Nonalcoholic　fatty　liver　disease　(NAFLD),　a　major　cause　of　chronic　liver　disorders,　has　become　a　serious　public　health　issue.　Although　the　Smad4　signaling　pathway　has　been　implicated　in　the　progression　of　NAFLD,　the　specific　role　of　Smad4　in　hepatocytes　in　NAFLD　pathogenesis　remains　unclear.　Hepatocyte-specific　knockout　Smad4　mice　(AlbSmad4-/-)　were　first　constructed　using　the　Cre-Loxp　recombinant　system　to　establish　a　high-fat　diet　induced　NAFLD　model.　The　role　of　Smad4　in　the　occurrence　and　development　of　NAFLD　was　determined　by　monitoring　the　body　weight　of　mice,　detecting　triglycerides　and　free　fatty　acids　in　serum　and　liver　tissue　homogenates,　staining　the　tissue　sections　to　observe　the　accumulation　of　liver　fat,　and　RT-qPCR　detecting　the　expression　of　genes　related　to　lipogenesis,　fatty　acid　intake,　and　fatty　acid　beta　oxidation.　The　molecular　mechanism　of　Smad4　in　hepatocytes　affecting　NAFLD　was　therefore　investigated　through　combining　in　vitro　and　in　vivo　experiments.　Smad4　deficiency　in　hepatocytes　mitigated　NAFLD　progression　and　decreased　inflammatory　cell　infiltration.　Moreover,　Smad4　deficiency　inhibited　CXCL1　secretion　by　suppressing　the　activation　of　the　ASK1/P38/JNK　signaling　pathway.　Furthermore,　targeting　CXCL1　using　CXCR2　inhibitors　diminished　hepatocyte　lipogenesis　and　inhibited　the　polarization　of　M1-type　macrophages.　Collectively,　these　results　suggested　that　Smad4　plays　a　vital　role　in　exacerbating　NAFLD　and　may　be　a　promising　candidate　for　anti-NAFLD　therapy.