USP8 stabilizes GPR37 via deubiquitination to regulate colorectal cancer progression through the NRF2/SLC7A11/GPX4 pathway.

Abstract

UNLABELLED: Colorectal cancer (CRC) is a prevalent malignancy with poor prognosis. Ferroptosis, an iron-dependent and non-apoptotic form of cell death characterized by lipid reactive oxygen species accumulation, has emerged as a critical process in CRC progression. The present study focuses on the regulatory mechanism through which ubiquitin-specific protease 8 (USP8) and G protein-coupled receptor 37 (GPR37) modulate ferroptosis in CRC. RT-qPCR and Western blotting were utilized to assess mRNA and protein expression, respectively. Cell viability, proliferation, apoptosis, migration, invasion, and angiogenesis were assessed using MTT, EdU, TUNEL, wound healing, transwell, and tube formation assays. The interaction and stability between USP8 and GPR37 were evaluated through co-immunoprecipitation (Co-IP), cycloheximide (CHX) chase, and ubiquitination assays. Ferroptosis-related indicators were detected using corresponding commercial kits. A mouse xenograft model was established to confirm in vivo effects. GPR37 was highly expressed in CRC tissues and cells. Silencing GPR37 inhibited cell viability, migration, and invasion, and promoted ferroptosis. USP8 stabilized GPR37 protein expression via deubiquitination, and overexpression of GPR37 reversed the tumor-suppressive effects caused by USP8 knockdown. Modulation of the USP8/GPR37 axis was accompanied by corresponding changes in NRF2, SLC7A11, and GPX4 protein expression. In vivo, GPR37 overexpression rescued the inhibitory effect of USP8 knockdown on tumor growth. USP8-mediated stabilization of GPR37 may contribute to ferroptosis resistance and CRC progression, potentially involving NRF2/SLC7A11/GPX4 signaling. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s10616-026-01063-y.

Key Findings

• USP8 stabilizes GPR37 protein expression via deubiquitination in colorectal cancer cells.
• Silencing GPR37 inhibits cell viability, migration, and invasion while promoting ferroptosis in colorectal cancer.
• The USP8/GPR37 axis regulates ferroptosis resistance through modulation of the NRF2/SLC7A11/GPX4 signaling pathway.
• In vivo, GPR37 overexpression rescues tumor growth inhibited by USP8 knockdown, indicating its role in colorectal cancer progression.

Clinical Significance

Citation

Zhu Rong-Hua, Dai Gang, Yu Ren-Taoet al.. USP8 stabilizes GPR37 via deubiquitination to regulate colorectal cancer progression through the NRF2/SLC7A11/GPX4 pathway. Cytotechnology. 2026-Oct.