with copper chelators, both clinically available drugs, significantly alleviate disease symptoms in pre-clinical ALD models. In conclusion, our study reveals a previously unrecognized interplay between the G9a epigenetic pathway, hepatic cholesterol metabolism, and alcohol-induced toxicity, establishing cuproptotic features as a key driver of ALD progression. These findings provide a basis for further investigation into modulating cholesterol and copper homeostasis in ALD pathophysiology.