Multi-omics analysis reveals oxidative stress and disrupted lipid homeostasis in a mouse model for fibrosis-associated hepatocellular carcinoma progression

Chronic liver fibrosis significantly increases the risk of hepatocellular carcinoma (HCC), a leading cause of cancer-related deaths. However, the molecular mechanisms linking fibrosis to inflammation-associated HCC development remain unclear, complicating early diagnosis and intervention. In this study, we employ multi-omics analyses, including untargeted and targeted metabolomics, lipidomics, and transcriptomics, in a mouse model of chemically induced liver fibrosis and HCC, integrating publicly available transcriptome data from LX-2 human hepatic stellate cell (HSC) line. Our results reveal a profound rewiring of NAD+ metabolism as a central driver of metabolic disturbance. Analysis of bulk liver tissue shows increased activity of the kynurenine pathway of tryptophan metabolism, enhancing NAD+ precursor production. Hepatic nicotinamide (NAM) levels decrease due to elevated expression of NAM N-methyltransferase (Nnmt) in HSCs. Despite reduced hepatic NAM, serum NAD+ level rise and is compartmentalized, triggering a disruption in NAD+ homeostasis and activating NF-κB-mediated oxidative stress pathways. Moreover, lipid dysregulation occurs, with NF-κB dominating the regulation of SIRT1/SREBP-controlled lipogenic and cholesterogenic genes, leading to imbalances in hepatic and serum lipids. These insights elucidate connections between NAD+ metabolism, inflammation, and lipid dysregulation, potentially aiding in developing diagnostic biomarkers and therapeutic targets for non-viral HCC.