Aspirin and hepatocellular carcinoma risk in metabolic dysfunction-associated steatotic liver disease: nationwide cohort study with genetic risk analysis.

BACKGROUND/AIMS: The association between aspirin use and hepatocellular carcinoma (HCC) risk in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study evaluated the effect of aspirin on HCC development in MASLD patients using Korean National Health Insurance Service (NHIS) and UK Biobank (UKB) databases. METHODS: A retrospective cohort analysis was conducted using the NHIS database with a 3-year landmark design. Baseline characteristics were balanced using inverse probability of treatment weighting (IPTW) and 1:3 propensity score matching (PSM). Additionally, Mendelian randomization analysis was performed in the UKB cohort using a genomic risk score (GRS) for salicylic acid, based on genetic variants related to aspirin metabolism, as a proxy for aspirin use. RESULTS: In the NHIS cohort, 6,584,155 eligible patients were included, of whom 1,723,435 had MASLD. After PSM, aspirin use was associated with a significantly lower risk of HCC compared to no aspirin use, in both the overall population (adjusted subdistribution hazard ratio [ASHR]=0.86; 95% confidence interval [CI] 0.78-0.95; P=0.002) and MASLD group (ASHR=0.86; 95% CI 0.75-0.99; P=0.036). Similar results were reproduced in the IPTW population and several sensitivity and subgroup analyses. In the UKB cohort, individuals in the top 95% of GRS had a significantly lower risk of HCC compared to those in the bottom 5%, in both the overall population (ASHR=0.61; 95% CI 0.39-0.95; P=0.028) and MASLD group (ASHR=0.47; 95% CI 0.29-0.76; P=0.002). CONCLUSIONS: Findings from both population-based and genetic analyses suggest a possible protective association between aspirin use and HCC in patients with MASLD, which warrants further validation.