LZTFL1 rewires NADPH-glutathione metabolism to amplify ferroptosis.
Ferroptosis, a form of oxidative cell death, represents a therapeutic vulnerability for treating apoptosis-resistant cancers. Here, we identify leucine zipper transcription factor-like 1 (LZTFL1) as a key regulator of ferroptosis that rewires glutathione (GSH) metabolism. Mechanistically, LZTFL1 promotes oxidation of glucose-6-phosphate dehydrogenase (G6PD), thereby limiting NADPH production and impairing GSH regeneration. GSH depletion in turn enhances LZTFL1 translation via an AKT-mammalian target of rapamycin (mTOR)-eukaryotic initiation factor 4E (eIF4E) pathway, establishing a feedforward loop that amplifies ferroptosis. In vivo, the LZTFL1-formin homology 2 domain-containing 1 (FHOD1)-G6PD axis sensitizes multiple tumor models, including patient-derived xenografts, to ferroptosis, leading to enhanced lipid peroxidation, reduced GSH levels, suppressed tumor growth, and prolonged survival. LZTFL1 expression restores cisplatin sensitivity in resistant lung and ovarian cancer cells and predicts improved survival outcomes in patients with lung adenocarcinoma. Moreover, FDA-approved agents upregulate LZTFL1 and re-sensitize resistant tumors to cisplatin. These findings highlight LZTFL1 as a potential biomarker and a therapeutic target for enhancing ferroptosis-based cancer therapy.