USP52 inhibits cell ferroptosis via Hippo–YAP pathway and blocks immunotherapy in colorectal cancer

Colorectal cancer (CRC) is one of the most prevalent malignancies in humans. Understanding its molecular mechanisms to guide clinical management is crucial. Ferroptosis represents a novel form of regulated cell death that is characterized by highly iron-dependent lipid peroxidation. Despite growing interest, the roles and vulnerabilities determining ferroptosis sensitivity in CRC remain unclear. In this study, we identified ubiquitin-specific peptidase 52 (USP52) as a specific deubiquitinating enzyme of Yes-associated protein (YAP) in CRC, which could stabilize YAP by removing the K11-linked ubiquitin chains. USP52 knockdown decreased the expression of YAP protein and its target gene (CTGF, CYR61). Through a series of comprehensive in vivo and in vitro experiments, we proved that USP52 promoted CRC cell proliferation, migration, and invasion and attenuated the sensitivity of CRC cells to ferroptosis. Notably, USP52 inhibition retarded tumor growth and enhanced CD8+ T-cell infiltration, which potentiated tumor response to anti-programmed death-ligand-1 immunotherapy in vivo. In general, our research uncovered that USP52 suppressed ferroptosis through the Hippo-YAP signaling and highlighted targeting USP52 as a potential therapeutic strategy to boost ferroptosis for enhancing cancer immunotherapy.