SLBP promotes lung adenocarcinoma progression by inhibiting ferroptosis and reprogramming glutamine metabolism via FADS2 interaction

Abstract

SLBP is significantly overexpressed in lung adenocarcinoma (LUAD) and correlates strongly with poor patient prognosis. Functional studies demonstrated that SLBP potently enhances proliferation, invasion, and metastasis of LUAD cells both in vitro and in vivo. Mechanistically, SLBP suppresses ferroptosis—a form of regulated cell death—by modulating key biochemical markers, including GSH, MDA, and Fe²⁺ levels, and it restores cell viability upon treatment with ferroptosis inducers. RNA-seq and biochemical analyses revealed that SLBP transcriptionally upregulates and stabilizes SLC7A11, a critical ferroptosis suppressor, thereby inhibiting lipid peroxidation and ferroptotic cell death. Additionally, immunopurification and mass spectrometry (IP-MS) identified FADS2 as a novel SLBP-interacting partner. SLBP binds to FADS2, promotes its expression, and drives metabolic reprogramming toward glutamine dependency, significantly altering choline and metal ion metabolism. This metabolic shift enhances cellular proliferation under nutrient stress. Crucially, SLBP-mediated proliferation was shown to be functionally dependent on FADS2, as FADS2 inhibition abrogates SLBP-driven growth without affecting SLBP levels. Collectively, these results uncover SLBP as a multifunctional oncoprotein that promotes LUAD progression through dual mechanisms: inhibiting ferroptosis via SLC7A11 and rewiring glutamine metabolism through FADS2, offering new potential targets for therapeutic intervention.