Causal Associations Between Lipids, NPC1L1, and Liver Cancer Risk: Insights From Mendelian Randomization and
Xiaoyan Guo1, Lili Wu1,2, Jing Lai1
1Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Journal of Gastroenterology and Hepatology
|May 2, 2025
Summary
Higher low-density lipoprotein cholesterol (LDL-C) levels may reduce liver cancer risk. However, NPC1L1 inhibition and elevated PPARɑ increase risk, with NPC1L1 impacting immune evasion in liver cancer.
Area of Science:
- Genetics
- Oncology
- Metabolomics
Background:
- Lipids play a crucial role in cellular processes and disease development.
- Understanding the relationship between lipid metabolism and liver cancer is vital for prevention and treatment strategies.
- Investigating lipid-lowering drug targets may offer new therapeutic avenues for liver cancer.
Purpose of the Study:
- To determine the causal impact of lipid traits on liver cancer risk.
- To evaluate the influence of lipid-lowering drug targets on liver cancer development.
- To explore the molecular mechanisms underlying the lipid-liver cancer association.
Main Methods:
- Utilized Mendelian randomization (MR) with genetic variants from the Global Lipids Genetics Consortium and liver cancer data from FinnGen.
- Performed functional analyses including protein-protein interaction, KEGG pathway enrichment, and transcription factor network analysis.
- Assessed NPC1L1 expression, DNA methylation, and immune infiltration using UALCAN, TCGA-LIHC, and TIMER databases.
Main Results:
- Higher genetically predicted low-density lipoprotein cholesterol (LDL-C) levels were associated with reduced liver cancer risk (OR=0.5981, p=0.034).
- Drug target MR indicated NPC1L1 inhibition (OR=1.0638, p=0.0311) and elevated PPARɑ levels (OR=1.1339, p<0.01) increased liver cancer risk.
- NPC1L1 exhibited high expression in liver cancer tissues, linked to hypomethylation and immune cell infiltration, suggesting a role in immune evasion.
Conclusions:
- Elevated LDL-C levels are linked to a decreased risk of liver cancer.
- NPC1L1 plays a significant role in regulating lipid metabolism and influencing immune evasion in the context of liver cancer.
- Targeting NPC1L1 warrants further investigation for potential therapeutic strategies in liver cancer.
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