Background:
Non-alcoholic fatty liver disease (
NAFLD) has gradually emerged as the most prevalent cause of chronic
liver diseases. However, specific changes during the progression of
NAFLD from non-
fibrosis to advanced
fibrosis and then
hepatocellular carcinoma (HCC) are unresolved. Here, we firstly identify the key gene linking
NAFLD fibrosis and HCC through analysis and experimental verification. Methods: Two GEO datasets (GSE89632, GSE49541) were performed for identifying differentially expressed genes (DEGs) associated with
NAFLD progression from non-
fibrosis to early
fibrosis and eventually to advanced
fibrosis. Subsequently, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis,
protein-
protein interaction (PPI) network were integrated to explore the potential function of the DEGs and hub genes. The expression of NUSAP1 was confirmed in vivo and in vitro
NAFLD models at
mRNA and
protein level. Then, cell proliferation and migration under high fat conditions were verified by cell counting kit-8 (CCK-8) and wound-healing assays. The
lipid content was measured with
Oil Red O staining. Finally, the analysis of clinical survival curves was performed to reveal the prognostic value of the crucial genes among HCC patients via the online web-tool GEPIA2 and KM plotter. Results: 5510 DEGs associated with non-
fibrosis NAFLD, 3913 DEGs about
NAFLD fibrosis, and 739 DEGs related to
NAFLD progression from mild
fibrosis to advanced
fibrosis were identified. Then, a total of 112 common DEGs were found. The result of enrichment analyses suggested that common DEGs were strongly associated with the
glucocorticoid receptor pathway, regulation of transmembrane transporter activity, peroxisome, and
proteoglycan biosynthetic process. Six genes, including KIAA0101, NUSAP1, UHRF1, RAD51AP1, KIF22, and ZWINT, were identified as crucial candidate genes via the PPI network. The expression of NUSAP1 was validated highly expressed in vitro and vivo
NAFLD models at
mRNA and
protein level. NUSAP1 silence could inhibit the ability of cell proliferation, migration and
lipid accumulation in vitro. Finally, we also found that NUSAP1 was significantly up-regulated at transcriptional and
protein levels, and associated with poor survival and advanced
tumor stage among HCC patients. Conclusion: NUSAP1 may be a potential therapeutic target for preventing
NAFLD progression to
liver cancer.