Weibing Wang, Xigang Hu
This study identifi es a previously unreported molecular regulatory axis governing DHODH degradationin CRC. It also establishes an innovative AUTAC-based targeted protein degradation strategy to selectively activateferroptosis. Collectively, these fi ndings highlight the promising translational potential of targeted ferroptosisinduction as a novel therapeutic approach for clinical CRC treatment.
BACKGROUND: Dihydroorotate dehydrogenase (DHODH) is a critical enzyme involved in pyrimidine biosynthesis anda key suppressor of ferroptosis. This enzyme is commonly overexpressed in colorectal cancer (CRC), and itsupregulation facilitates the malignant progression of CRC tumors.
METHODS & MECHANISMS: This study explored the endogenous degradation mechanism of DHODH in CRC.Mechanistically, DHODH is eliminated through KCTD10-mediated selective autophagy. As a substrate-specifi cadaptor for the CUL3-RBX1 E3 ubiquitin ligase complex, KCTD10 induces K63-linked ubiquitination of DHODH. Theautophagy receptor SQSTM1/p62 subsequently recognizes the ubiquitinated DHODH and mediates its lysosomal-dependent degradation. Based on this molecular regulatory axis, we constructed DH-AUTAC, a novel autophagy-targeting chimera designed to specifi cally recruit endogenous DHODH to the autophagy system for targeteddegradation.
RESULTS: In vitro cell experiments and in vivo animal model assays consistently verifi ed the functional effi cacy ofDH-AUTAC. DH-AUTAC treatment effi ciently degraded DHODH protein, triggered robust ferroptosis, and therebymarkedly suppressed the proliferation of CRC cells and the growth of subcutaneous tumors. Pharmacologicalintervention experiments further showed that inhibiting ferroptosis completely abrogated the antitumor eff ects ofDH-AUTAC, whereas combined treatment with the autophagy and ferroptosis activator ATA194 signifi cantlyaugmented its therapeutic effi cacy. Moreover, animal model observations confi rmed that DH-AUTAC possessed agood in vivo safety profi le with no obvious adverse eff ects.
CONCLUSION: This study identifi es a previously unreported molecular regulatory axis governing DHODH degradationin CRC. It also establishes an innovative AUTAC-based targeted protein degradation strategy to selectively activateferroptosis. Collectively, these fi ndings highlight the promising translational potential of targeted ferroptosisinduction as a novel therapeutic approach for clinical CRC treatment.