The Impact of Serum ۲۵-Hydroxyvitamin D and Genetic Factors on Liver Cancer Risk: An Updated Review and Mendelian Randomization Analysis

Background: Liver cancer, mainly hepatocellular carcinoma (HCC), presents a major global health challenge with high mortality. While established risk factors such as viral hepatitis and alcohol consumption are widely recognized, there is growing interest in modifiable factors like vitamin D (VD) deficiency. Observational studies indicate a link between low serum ۲۵-hydroxyvitamin D (۲۵(OH)D) and increased liver cancer risk, though confounding factors and reverse causality complicate causal conclusions.Objectives: This review aims to integrate current findings on the relationship between serum ۲۵(OH)D and liver cancer risk, critically assess causality using Mendelian randomization (MR) evidence, and explore mechanistic insights from genetic research.Methods: A narrative literature review was conducted using PubMed and Google Scholar, focusing on epidemiological studies, MR analyses, and mechanistic research published up to ۲۰۲۵. Search terms included "۲۵-hydroxyvitamin D," "liver cancer," "hepatocellular carcinoma," "Mendelian randomization," and "genetic polymorphisms."Results: Case-control and cohort studies consistently show that liver cancer patients have significantly lower serum ۲۵(OH)D levels compared to healthy individuals. MR studies, using genetic variants in DHCR۷, CYP۲R۱, and VDR genes as instrumental variables, strongly indicate a causal protective effect of higher ۲۵(OH)D concentrations on liver cancer risk. For example, alleles associated with increased ۲۵(OH)D, such as those in DHCR۷ (rs۱۲۷۸۵۸۷۸) and VDR (rs۲۲۲۸۵۷۰), correlate with a ۲۰-۳۰% reduction in liver cancer odds. These findings are supported by biological mechanisms, including VD's anti-proliferative, pro-apoptotic, and anti-inflammatory actions mediated through the VDR receptor in liver cells.Conclusion: The alignment of epidemiological and genetic evidence reinforces the likely causal, protective role of vitamin D in liver cancer. Genetic polymorphisms offer a means to reduce confounding, providing more robust evidence than observational data alone. Future research should emphasize large-scale randomized controlled trials of VD supplementation in high-risk groups and further investigation of gene-environment

کلیدواژه ها:

Serum ۲۵-Hydroxyvitamin D ، genetic factors ، Liver