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Causal Associations Between Lipids, NPC1L1, and Liver Cancer Risk: Insights From Mendelian Randomization and Bioinformatics
Author(s) -
Guo Xiaoyan,
Wu Lili,
Lai Jing,
Wu Yuankai,
Chen Dianke
Publication year - 2025
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.16897
ABSTRACT Background and Aim The study aims to investigate the potential causal effects of lipids on liver cancer risk and to analyze the possible impact of lipid‐lowering drug targets on liver cancer. Methods Genetic variants linked to lipid traits and drug targets were obtained from the Global Lipids Genetics Consortium and DrugBank. Liver cancer data were sourced from FinnGen. Mendelian randomization (MR) was used to assess causal relationships between lipid traits and liver cancer. Functional analyses included protein–protein interaction (PPI), KEGG pathway enrichment, transcription factor (TF) network analysis, and survival analysis. NPC1L1 expression, DNA methylation, and immune infiltration were analyzed using UALCAN, TCGA‐LIHC, and TIMER, respectively. Results MR analysis showed higher genetically predicted LDL‐C levels reduced liver cancer risk (OR = 0.5981, p  = 0.034). Drug target MR indicated that NPC1L1 inhibition (OR = 1.0638, p  = 0.0311) and elevated PPARɑ levels (OR = 1.1339, p  < 0.01) increased liver cancer risk. Functional analysis revealed NPC1L1 was highly expressed in liver cancer tissues due to hypomethylation and linked to immune cell infiltration, indicating its role in immune evasion and tumor progression. Conclusion The study demonstrates that elevated LDL‐C levels are associated with a reduced risk of liver cancer and NPC1L1 plays a key role in regulating lipid metabolism and influencing immune evasion.

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