This integrative proteomic and lipidomic study from mouse to human and from liver to blood identified the following disease signatures: (i) an HCC signature: upregulated hepatic scd1/scd2, fads2, and acsl5:acsl1 ratio, elevated vaccenic and erucic acids, and reduced margaric and linoleic acids in both liver and plasma; (ii) a NASH signature that correlates with tumor burden: upregulated hepatic elovl6, elevated oleic, adrenic, and osbond acids, and reduced cervonic acid in liver and plasma; and (iii) a NASH signature: reduced hepatic and circulating lignoceric and eicosapentaenoic acids.