Liver　fibrosis　is　a　wound-healing　response　caused　by　the　abnormal　accumulation　of　extracellular　matrix,　which　is　produced　by　activated　hepatic　stellate　cells　(HSCs).　Most　studies　have　focused　on　the　activated　HSCs　themselves　in　liver　fibrosis,　and　whether　hepatocytes　can　modulate　the　process　of　fibrosis　is　still　unclear.　Sma　mothers　against　decapentaplegic　homologue　4　(Smad4)　is　a　key　intracellular　transcription　mediator　of　transforming　growth　factor-beta　(TGF-beta)　during　the　development　and　progression　of　liver　fibrosis.　However,　the　role　of　hepatocyte　Smad4　in　the　development　of　fibrosis　is　poorly　elucidated.　Here,　to　explore　the　functional　role　of　hepatocyte　Smad4　and　the　molecular　mechanism　in　liver　fibrosis,　a　CCl4-induced　liver　fibrosis　model　was　established　in　mice　with　hepatocyte-specific　Smad4　deletion　(Smad4(Delta　hep)).　We　found　that　hepatocyte-specific　Smad4　deficiency　reduced　liver　inflammation　and　fibrosis,　alleviated　epithelial-mesenchymal　transition,　and　inhibited　hepatocyte　proliferation　and　migration.　Molecularly,　Smad4　deletion　in　hepatocytes　suppressed　the　expression　of　inhibitor　of　differentiation　1　(ID1)　and　the　secretion　of　connective　tissue　growth　factor　(CTGF)　of　hepatocytes,　which　subsequently　activated　the　p38　and　p65　signaling　pathways　of　HSCs　in　an　epidermal　growth　factor　receptor-dependent　manner.　Taken　together,　our　results　clearly　demonstrate　that　the　Smad4　expression　in　hepatocytes　plays　an　important　role　in　promoting　liver　fibrosis　and　could　therefore　be　a　promising　target　for　future　anti-fibrotic　therapy.