过氧化还原蛋白 1 (PRDX1) 是一种有效的抗氧化蛋白，具有独特的分子伴侣活性。然而，PRDX1 过度表达在结直肠癌 (CRC) 中的作用尚不清楚。在此，我们发现 PRDX1 敲除小鼠中 AOM/DSS 诱导的结肠炎相关 CRC 数量显着低于野生型小鼠，同时 NRF2 和 GPX4 下调。从机制上讲，RNA测序结果表明，PRDX1的敲除导致NRF2显着减少，这进一步触发了CRC细胞中ROS诱导的线粒体功能障碍和脂质过氧化诱导的铁死亡。值得注意的是，PRDX1抑制NRF2降解并促进NRF2核转位，从而触发GPX4的转录。免疫沉淀-质谱 (IP-MS) 和免疫共沉淀 (Co-IP) 分析表明，PRDX1 可以作为分子伴侣，通过与 CUL3 结合来抑制 NRF2 泛素化。重要的是，PRDX1 与 CUL3 的结合被 conoidin A 增强，但被 PRDX1 Cys83Ser 突变体消除。 PRDX1 敲低对 CRC 的抑制作用可以通过 NRF2 激活或体内施用 ferostatin-1 来减弱。总的来说，这些结果为 PRDX1 通过抑制 CUL3 介导的 NRF2 降解促进 CRC 进展的分子伴侣活性提供了新的见解，表明 PRDX1 Cys83 是抑制 CRC 的潜在药物靶标。© 作者。

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, concomitant 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, thereby triggering the transcription of GPX4. Immunoprecipitation-mass spectrometry (IP-MS) and Co-immunoprecipitation (Co-IP) assays revealed that PRDX1 could act as a molecular chaperone by binding to CUL3 to inhibit NRF2 ubiquitination. Importantly, the binding of PRDX1 to CUL3 was enhanced by conoidin A but abolished by the PRDX1 Cys83Ser mutant. The inhibitory effects of PRDX1 knockdown on CRC could be attenuated by NRF2 activation or ferrostatin-1 administration in vivo. Collectively, these results provide a novel insight into the molecular chaperone activity of PRDX1 in promoting CRC progression through suppression of CUL3-mediated NRF2 degradation, suggesting PRDX1 Cys83 is a potential drug target in inhibiting CRC.© The author(s).