Causal Associations Between Lipids, NPC1L1, and Liver Cancer Risk: Insights From Mendelian Randomization and Bioinformatics

IF 3.7 3区医学 Q2 GASTROENTEROLOGY & HEPATOLOGY

Journal of Gastroenterology and Hepatology Pub Date : 2025-05-01 DOI:10.1111/jgh.16897

Xiaoyan Guo, Lili Wu, Jing Lai, Yuankai Wu, Dianke Chen

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引用次数: 0

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.

查看原文本刊更多论文

血脂、NPC1L1和肝癌风险之间的因果关系：来自孟德尔随机化和生物信息学的见解。

背景与目的：本研究旨在探讨血脂与肝癌风险的潜在因果关系，并分析降脂药物靶点对肝癌的可能影响。方法：从全球脂质遗传联盟和药物银行获得与脂质性状和药物靶点相关的遗传变异。肝癌数据来源于FinnGen。孟德尔随机化（MR）用于评估脂质性状与肝癌之间的因果关系。功能分析包括蛋白-蛋白相互作用（PPI）、KEGG通路富集、转录因子（TF）网络分析和生存分析。分别使用UALCAN、TCGA-LIHC和TIMER分析NPC1L1表达、DNA甲基化和免疫浸润。结果：磁共振分析显示，基因预测的LDL-C水平越高，患肝癌的风险就越低（OR = 0.5981, p = 0.034）。药物靶MR提示NPC1L1抑制（OR = 1.0638, p = 0.0311）和PPAR α水平升高（OR = 1.1339, p）。结论：LDL-C水平升高与肝癌风险降低相关，NPC1L1在调节脂质代谢和影响免疫逃避中起关键作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Gastroenterology and Hepatology 医学-胃肠肝病学

CiteScore

7.90

自引率

2.40%

发文量

326

审稿时长

2.3 months

期刊介绍： Journal of Gastroenterology and Hepatology is produced 12 times per year and publishes peer-reviewed original papers, reviews and editorials concerned with clinical practice and research in the fields of hepatology, gastroenterology and endoscopy. Papers cover the medical, radiological, pathological, biochemical, physiological and historical aspects of the subject areas. All submitted papers are reviewed by at least two referees expert in the field of the submitted paper.