Causal Relationships Between Plasma Metabolites, Inflammatory Factors, and Oral Cancer Risk: A Comprehensive
Shaonan Hu1, Chufeng Liu1, Minghua Ren1
1Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou City, Guangdong Province, China, fimmu.com.
Human Mutation
|February 9, 2026
Summary
This study reveals how specific metabolites causally influence oral cancer risk, identifying key inflammatory pathways. These findings offer new avenues for precision prevention and targeted therapies in oral cancer.
Area of Science:
- Genetics
- Metabolomics
- Oncology
Background:
- Oral cancer remains a significant global health challenge with complex etiological factors.
- Understanding the interplay between metabolism and inflammation in oral cancer development is crucial for effective interventions.
Purpose of the Study:
- To investigate the causal relationships between circulating metabolites and oral cancer risk using a large-scale Mendelian randomization analysis.
- To identify key inflammatory mediators in the metabolic pathways influencing oral cancer.
- To validate findings through experimental cell-based studies.
Main Methods:
- Genome-wide Mendelian randomization analysis utilizing single nucleotide polymorphisms (SNPs) from the Canadian Longitudinal Study on Aging (CLSA) cohort and IEU OpenGWAS database.
- Mediation analysis to identify inflammatory factors as key mediators.
- CAL-27 cell line experiments for mechanistic validation.
Main Results:
- Identified 61 metabolites with significant causal links to oral cancer risk (29 protective, 32 risk-increasing).
- Revealed 14 inflammatory factors as crucial mediators, explaining 1.4%-17.4% of total effects.
- Aspartate demonstrated anti-inflammatory effects by downregulating CCL11 and related cytokines (IL-1β, IL-6, TNF-α), while CCL11 overexpression promoted malignancy.
Conclusions:
- Elucidated a novel "metabolism-inflammation" carcinogenic pathway driven by genetic variants in oral cancer.
- Aspartate's anti-inflammatory role and inhibition of NF-κB and MAPK pathways were confirmed experimentally.
- Findings provide significant translational potential for precision prevention and therapy strategies in oral cancer.
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