Psammaplysene D overcomes sorafenib resistance in liver cancer by targeting FGFR4/CYP26A1-retinoic acid axis to drive ferroptosis

BACKGROUND: Overcoming sorafenib resistance remains a major challenge in liver cancer treatment. This study evaluates the novel compound Psammaplysene D, alone or combined with sorafenib, against liver cancer, focusing on overcoming resistance. METHODS: The efficacy of Psammaplysene D, alone or with sorafenib, was assessed using liver cancer cell lines and xenograft mouse models, including sorafenib-resistant variants. The direct binding interaction between Psammaplysene D and FGFR4 was confirmed through molecular docking and Cellular Thermal Shift Assay (CETSA). Transcriptomic profiling (RNA-seq) identified key differentially expressed genes. Ferroptosis induction was evaluated using key markers, and functional roles were validated using genetic and pharmacological approaches. RESULTS: Psammaplysene D inhibited liver cancer growth in vitro and in vivo, alone or synergistically with sorafenib, and overcame sorafenib resistance in both models. Mechanistic investigations revealed that Psammaplysene D directly targets FGFR4, inducing ferroptosis. In sorafenib-resistant cells, Psammaplysene D downregulates CYP26A1 expression, elevating retinoic acid (RA) levels. FGFR4 inhibition triggered ferroptosis and reduced CYP26A1 expression, while accumulated RA drove ferroptosis in resistant cells. CONCLUSIONS: 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.