2. Academic Validation
  3. Trifluridine/tipiracil induces ferroptosis by targeting p53 via the p53-SLC7A11 axis in colorectal cancer 3D organoids

Trifluridine/tipiracil induces ferroptosis by targeting p53 via the p53-SLC7A11 axis in colorectal cancer 3D organoids

  • Cell Death Dis. 2025 Apr 5;16(1):255. doi: 10.1038/s41419-025-07541-z.
Maosen Huang # 1 2,  Yancen Wu # 3,  Xiaoxia Wei # 1 2,  Linyao Cheng 1 2,  Lihua Fu 1 2,  Haochao Yan 1 2,  Wene Wei 1 2,  Bo Li 4,  Haiming Ru 1 2,  Xianwei Mo 1 2,  Weizhong Tang 1 2,  Zijie Su 5,  Linhai Yan 6 7
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, China.
  • 2 Guangxi Clinical Research Center for Colorectal Cancer, Nanning, 530021, Guangxi Zhuang Autonomous Region, China.
  • 3 Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, China.
  • 4 Liaoning Provincial Engineering Laboratory of Anti-tumor Immunity and Molecular Theranostics Technology, Collaborative Innovation Center for Age-related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China.
  • 5 Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, China. zijiesu@126.com.
  • 6 Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, China. yanlinhai000@163.com.
  • 7 Guangxi Clinical Research Center for Colorectal Cancer, Nanning, 530021, Guangxi Zhuang Autonomous Region, China. yanlinhai000@163.com.
  • # Contributed equally.
PMID: 40188162 DOI: 10.1038/s41419-025-07541-z
Abstract

Trifluridine/Tipiracil (FTD/TPI, TAS102) has been approved for the treatment of patients with colorectal Cancer (CRC) for its promising Anticancer activity enabled by its incorporation into double strands during DNA synthesis. However, the mechanisms underlying the Anticancer targets of FTD/TPI remain not fully understood. Here we report our observation of the activation of Ferroptosis in CRC by FTD/TPI. Mechanistically, FTD/TPI directly promotes the ubiquitination and degradation of MDM2, thereby stabilizing the p53. Nuclear accumulation of p53 subsequently downregulates SLC7A11 expression, leading to Ferroptosis. Furthermore, we observed that FTD/TPI combined with sulfasalazine (SAS), a system Xc- inhibitor, works in a synergistic manner to induce Ferroptosis and further inhibit the proliferation of CRC cells. Finally, we confirmed the synergistic effect of SAS and FTD/TPI on patient-derived organoids in vitro and patient-derived xenograft mouse models in vivo. Our findings are the first to reveal that FTD/TPI induces Ferroptosis via the p53-SLC7A11 axis and that SAS enhances the sensitivity and therapeutic effect of FTD/TPI. These findings suggest that the synergistic effect of FTD/TPI and SAS may represent a new therapeutic strategy for patients with CRC.

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