USP5 regulates ferroptosis in colorectal cancer by targeting the YBX3/SLC7A11 axis through lysosomal degradation.

Colorectal cancer (CRC) is the third most common cancer worldwide and a significant public health threat. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a promising therapeutic target in CRC treatment. Despite its significant clinical potential, the precise regulatory mechanisms underlying ferroptosis, particularly its role in ferroptosis within CRC, remain to be fully elucidated. Previous studies, including our own work, have revealed that various deubiquitinases (DUBs) are involved in regulating cellular processes; however, the specific mechanisms by which these enzymes contribute to ferroptosis in CRC remain unclear. In this study, we identify USP5 as a key regulator of ferroptosis in CRC. Traditionally recognized as a deubiquitinase, USP5 modulates cellular physiological activities through deubiquitination. However, our findings show that USP5, distinct from its conventional deubiquitination function, suppresses ferroptosis by promoting the lysosomal degradation of YBX3 (Y-box binding protein 3). Under normal conditions, YBX3 promotes the degradation of SLC7A11 (solute carrier family 7 member 11). However, USP5 facilitates the degradation of YBX3, leading to the stabilization of SLC7A11 and thereby promoting CRC cell survival and tumor progression. In patient-derived organoid and xenograft models, USP5 knockout significantly increased the sensitivity of cancer cells to ferroptosis and inhibited tumor growth. Moreover, additional knockout of YBX3 restored the stability of SLC7A11, highlighting the complex regulatory network between USP5, YBX3, and SLC7A11. Systematic functional assays and mechanistic studies further confirmed that the USP5/YBX3/SLC7A11 axis is a central pathway for ferroptosis resistance in CRC. These findings provide novel insights into therapeutic strategies for CRC, especially ferroptosis-based treatments.