TRIM26 triggers ferroptosis via ZEB1 degradation to suppress nasopharyngeal carcinoma progression.

Although ferroptosis contributes to tumor progression, the key regulators of this process in nasopharyngeal carcinoma (NPC) remain largely unknown. TRIM26, an E3 ubiquitin ligase, has not been systematically studied in NPC or ferroptosis. Ferroptosis-related NPC genes were screened using GeneCards, FerrDb, and UbiBrowser2.0 databases. TRIM26 expression in NPC cells was determined via RT-qPCR and Western blot. TRIM26 overexpression models were established in C666-1 and NPC/HK1 cells, and a ZEB1 rescue model was further constructed in C666-1 cells. Cell viability, migration, and invasion were tested using CCK-8, wound healing, and Transwell assays. Ferroptosis was evaluated using C11-BODIPY581/591 probe, malondialdehyde (MDA), glutathione (GSH), and Fe²⁺ measurements. Co-immunoprecipitation, ubiquitination, and cycloheximide chase assays were performed to investigate TRIM26 regulation of ZEB1. Dual-luciferase reporter assays and ChIP-qPCR were conducted to verify the transcriptional regulation of SLC7A11 by ZEB1. In vivo validation was conducted using a subcutaneous xenograft model. TRIM26 was significantly downregulated in NPC cells, most markedly in C666-1 cells. TRIM26 overexpression remarkably inhibited NPC cell viability, migration, and invasion. It markedly promoted ferroptosis, with increased lipid peroxidation, elevated MDA and Fe²⁺ levels, reduced GSH content, and downregulated GPX4 and SLC7A11. Mechanistic studies revealed that TRIM26 interacted with ZEB1, promoted its ubiquitination, and accelerated its protein degradation. Furthermore, ZEB1 directly regulated SLC7A11 transcription through binding to its promoter region. ZEB1 overexpression significantly reversed the ferroptotic phenotype induced by TRIM26. In vivo, TRIM26 overexpression inhibited xenograft tumor growth and activated ferroptosis, whereas co‑overexpression of ZEB1 partially attenuated these tumor-suppressive effects. TRIM26 activates ferroptosis by promoting the ubiquitination and degradation of ZEB1 protein, thereby inhibiting NPC growth and progression. The TRIM26-ZEB1 axis may represent a potential molecular target for NPC.