System Biology Analysis Reveals The Role Of Voltage Dependent Anion Channel 1(VDAC1) In Mitochondrial Dysfunction During Non-alcoholic Fatty Liver Disease(NAFLD) Progression Into Hepatocellular Carcinoma(HCC)

Objective:The underlying mechanisms behind the correlation of non-alcoholic fatty liver disease(NAFLD)with hepatocellular carcinoma(HCC)are unclear.We aim to uncover the genes and potential mechanisms that drive the progression.To provides a new drug target for hepatocellular carcinoma associated with nonalcoholic fatty liver disease.Methods:In this study,we uncovered the genes and potential mechanisms through a multiple-omics integration approach.Label-free quantitative proteomics was used to identify normal and tumor tissues of 6 patients with primary liver cancer related to nonalcoholic fatty liver disease from Shandong Provincial Hospital to obtain differential proteins and combined with phenotype-association analysis.To investigate the potential mechanisms,a comprehensive transcriptome/lipidome/phenome-wide association analysis was performed in Genetic reference panel BXD mice strains.Results:The quantitative proteomics combined with phenotype-association results showed that VDAC1 was significantly increased in tumor tissues and correlated with NAFLD related traits.The gene co-expression network analysis indicated that VDAC1 is involved in mitochondria dysfunction in the tumorigenesis progress.The association between VDAC1 and mitochondria dysfunction can be explained by VDAC1 is associated with mitochondria membrane lipids cardiolipin(CL)composition shift.VDAC1 is correlated with the suppression of mature specie CL(LLLL)and elevation level of nascent CL species.Such profiling shift was supported by the significant positive correlation between VDAC1 and PTPMT1,as well as negative correlation with CL remodeling enzyme Tafazzin(TAZ).Conclusion:Our study confirmed that the expression of VADC1 is dysregulated in NAFLDdriven HCC and associated with NAFLD progression.The VDAC1-driven mitochondria dysfunction is associated with cardiolipin composition shift,which caused mitochondria membrane property alteration.Suggesting a new therapeutic target for non-alcoholic fatty liver and non-alcoholic fatty liver associated primary hepatocellular carcinoma.