SENP1 inhibition suppresses the growth of lung cancer cells through activation of A20 -mediated ferroptosis

Ferroptosis is a type of cell death driven by iron accumulation and lipid peroxidation, which is involved in the pathogenesis of various tumors. Small ubiquitin-like modifier (SUMO)-specific protease 1 ( ) is a critical SUMO-specific protease, which controls multiple cellular signaling processes. However, the roles and mechanisms of -mediated protein SUMOylation in the regulation of cell death and ferroptosis remain unexplored. The gene expression of and ferroptosis-related genes in samples of lung cancer patient and cells were determined by immunohistochemical staining, real-time polymerase chain reaction (RT-qPCR) and Western blot. The association of gene expression with the survival rate of lung cancer patients was analyzed from public database. The erastin and cisplatin was used to induce ferroptosis, and cell ferroptosis were determined by evaluated lipid-reactive oxygen species (ROS), cell viability and electron microscopy. The protein interaction was determined by immunoprecipitation (IP) and shotgun proteomics analysis. An tumor transplantation model of immunodeficient mice was used to evaluate the effect of on tumor growth . is aberrantly overexpressed in lung cancer cells and is associated with the low survival rate of patients. inhibition by short hairpin RNA transduction or a specific inhibitor suppressed the proliferation and growth of lung cancer cells both and . overexpression protected lung cancer cells from ferroptosis induced by erastin or cisplatin. Transcriptome and proteomics profiles revealed the involvement of SUMOylation regulation of the inflammation signal in 1 inhibition-induced ferroptosis. Functional studies proved that functions as a positive inducer and enhances the ferroptosis of A549 cells. was shown to interact with and to regulate the ferroptosis of lung cancer cells. was identified as a suppressor of ferroptosis through a novel network of SUMOylation links and in lung cancer cells. inhibition promotes ferroptosis and apoptosis and represents a novel therapeutic target for lung cancer therapy.