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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月6日

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  • Ting Yang,
  • Yanlu Han,
  • Yuting Wang,
  • Ruyu Li,
  • Xiaonan Zhang,
  • Xinxin Zhang,
  • Xiaohan Xu,
  • Jing Xu,
  • Xiaoyu Li,
  • Chunhua Lin,
  • Wen Wang,
  • Jinbo Yang

摘要

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.

Graphical Abstract