Long-chain　fatty　acyl-Coa　ligase　4　(ACSL4)　is　an　important　enzyme　that　converts　fatty　acids　to　fatty　acyl-Coa　esters,　there　is　increasing　evidence　for　its　role　in　carcinogenesis.　However,　the　precise　role　of　ACLS4　in　hepatocellular　carcinoma　(HCC)　is　not　clearly　understood.　In　the　present　study,　we　provide　evidence　that　ACSL4　expression　was　specifically　elevated　in　HCC　and　is　associated　with　poor　clinical　outcomes.　ACSL4　significantly　promotes　the　growth　and　metastasis　of　HCC　both　in　vitro　and　in　vivo.　RNA　sequencing　and　functional　experiments　showed　that　the　effect　of　ACSL4　on　HCC　development　was　heavily　dependent　on　PAK2.　ACSL4　expression　is　well　correlated　with　PAK2　in　HCC,　and　ACSL4　even　transcriptionally　increased　PAK2　gene　expression　mediated　by　Sp1.　In　addition,　emodin,　a　naturally　occurring　anthraquinone　derivative,　inhibited　HCC　cell　growth　and　tumor　progression　by　targeting　ACSL4.　In　summary,　ACSL4　plays　a　novel　oncogene　in　HCC　development　by　regulating　PAK2　transcription.　Targeting　ACSL4　could　be　useful　in　drug　development　and　therapy　for　HCC.　©　2024