LZTFL1 Rewires NADPH–Glutathione Metabolism to Amplify Ferroptosis
Description
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.
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Steps to reproduce
All raw data presented here were generated via western blot (WB) and flow cytometry assays. For western blot analysis: Total protein was extracted from samples following standard lysis protocols. Protein samples were separated by SDS-PAGE and then transferred onto membranes. Target proteins were detected using specific primary antibodies and corresponding secondary antibodies. Protein bands were visualized and recorded using a gel imaging system. For flow cytometry analysis: Cells were collected and processed in accordance with standard experimental procedures. Cells were stained with SYTOX and C11-BODIPY 581/591 to evaluate cell death and lipid ROS levels, respectively. Samples were analyzed on a BD FACSCanto II flow cytometer, and the acquired raw data were processed with FlowJo software.
Institutions
- Shanghai Jiao Tong UniversityShanghai, Shanghai