GNL3L-LMNB1 signaling axis promotes lung squamous cell carcinoma growth and ferroptosis resistance via NF-κB activation.

Background: Lung squamous cell carcinoma (LUSC) remains one of the leading causes to global cancer mortality, yet effective molecular-targeted therapies are lacking. Dysregulation of cell cycle checkpoint genes is common in LUSC, but therapeutic inhibition of CDK4/6 has yielded disappointing clinical outcomes. Guanine nucleotide-binding protein-like 3-like protein (GNL3L), a conserved nucleolar GTPase and G2/M checkpoint regulator, has been implicated in several malignancies, though its role in LUSC remains undefined. Methods: We analyzed GNL3L expression in LUSC tissues from The Cancer Genome Atlas (TCGA) and 90 clinical samples by RNA sequencing and immunohistochemistry. Functional assays-including Celigo cell counting, cell cycle and cell apoptosis analyses, wound healing, transwell migration, and Results: GNL3L expression was significantly elevated in LUSC and correlated with poor overall survival. Functional experiments revealed that GNL3L enhanced LUSC cell proliferation, migration, and tumor growth in vivo. Transcriptomic and functional validation identified LMNB1 as a critical downstream effector of GNL3L. Mechanistically, GNL3L directly interacted with STAT4 to enhance its binding and transcriptional activation of the LMNB1 promoter. Overexpression of GNL3L or LMNB1 activated NF-κB signaling, promoting cell proliferation and suppressing apoptosis, whereas inhibition of NF-κB with pyrrolidinedithiocarbamate (PDTC) reversed these effects. Furthermore, the GNL3L-LMNB1 axis was associated with ferroptosis resistance through NF-κB activation, as evidenced by increased GSH and SLC7A11 levels and decreased intracellular Fe Conclusions: Our findings define a previously unrecognized oncogenic signaling cascade in LUSC, whereby GNL3L cooperates with STAT4 to upregulate LMNB1 expression, leading to NF-κB activation and ferroptosis resistance. The GNL3L-LMNB1-NF-κB axis thus represents a potential therapeutic target for LUSC.