PRDX1 drives colorectal cancer progression by inhibiting ferroptosis through suppression of Cullin-3-mediated NRF2 degradation

Abstract

Peroxiredoxin 1 (PRDX1) is a potent antioxidant protein that displays a unique molecular chaperone activity. However, the role of overexpression of PRDX1 in colorectal cancer (CRC) was elusive. Herein, we found that the number of AOM/DSS-induced colitis-associated CRC in PRDX1 knockout mice was significantly lower than that in wild-type mice, concurrent with the downregulation of NRF2 and GPX4. Mechanistically, RNA sequencing results indicated that knockdown of PRDX1 resulted in a significant reduction of NRF2, which further triggered ROS-induced mitochondrial dysfunction and lipid peroxidation-induced ferroptosis in CRC cells. Notably, PRDX1 inhibited NRF2 degradation and promoted NRF2 nuclear translocation and consequently triggered the transcription of GPX4. Immunoprecipitation-mass spectrometry (IP-MS) and Co-immunoprecipitation (Co-IP) assays revealed that PRDX1 could function as a molecular chaperone binding to CUL3 to inhibit the ubiquitination of NRF2. Importantly, the binding of PRDX1 to CUL3 was enhanced by conoidin A but abrogated by PRDX1 Cys83Ser mutant. The inhibitory effects of silencing PRDX1 on CRC could be attenuated by NRF2 activation or ferrostatin-1 administration in vivo. Collectively, these results provide a new insight into the molecular chaperone activity of PRDX1 in triggering CRC progression through suppression of CUL3-mediated NRF2 degradation, suggesting PRDX1 Cys83 is a potential drug target in inhibiting CRC.