Lipocalin 2 orchestrates resistance to ferroptosis via AXL

Glioblastoma (GBM) remains a lethal tumor, largely due to robust mechanisms that prevent effective induction of cell death. Ferroptosis, a form of iron-dependent cell death, is a promising vulnerability in GBM. Here, we demonstrate that lipocalin-2 (LCN2) suppresses ferroptosis in GBM cells via the receptor tyrosine kinase AXL. LCN2 was elevated in GBM cells compared to lower-grade tumor and non-transformed cells, and Lcn2 knockdown impaired GBM cell fitness and growth in vitro and in vivo. Mechanistically, Lcn2 knockdown triggered ferroptosis, which was specifically rescued with ferroptosis inhibitors but not apoptosis or necroptosis inhibitors. Lcn2 knockdown reduced AXL phosphorylation, which was elevated in GBM patient tumors relative to non-tumor tissue. Notably, the combination of Lcn2 knockdown and pharmacological AXL inhibition extended survival compared to Lcn2 knockdown alone. Taken together, these data reveal a link between LCN2-mediated suppression of ferroptosis with AXL phosphorylation and support this axis as a potential therapeutic target for GBM.