Identification of PLK1 as the Target of Tubocapsenolide A for the Activation of Colorectal Cancer Ferroptosis by PROTAC Technology

Drug resistance seriously affects the treatment effect and survival rate of colorectal cancer (CRC) patients. The discovery of novel drugs and mechanisms is an important way to overcome drug resistance. Here, Tubocapsenolide A (TA), a major withanolide isolated from Tubocapsicum anomalum, significantly inhibited the growth of patient-derived organoids with oxaliplatin or 5-fluorouracil resistance and HCT116-/DLD-1-derived xenografts. Leveraging Proteolysis Targeting Chimera (PROTAC)-based target identification approach, PLK1 was identified as a direct target of TA. Mechanistically, PLK1 was first determined as a p53 cytoplasmic anchoring factor to prevent p53 from inducing ferroptosis in CRC. TA competitively inhibits the formation of PLK1-p53 heterodimers, promotes the nuclear translocation of p53, and then activates ferroptosis. Collectively, our study clarified the key role of PLK1 in p53-mediated ferroptosis for the first time and elucidated a novel mechanism of TA as a natural ferroptosis inducer in CRC treatment. The activation of the PLK1-p53-ferroptosis signaling axis may provide a brand-new strategy for the treatment of CRC.