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Chronic inflammation plays a central role in hepatocellular carcinoma (HCC), but the contribution of hepatocytes to tumor-associated inflammation is not clear. Here, we report that the zinc finger transcription factor Miz1 restricted hepatocyte-driven inflammation to suppress HCC, independently of its transcriptional activity. Miz1 was downregulated in HCC mouse models and a substantial fraction of HCC patients. Hepatocyte-specific Miz1 deletion in mice generated a distinct sub-group of hepatocytes that produced pro-inflammatory cytokines and chemokines, which skewed the polarization of the tumor-infiltrating macrophages toward pro-inflammatory phenotypes to promote HCC. Mechanistically, Miz1 sequestrated the oncoprotein metadherin (MTDH), preventing MTDH from promoting transcription factor nuclear factor κB (NF-κB) activation. A distinct sub-group of pro-inflammatory cytokine-producing hepatocytes was also seen in a subset of HCC patients. In addition, Miz1 expression inversely correated with disease recurrence and poor prognosis in HCC patients. Our findings identify Miz1 as a tumor suppressor that prevents hepatocytes from driving inflammation in HCC. [Display omitted] • Miz1 suppresses liver cancer independently of its transcriptional activity • Miz1 restricts the ability of hepatocytes to drive macrophage-dependent inflammation • Miz1 prevents oncoprotein MTDH from promoting hepatocyte NF-κB activity • Miz1 expression inversely correlates with recurrence and poor prognosis in HCC patients Chronic inflammation plays a crucial role in hepatocellular carcinoma (HCC), but the contribution of tumor hepatocytes to tumor-associated inflammation remains unclear. Zhang et al. find that loss of the transcription factor Miz1 in hepatocytes promotes NF-κB activation, producing a distinct sub-cluster of tumor hepatocytes that skew tumor-infiltrating macrophages toward a pro-inflammatory phenotype and drive inflammation in HCC. [ABSTRACT FROM AUTHOR]