MafF is a member of the bZIP transcription factor Maf family and commonly down-regulated inmultiple cancers. But the expression and function of MafF in HCC remain unclear. In thisstudy, we investigated the relationship between endogenous MafF expression and HCCprogression, and explored the regulatory mechanism of MafF expression in HCC. We found thatMafF decreased in HCC tissues and cells. Lentivirus-mediated MafF overexpression inhibitedHCC cell proliferation and induced cell apoptosis. Bioinformatics analysis and luciferase assayidentified MafF was a direct target of miR-224-5p. RNA pull down assay demonstrated thatcircular RNA circ-ITCH could sponge miR-224-5p specifically in HCC. The rescueexperiments further elucidated that the expression and antitumor effects of MafF could beregulated via circ-ITCH/miR-224-5p axis. This study verified that MafF acted as a tumorsuppressor in HCC and revealed the upstream regulation mechanism of MafF, which provided anew perspective for potential therapeutic targets of HCC.