Rising rates of alcohol use disorder (AUD) combined with increases in alcohol-related liver disease (ALD) and other liver disease have resulted in the need to develop alcohol management strategies at all levels of patient care. For those with pre-existing liver disease, whether ALD or others, attention to alcohol use treatment and abstinence becomes critical to avoiding worsening liver-related consequences. Modalities to help patients reduce or stop alcohol include screening/brief intervention/referral to treatment, various therapeutic modalities including cognitive behavioral therapy, motivational enhancement therapy and 12-step facilitation, and alcohol relapse prevention medications. Harm reduction approaches versus total abstinence may be considered, but for those with existing ALD, particularly advanced ALD (cirrhosis or acute alcoholic hepatitis), total abstinence from alcohol is the recommendation, given clear data that ongoing alcohol use worsens mortality and liver-related morbidity. For certain populations, alcohol cessation is even more critically important. For those with hepatitis C or NAFLD, alcohol use accelerates negative liver-related outcomes. In women, alcohol use accelerates liver damage and results in worsened liver-related mortality. Efforts to integrate AUD and liver disease care are urgently needed and can occur at several levels, with establishment of multidisciplinary ALD clinics for fully integrated co-management as an important goal.

BACKGROUND AND AIMS: Cholesterol ester (CE) biosynthesis and homeostasis play critical roles in many cancers, including HCC, but their exact mechanistic contributions to HCC disease development require further study. APPROACH AND RESULTS: Here, we report on a proposed role of tumor suppressor P53 in its repressing ubiquitin-specific peptidase 19 (USP19) and sterol O-acyltransferase (SOAT) 1, which maintains CE homeostasis. USP19 enhances cholesterol esterification and contributes to hepatocarcinogenesis (HCG) by deubiquitinating and stabilizing SOAT1. Loss of either SOAT1 or USP19 dramatically attenuates cholesterol esterification and HCG in P53-deficient mice fed with either a normal chow diet or a high-cholesterol, high-fat diet (HCHFD). SOAT1 inhibitor avasimibe has more inhibitory effect on HCC progression in HCHFD-maintained P53-deficient mice when compared to the inhibitors of de novo cholesterol synthesis. Consistent with our findings in the mouse model, the P53-USP19-SOAT1 signaling axis is also dysregulated in human HCCs. CONCLUSIONS: Collectively, our findings demonstrate that SOAT1 participates in HCG by increasing cholesterol esterification, thus indicating that SOAT1 is a potential biomarker and therapeutic target in P53-deficient HCC.