USP7/SETDB1 promotes non-small cell lung cancer progression by regulating ferroptosis via NRF2/SLC7A11/GPX4 axis

Non-small cell lung cancer (NSCLC) is a malignant tumor with high morbidity and mortality. Given the reported associations of both SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) with various cancers and ubiquitin-specific protease 7 (USP7) with NSCLC progression, this study aims to elucidate the role of SETDB1 and USP7 in NSCLC progression. mRNA and protein levels were measured by qRT-PCR and Western blot, respectively. Cell biological phenotypes were evaluated using MTT, EdU, flow cytometry, transwell, and sphere formation assays. Ferroptosis was analyzed by measuring Fe2+, MDA GSH, and ROS levels. Relationship between USP7 and SETDB1 was examined through Co-IP, cycloheximide (CHX) chase, and deubiquitination assays. Xenograft tumor models were established to investigate the role of SETDB1 and USP7 in NSCLC in vivo. In NSCLC tissues and cells, SETDB1 levels were elevated. Knockdown of SETDB1 inhibited NSCLC cell viability, proliferation, invasion, and sphere formation ability, while promoting apoptosis and ferroptosis. Mechanistically, USP7 enhanced the stability of SETDB1 protein by its deubiquitination. USP7 knockdown suppressed NSCLC cell biological behavior by downregulating SETDB1. Moreover, USP7 knockdown repressed in vivo tumor growth of NSCLC. Taken together, USP7 suppresses ferroptosis and enhances growth in NSCLC cells by stabilizing SETDB1 protein through deubiquitination.