LZTFL1 Rewires NADPH–Glutathione Metabolism to Amplify Ferroptosis

Ferroptosis, an iron-dependent form of regulated cell death, represents a therapeutic vulnerability in apoptosis-resistant cancers. Here, we identify leucine zipper transcription factor-like 1 (LZTFL1) as a key regulator of ferroptosis that rewires glutathione (GSH) metabolism. A genome-wide CRISPR-Cas9 screen and multi-omics analysis revealed that LZTFL1 promotes oxidation of glucose-6-phosphate dehydrogenase (G6PD), limiting NADPH production and GSH regeneration. GSH depletion in turn enhanced LZTFL1 translation via an AKT–mTOR–eIF4E pathway, establishing a feed-forward loop that amplifies ferroptosis. In vivo, the LZTFL1–FHOD1–G6PD axis sensitized xenograft and patient-derived xenograft models to ferroptosis, correlating with lipid peroxidation, reduced GSH, and extended survival. Clinically, LZTFL1 expression restored cisplatin efficacy in resistant lung and ovarian cancer cells and predicted better survival outcomes in LUAD patients. Moreover, FDA-approved compounds upregulated LZTFL1 and re-sensitized resistant tumors to cisplatin. These findings define LZTFL1 as both a biomarker and therapeutic target for enhancing ferroptosis-based cancer therapy. The files below contain raw western blot images and flow cytometry data from this study.