As　sorafenib　is　a　first-line　drug　for　treating　advanced　hepatocellular　carcinoma,　sorafenib　resistance　has　historically　attracted　attention.　However,　most　of　this　attention　has　been　focused　on　a　series　of　mechanisms　related　to　drug　resistance　arising　after　sorafenib　treatment.　In　this　study,　we　used　proteomic　techniques　to　explore　the　potential　mechanisms　by　which　pretreatment　factors　affect　sorafenib　resistance.　The　degree　of　redundant　pathway　PI3K/AKT　activation,　biotransformation　capacity,　and　autophagy　level　in　hepatocellular　carcinoma　patients　prior　to　sorafenib　treatment　might　affect　their　sensitivity　to　sorafenib,　in　which　ADH1A　and　STING1　are　key　molecules.　These　three　factors　could　interact　mechanistically　to　promote　tumor　cell　survival,　might　be　malignant　features　of　tumor　cells,　and　are　associated　with　hepatocellular　carcinoma　prognosis.　Our　study　suggests　possible　avenues　of　therapeutic　intervention　for　patients　with　sorafenibresistance　and　the　potential　application　of　immunotherapy　with　the　aim　of　improving　the　survival　of　such　patients.　&　COPY;　2023　The　Author(s).　Published　by　Elsevier　B.V.　on　behalf　of　Research　Network　of　Computational　and　Structural　Biotechnology.　This　is　an　open　access　article　under　the　CC　BY-NC-ND　license　(http://creativecommons.org/licenses/by-nc-nd/4.0/).