Sex-specific disparities in alcohol-associated liver disease and cancers: Insights from a large prospective cohort and plasma proteomics
Cancer Epidemiology, 2026
Fang L., Zhao J., Liu G., Shi Y., Zeng H., Ding Z., Pu R., Liu W., Cao G.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Oncology Hepatology | Pathophysiology | Plasma |  Olink Explore 3072/384 |
Abstract
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).ConclusionThis 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.