Hepatocellular　carcinoma　(HCC)　takes　the　predominant　malignancy　of　hepatocytes　with　bleak　outcomes　owing　to　high　heterogeneity　among　patients.　Personalized　treatments　based　on　molecular　profiles　will　better　improve　patients’　prognosis.　Lysozyme　(LYZ),　a　secretory　protein　with　antibacterial　function　generally　expressed　in　monocytes/　macrophages,　has　been　observed　for　the　prognostic　implications　in　different　types　of　tumors.　However,　studies　about　the　explicit　applicative　scenarios　and　mechanisms　for　tumor　progression　are　still　quite　limited,　especially　for　HCC.　Here,　based　on　the　proteomic　molecular　classification　data　of　early-stage　HCC,　we　revealed　that　the　LYZ　level　was　elevated　significantly　in　the　most　malignant　HCC　subtype　and　could　serve　as　an　independent　prognostic　predictor　for　HCC　patients.　Molecular　profiles　of　LYZ-high　HCCs　were　typical　of　those　for　the　most　malignant　HCC　subtype,　with　impaired　metabolism,　along　with　promoted　proliferation　and　metastasis　characteristics.　Further　studies　demonstrated　that　LYZ　tended　to　be　aberrantly　expressed　in　poorly　differentiated　HCC　cells,　which　was　regulated　by　STAT3　activation.　LYZ　promoted　HCC　proliferation　and　migration　in　both　autocrine　and　paracrine　manners　independent　of　the　muramidase　activity　through　the　activation　of　downstream　protumoral　signaling　pathways　via　cell　surface　GRP78.　Subcutaneous　and　orthotopic　xenograft　tumor　models　indicated　that　targeting　LYZ　inhibited　HCC　growth　markedly　in　NOD/SCID　mice.　These　results　propose　LYZ　as　a　prognostic　biomarker　and　therapeutic　target　for　the　subclass　of　HCC　with　an　aggressive　phenotype.　Copyright　©　2023　the　Author(s).