Mendelian Randomization Analysis of Systemic Iron Status and Risk of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Objective

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global public health crisis, progressing to hepatic cirrhosis and hepatocellular carcinoma. This study investigated the causal role of systemic iron status in MASLD progression.

Methods

A two-sample Mendelian randomization (MR) design was implemented, with genetic variants serving as instrumental variables for four core systemic iron biomarkers. Outcome data for hepatic steatosis (8785 cases; 912,105 controls) and hepatic fibrosis/cirrhosis (3798 cases; 904,599 controls) were extracted from the FinnGen and UK Biobank databases. Multiple complementary MR methodologies and three instrumental variable selection strategies were applied to ensure robust causal inference.

Results

Genetically predicted higher serum iron (odds ratio, OR: 1.42, 95% confidence interval, 95% CI: 1.34, 1.50), ferritin (OR: 1.84, 95% CI: 1.55, 2.18), and transferrin saturation (TfSat, OR: 1.24, 95% CI: 1.19, 1.30), together with lower total iron-binding capacity (TIBC, OR: 0.81, 95% CI: 0.77, 0.85), were significantly associated with increased hepatic steatosis risk (p < 0.00625). Similar associations were observed for hepatic fibrosis/cirrhosis: serum iron (OR: 1.66, 95% CI: 1.29, 2.14), ferritin (OR: 2.52, 95% CI: 1.52, 4.18), TfSat (OR: 1.40, 95% CI: 1.19, 1.63), and reduced TIBC (OR: 0.70, 95% CI: 0.60, 0.81). MR-Bayesian model averaging prioritized serum iron (MIP: 0.85, θ^MACE: 0.295; PP: 0.725; θ^λ: 0.344) as the top-ranked factors for steatosis and TIBC (MIP: 0.604, θ^MACE: -0.240; PP: 0.476, θ^λ: -0.358) for fibrosis/cirrhosis.

Conclusions

Elevated systemic iron status causally drives MASLD onset and progression, highlighting iron homeostasis and ferroptosis as potential targets for prevention and clinical management.