ObjectiveTo investigate the association between chronic liver disease （CLD） and depression and the mediating role of nocturnal sleep duration， as well as the consistency of this association between Chinese and American populations. MethodsThe data from two databases were integrated， i.e.， China Health and Retirement Longitudinal Study （CHARLS） （n=14 225） in China and National Health and Nutrition Examination Survey （NHANES） （n=11 353） in the United States， and the subjects were divided into CLD group and non-CLD group. A stepwise Logistic regression model was used to assess the independent association between CLD and depression. Bootstrap resampling （1 000 times） was used to quantify the proportion of the mediating effect of nocturnal sleep duration， and interaction effects were evaluated through stratified analyses based on the factors including registered residence/race and income. The independent-samples t test was used for comparison of continuous data between two groups； the chi-square test or the Fisher’s exact test was used for comparison of categorical data； a multivariate Logistic regression model analysis was used to investigate the association of different types of CLD with depression. ResultsAfter multivariate adjustment， CLD was significantly associated with the increased risk of depression （CHARLS： odds ratio ［OR］=1.76， 95% confidence interval ［CI］： 1.46 — 2.12， P<0.001； NHANES： OR=1.87， 95%CI： 1.50 — 2.35， P<0.001）. Nocturnal sleep duration played a partial mediating role in the association between CLD and depression， with a mediating effect accounted for 12.41% in CHARLS and 2.16% in NHANES （P<0.05）. The interaction analysis showed that in CHARLS， the association between CLD and depression was more significant in the residents with agricultural registered permanent residence （OR=2.07， 95%CI： 1.67 — 2.57， P<0.001）， and in NHANES， this association was more significant in the population with moderate poverty income ratio （OR=2.66， 95% CI： 1.92 — 3.69， P<0.001）. The subtype analysis showed that autoimmune hepatitis （OR=3.63， 95%CI： 1.49 — 8.88， P=0.005）， liver cirrhosis （OR=2.46， 95%CI： 1.32 — 4.60， P=0.005）， and fatty liver disease （OR=1.75， 95%CI： 1.27 — 2.39， P=0.001） significantly increased the risk of depression， while no statistical significance was observed for viral hepatitis or other liver diseases （P>0.05）. ConclusionThis study reveals the significant association between CLD and depression at the population level and suggests that nocturnal sleep duration may play a partial mediating role， which is consistent between the Chinese and American populations. These research findings provide quantitative evidence-based support for understanding the underlying mechanism of CLD-related depression and points out the potential significance of sleep issues in CLD management.

The term “metabolic and alcohol-related liver disease （MetALD）” recently proposed emphasizes the synergistic role of metabolic dysfunction and alcohol exposure in the progression of liver injury. Although this theoretical framework improves the understanding of the multifactorial and complex nature of liver disease， its clinical application still faces numerous new challenges in diagnosis and treatment. This article summarizes the latest evidence for the prevalence， potential pathogenesis， clinical diagnostic markers， and treatment of MetALD and particularly emphasizes the urgency to develop reliable preclinical models that can accurately simulate the intricate pathophysiology of this disease due to various factors. This article also provides a systematic evaluation of emerging therapies including fecal microbiota transplantation and nutritional interventions and proposes the future directions for drug innovation in MetALD.