IGF-1 as a mediator in the association between body mass index and risk of liver cancer: A prospective analysis of 432,203 participants from the UK biobank

PURPOSE: This study aimed to quantify the extent to which IGF-1 mediates the association between BMI and liver cancer risk, clarifying its role in adiposity-related liver carcinogenesis. METHODS: A prospective analysis was conducted using data from 432,203 UK Biobank participants, using four liver cancer definitions: ICD-10 C22 and C220, each excluding diagnoses within 24 or 60 months post-baseline. Linear regression assessed the BMI-IGF-1 relationship. Cox proportional hazards models and restricted cubic spline analyses examined associations between BMI, IGF-1, and liver cancer risk, with adjustments for covariates. Mediation analysis with 5000 bootstrap iterations evaluated IGF-1's mediating effect. RESULTS: Elevated BMI was positively correlated with liver cancer risk (multivariable HR = 1.071; p < 0.0001). This association attenuated after adjusting for IGF-1 (HR = 1.037; p < 0.0001). BMI negatively correlated with IGF-1 (multivariable β = -0.150; p < 0.0001). IGF-1 showed a non-linear relationship with liver cancer risk, with lower levels (approximately less than 18 nmol/L) linked to higher risk. IGF-1 mediated 37.76%-53.64% of the BMI-liver cancer association. CONCLUSION: IGF-1 substantially mediates the association between BMI and liver cancer risk, suggesting BMI-related IGF-1 reduction is a potential mechanistic pathway.