Herein, we demonstrate that TACC3, which is highly expressed in immunotherapy-resistant HCC tissues, reprograms acyl-CoA synthetase long-chain family member 4 (ACSL4)-mediated PUFA metabolism via la-related protein 1 (LARP1) and poly(A)-binding protein cytoplasmic 1 (PABPC1)-regulated ACSL4 mRNA stability. Here, TACC3 is linked to hepatocellular carcinoma.