CYP26A1 and liver cancer: FGFR4 inhibition triggered ferroptosis and reduced CYP26A1 expression, while accumulated RA drove ferroptosis in resistant cells.<h4>Conclusions</h4>Overall, Psammaplysene D is a potent therapeutic agent for liver cancer, effective alone or combined with sorafenib, and overcomes resistance through direct targeting of FGFR4, initiating a cascade of CYP26A1 downregulation, RA accumulation, and ferroptosis induction-defining a novel FGFR4/CYP26A1/RA axis regulating ferroptosis in resistant liver cancer.