Abstract

Objective This study investigated the role of UCHL5 in thyroid carcinoma (THCA) progression, focusing on its tumor-suppressive mechanisms and regulation of ferroptosis.Methods We performed multi-omics analysis of TCGA and GEO datasets and validated the findings using clinical samples. The CRISPR/Cas9-mediated knockout and stable overexpression in THCA cell lines were constructed, followed by comprehensive functional assays including co-immunoprecipitation (Co-IP), ubiquitination analysis, xenograft tumor models, and ferroptosis sensitivity tests using erastin/ferrostatin-1 with BODIPY C11 lipid ROS measurement. Weighted gene co-expression network analysis (WGCNA) was performed to identify hub genes and to analyze associated pathways.Results Clinical data revealed significant downregulation of UCHL5 in advanced thyroid cancers, particularly in lymph node metastases. UCHL5 knockout markedly accelerated cell proliferation and xenograft tumor growth, while its overexpression suppressed both. Mechanistically, we identified a direct interaction between UCHL5 and ZRANB1 through co-IP, with UCHL5 extending the protein half-life of ZRANB1 by over 2-fold. In ferroptosis regulation, erastin treatment (10 μM) revealed that UCHL5 overexpression enhanced sensitivity, while UCHL5 knockout conferred significant protection, accompanied by altered GSH levels, Fe²⁺ accumulation, and lipid ROS production. Western blot analysis revealed that UCHL5 upregulated ZRANB1 and downregulated SLC7A11/GPX4 expression.Conclusion This study demonstrates that UCHL5 acts as a critical tumor suppressor in thyroid cancer by stabilizing ZRANB1 through deubiquitination and regulating ferroptosis via the SLC7A11-GPX4 axis.