OSGIN1 promotes ferroptosis resistance by directly enhancing GCLM activity.

Oxidative stress induced growth inhibitor 1 (OSGIN1) is a tumor protein p53 (TP53)-target gene involved in the oxidative stress response and promotes apoptosis. Here, we present the first evidence that OSGIN1 functions conversely by inhibiting ferroptosis, a distinct form of oxidative cell death driven by excessive lipid peroxidation. OSGIN1 expression is upregulated by pharmacological ferroptosis inducers in an NFE2 like BZIP transcription factor 2 (NFE2L2)-dependent manner, rather than through the TP53 pathway, in human pancreatic ductal adenocarcinoma (PDAC) cells. Genetic depletion of OSGIN1 or NFE2L2 similarly promotes ferroptosis, while re-expression of OSGIN1 rescues ferroptosis resistance in NFE2L2-knockout cells, both in vitro and in animal models. Mechanistically, immunoprecipitation combined with mass spectrometry revealed that OSGIN1 interacts with glutamate-cysteine ligase modifier subunit (GCLM), enhancing glutathione production and thereby mitigating oxidative stress. Additionally, OSGIN1 expression shows a positive correlation with NFE2L2 expression in pancreatic tumors, which is linked to poorer prognosis in PDAC patients. Collectively, these findings establish a novel defense mechanism that regulates ferroptosis and may influence tumor suppression in PDAC.