September 30, 2025Open Access

Mendelian randomization analysis reveals no causal association between non-alcoholic fatty liver disease and hepatocellular carcinoma: implications for lipid metabolomics and shared pathophysiological mechanisms

Key Points

No significant causal association was found between non-alcoholic fatty liver disease and hepatocellular carcinoma across multiple methods.
Using four statistical methods, including Mendelian randomization, the study analyzed 55 SNPs for HCC and 6 SNPs for NAFLD.
The analysis evaluated over 30 metabolic biomarkers, including triacylglycerols and phosphatidylcholines, but found limited direct causal effects.
Sensitivity analyses confirmed result robustness, challenging previously held assumptions about the relationship between NAFLD, HCC, and lipid metabolism.

Abstract

Non-alcoholic fatty liver disease (NAFLD) has been increasingly associated with hepatocellular carcinoma (HCC) risk in observational studies, yet the causal nature of this relationship and its impact on systemic lipid metabolism remains unclear. This study aimed to evaluate the bidirectional causal relationships between NAFLD and HCC, and their effects on lipid metabolomics profiles using Mendelian randomization. We conducted comprehensive Mendelian randomization analyses using genetic variants as instrumental variables. For NAFLD exposure analysis, 6 single nucleotide polymorphisms (SNPs) were selected, while 55 SNPs were used for HCC exposure in reverse analysis. Four statistical methods were employed: inverse variance weighted (IVW), MR Egger regression, weighted mode, and simple mode. The study evaluated causal effects on over 30 metabolic biomarkers, including triacylglycerols, phosphatidylcholines, phosphatidylinositols, ceramides, and sphingolipids. Comprehensive sensitivity analyses were performed to assess horizontal pleiotropy and result robustness. No statistically significant causal association was found between NAFLD and HCC risk across all four methods (MR Egger: OR 0.996, 95% CI 0.993-0.999, P = 0.088; IVW: OR 1.000, 95% CI 0.999-1.001, P = 0.969; weighted mode: OR 0.999, 95% CI 0.998-1.001, P = 0.447; simple mode: OR 1.001, 95% CI 0.999-1.002, P = 0.402). Reverse Mendelian randomization showed no significant causal effect of HCC on NAFLD development. Both NAFLD and HCC demonstrated limited direct causal effects on lipid metabolomics profiles, with confidence intervals for most metabolites clustering tightly around the null value (0.990-1.010). Only a few phospholipid compounds showed marginal significance in NAFLD analysis. Sensitivity analyses confirmed result robustness without evidence of horizontal pleiotropy. This comprehensive Mendelian randomization study challenges the assumption of direct causal relationships between NAFLD, HCC, and systemic lipid metabolism.

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