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

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 inhib

SUBMITTER: Huang M 

PROVIDER: S-EPMC11972347 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature