SGK1 suppresses ferroptosis in ovarian cancer via NRF2-dependent and -independent pathways

High-grade serous ovarian Cancer (HGSOC) is a highly aggressive disease often developing resistance to current therapies, necessitating new treatment strategies. Our study identifies SGK1, a key effector in the PI3K pathway, as a promising therapeutic target to exploit Ferroptosis, a distinct form of cell death induced by iron overload and lipid peroxidation. Importantly, SGK1 activation, whether through high expression or the constitutively active SGK1-S422D mutation, confers resistance to Ferroptosis in HGSOC. Conversely, SGK1 inhibition significantly enhances sensitivity to Ferroptosis, as shown by increased PTGS2 expression (a Ferroptosis marker), lipid peroxidation, and toxic-free iron levels. Remarkably, this enhanced cytotoxicity is reversed by ferrostatin-1 and the iron chelator deferoxamine, highlighting the pivotal roles of lipid peroxidation and iron dysregulation in the process. Mechanistically, SGK1 protects HGSOC cells from Ferroptosis via NRF2-dependent pathways, promoting glutathione synthesis and iron homeostasis, and NRF2-independent pathways via mTOR/SREBP1/SCD1-mediated lipogenesis. Notably, pharmacological SGK1 inhibition sensitizes HGSOC xenograft models to Ferroptosis induction, highlighting its therapeutic potential. These findings establish SGK1 as a critical regulator of Ferroptosis and suggest targeting SGK1 alongside Ferroptosis pathways as a potential therapeutic strategy for HGSOC patients.