Sex-specific disparities in alcohol-associated liver disease and cancers: Insights from a large prospective cohort and plasma proteomics.

BACKGROUND: Alcohol consumption is a known risk factor for liver disease and cancers, however, sex-specific susceptibilities and biological mechanisms linking various alcohol intake dimensions to alcohol-associated liver disease (ALD) and cancers remain poorly understood. METHODS: We analyzed 365,966 participants from the UK Biobank to evaluate hazard ratios (HRs) of alcohol dose, frequency, and pattern with ALD and alcohol-related cancers. Sex-stratified Cox models and restricted cubic splines were employed. In a representative subcohort (n = 38,328), we conducted plasma proteomic profiling (2911 proteins) using LASSO regression, mediation analysis, and protein-protein interaction (PPI) networks to identify sex-specific biological drivers. RESULTS: Over a median 13.8-year follow-up, every 70 g/week increment in alcohol intake was associated with a disproportionately higher risk of ALD in females (HR = 1.21, 95% CI: 1.19-1.23) than in males (HR = 1.06, 95% CI: 1.06-1.06; P for interaction < 0.001). Females exhibited a 2.8-fold higher risk for ALD than males at 200 g/week. Females also exhibited greater vulnerability to esophageal cancer at higher intake levels. Daily drinking and drinking without meals significantly amplified risks across both sexes. Proteomic analysis identified sex-specific mediators. Carcinoembryonic antigen related cell adhesion molecule 16 was identified as the leading shared plasma protein mediator for ALD in both sexes (Mediation Proportion: 16.7% in males, 9.7% in females). Alcohol-associated mediators in males were predominantly enriched in pro-inflammatory cascades (MAPK and NF-kappa B pathways), whereas the female mediation core centered on cellular homeostasis and tissue integrity (cell-cell adhesion and PI3K-Akt pathways). CONCLUSION: This study provides epidemiological and proteomic evidence that sex significantly modifies alcohol-induced health risks, warranting the implementation of sex-stratified guidelines and clinical screening for alcohol-associated diseases.