IRF8 Suppresses Hepatocellular Carcinoma Progression Through LIAS-Dependent IFN Production and Cuproptosis Activation.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. Cuproptosis is a novel form of regulated cell death closely linked to tumor progression. Although interferon regulatory factors (IRFs) exert tumor-suppressive effects in various cancers, its precise regulatory mechanisms concerning cuproptosis in HCC remain largely elusive. METHODS: IRF8 expression was evaluated in clinical HCC specimens and cell lines. Gain- and loss-of-function assays were conducted. Underlying transcriptional mechanisms were elucidated using ChIP-qPCR and dual-luciferase reporter assays. Subcutaneous nude mouse xenograft models were utilized to validate in vivo phenotypes. RESULTS: IRF8 was significantly downregulated in HCC. IRF8 overexpression induced oxidative stress and cuproptosis, as evidenced by excessive intracellular copper accumulation, elevated reactive oxygen species (ROS), and lipid peroxidation. Mechanistically, IRF8 directly bound to the promoter region of lipoyl synthase (LIAS) to activate its transcription. Phenotypic rescue assays confirmed that LIAS is indispensable for IRF8-induced interferon (IFN-α/β) production, copper engorgement, and cuproptosis. Furthermore, in vivo xenograft models demonstrated that IRF8 profoundly impeded tumor growth, an effect that was effectively abrogated by LIAS silencing. CONCLUSION: IRF8 inhibits HCC progression by directly upregulating LIAS to instigate lethal cuproptosis and interferon responses. The IRF8/LIAS axis may serve as a potential mechanistic basis and candidate axis for developing HCC therapeutic strategies.