# Metabolomic insights into associations between adiposity markers and liver cancer risk: Results from a prospective cohort study and Mendelian randomization analysis

## TL;DR

This study identifies 27 metabolites linking obesity to liver cancer risk and uses genetic evidence to suggest some are causally involved, offering new insights into how obesity drives liver cancer.

## Contribution

The study integrates metabolomic profiling with Mendelian randomization to identify specific causal metabolic pathways linking adiposity to liver cancer.

## Key findings

- 27 metabolites were associated with both adiposity markers and liver cancer risk, forming an interconnected network.
- Pyroglutamic acid showed the strongest association with BMI and liver cancer risk.
- Mendelian randomization identified 23 causal associations, emphasizing amino acid and energy metabolism pathways.

## Abstract

The association between adiposity and increased liver cancer risk is well-recognized, yet underlying metabolic mechanisms require elucidation. This study aimed to identify metabolic mediators linking adiposity markers to liver cancer and assess their potential causality using two-sample Mendelian randomization (MR) analysis.

We conducted a 1:1 matched nested case-control study within a population-based and prospective cohort study—the Shanghai Men’s Health Study (SMHS). The SMHS was initiated in 2002–2006, including 61,469 Chinese men aged 40–74 years, and has been followed up for over 20 years. Targeted metabolomic profiling was performed on baseline plasma samples. Associations between seven anthropometric measurements (body mass index [BMI], waist circumference, waist-to-hip ratio, waist-to-height ratio, a body shape index, hip circumference, and adult weight gain), 186 circulating metabolites, and liver cancer risk were assessed. Linear and conditional logistic regression model adjusted for multiple confounders (including smoking, alcohol drinking, physical activity, chronic hepatitis and cirrhosis, diabetes, etc.) were used. Pathway analysis and network analysis were conducted to explore the biological functions of these metabolites. Parallel mediation analysis was employed to quantify the mediating effects through metabolites. Subsequently, MR analysis was performed to investigate potential causal relationships. This study incorporated 322 incident liver cancer cases and 322 cancer-free controls. Participants diagnosed with liver cancer had higher proportions of seropositive hepatitis B surface antigen (63.7%) compared to their matched controls (6.2%). We identified 27 intermediate metabolites associated with both adiposity markers and liver cancer risk, which formed an interconnected functional network. Pyroglutamic acid demonstrated the most robust consistency, being significantly associated with seven anthropometric measurements (β per doubling with BMI = 0.17; 95% confidence interval [CI]: [0.09, 0.24]) and liver cancer (odds ratio per doubling = 1.56; 95% CI: [1.13, 2.15]). Pathway analysis highlighted significant alterations in energy, lipid, and amino acid metabolism. Specifically, Phenylalanine, tyrosine, and tryptophan biosynthesis showed the highest impact, suggesting a key role for aromatic amino acid metabolism. Parallel mediation analysis demonstrated significant indirect effects via intermediate metabolites for six of the seven anthropometric measurements, with the proportion mediated by the identified metabolite clusters reaching 0.16 (95% CI: [0.05, 0.29]) for BMI. MR analysis provided evidence supporting potential causality for 23 of 108 initially observed associations. The strongest association was observed between WC and oxoglutaric acid (βIVW per standard deviation = 0.31; 95% CI: [0.17, 0.43]). Notably, while the observational analysis suggested a broad metabolic mediation of the adiposity marker-liver cancer association, the MR findings pinpointed a more specific and limited set of causal metabolic mediators. The main limitation of this study was the population mismatch between the observational (Chinese men) and the MR (European ancestry) analyses, which may limit the generalizability of the findings to other populations.

Integrating prospective observational and genetic evidence, we identified specific metabolic mediators linking adiposity to liver cancer, particularly involving amino acid, lipid and energy metabolism. These findings enhanced molecular understanding of adiposity-driven hepatocarcinogenesis and provided potential metabolic targets for future primary prevention strategies.

While it is well-known that adiposity increases liver cancer risk, the specific biological mechanisms connecting them are not fully understood.

This study was conducted to identify the key circulating metabolites that intermediate the association between adiposity markers and liver cancer and to assess whether these links are causal.

We comprehensively analyzed metabolomics data from a nested case-control study of 322 liver cancer cases and 322 matched controls within the prospective Shanghai Men’s Health Study.

We identified 27 specific metabolites, primarily involved in energy, lipid, and amino acid metabolism, that were associated with both various adiposity markers and liver cancer risk.

To investigate causality, we then applied a Mendelian randomization (MR) approach, which provided genetic evidence supporting a potential causal role of 21 associations between adiposity markers and metabolites, characterized primarily by elevated levels of adiposity markers and specific amino acids and organic acids (e.g., creatine, tyrosine, and 2-hydroxybutyric acid).

By integrating observational data with genetic evidence, our findings offer new molecular insights into how adiposity may drive the development of liver cancer, highlighting specific dysregulated metabolic pathways.

These identified metabolites could represent potential new biomarkers for early risk detection or targets for future prevention strategies aimed at breaking the link between adiposity and liver cancer.

While our findings from a specific cohort of Chinese men require validation in other populations, they significantly advance the understanding of liver carcinogenesis and suggest new avenues for public health interventions.

Zhuo-Ying Li and colleagues identify metabolic mediators linking adiposity markers to liver cancer in a nested case–control study, then assess their potential causality using a two-sample Mendelian randomization approach.