The　hepatic　stellate　cells　(HSCs)　activation　by　myofibroblastic　differentiation　is　critical　for　liver　fibrosis.　Crosstalk　between　stromal　cells　and　tumor　cells　in　the　microenvironment　alters　the　properties　and　facilitates　the　growth　and　metastasis　of　tumor　cells.　How　mechanical　stimuli　originally　stiffness　of　extracellular　matrix　(ECM)　contribute　to　tumor　development　remains　poorly　understood.　Here,　we　demonstrated　that　stiffness　contributes　to　mechanosignal　transduction　in　HSCs,　which　promotes　hepatocellular　carcinoma　(HCC)　cells　growth　and　metastasis　through　secretion　of　FGF2.　On　stiffness　matrix,　HSCs　activation　was　confirmed　by　immunofluorescence　(IF)　and　Western　blot　(WB)　for　alpha-smooth　muscle　actin　(SMA).　Increasing　matrix　stiffness　promoted　HSCs　activation　by　CD36-AKT-E2F3　mechanosignaling　through　shRNA-mediated　E2F3　knockdown,　AKT　inhibitors,　and　CD36　shRNA.　Moreover,　ChIP-qPCR.　Confirmed　that　E2F3　combined　the　promoter　of　FGF2,　and　stiffness　promoted　FGF2　expression.　On　a　stiff　matrix,　HCC　cells　cultured　with　conditioned　media　(CM)　from　HSCs　increased　HCC　cells　growth　and　metastasis　by　binding　FGFR1　to　activate　PI3K/AKT　and　MEK/ERK　signaling　pathways.　Moreover,　conditional　E2F3　knockout　mice　were　subjected　to　CCl4　treatment　to　assess　the　role　of　E2F3　in　HSC　activation.　Additionally,　the　DEN-induced　HCC　model　was　also　used　to　evaluate　the　role　of　E2F3　in　liver　fibrosis　and　HCC　growth.　In　conclusion,　we　demonstrated　that　stiffness-induced　HSC　activation　by　E2F3　dependent.　Stiffness　activated　CD36-AKT-E2F3　signaling　and　targeted　FGF2　transcription,　subsequently,　activated　HCC　growth　and　metastasis　by　FGFR1-mediated　PI3K/AKT　and　MEK/ERK　signaling.