UC San Diego

Liver cancer is the fifth most diagnosed cancer and second leading cause of cancer deaths globally. Hepatocellular carcinoma (HCC) represents 75-85% of all primary liver cancers in which around 15-50% of cases arise from metabolic dysfunction-associated steatohepatitis (MASH) patients without cirrhosis. While MASH and HCC are interlinked liver pathologies, each yields distinct mechanisms that have yet to be further elucidated. Senescence acts as an anti-tumorigenic response to DNA damage in MASH hepatocytes, blunting excessive DNA damage, while in HCC, senescence is downregulated. Treatment with etoposide, high-fructose diet, or hydrodynamic NRAS(G12V) injection were shown to induce DNA damage and lead to hepatocyte senescence. FBP1 loss can trigger responses that reverse senescence and induce MASH-HCC hepatocarcinogenesis. Curiously, RNA-seq analysis revealed the senescence gene signature to include interferon response genes. However, it is unclear whether the induction of senescence depends on activation of the interferon response. In this study, primary mouse hepatocytes were treated with a chemotherapy, etoposide, to induce DNA damage and assess interferon response activation. Elevated mRNA of interferon genes and protein expressions of interferon pathways such as JAK-STAT, cGAS-STING were observed in hepatocytes treated with etoposide. These results suggest a unique relationship between DNA damage, senescence, and interferon response pathways, potentially opening new targeting pathways for MASH and HCC.