Knockdown of TFB2M induces ferroptosis in lung adenocarcinoma via mitophagy-mediated GPX4 degradation

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer, with a low survival rate. TFB2M, a mitochondrial transcription factor, maintains normal mitochondrial function. Its role in LUAD is unclear. We analyzed TFB2M expression in LUAD and normal tissues based on TCGA database. GSEA analyzed pathway enrichment. TFB2M-knockdown LUAD and control groups were constructed. Western blot detected levels of mitophagy- and ferroptosis-related proteins with/without mitophagy inhibitor (Mdivi-1, 10 μM). Malondialdehyde, glutathione, 4-hydroxynonenal, reactive oxygen species, and Fe2+ levels were measured to evaluate ferroptosis. CCK-8, EdU experiments, and flow cytometry evaluated cell survival. Immunofluorescence detected co-localization of glutathione peroxidase 4 and mitochondrial outer membrane transferase 20. Mitochondrial-specific fluorescent probes evaluated mitochondrial changes. A LUAD xenograft mouse model was constructed, with tumor volume and weight (with/without mitophagy inhibitors, 50 mg/kg) measured. IHC detected TFB2M and ki67 expression. TFB2M was upregulated (p < 0.05), and enriched in ferroptosis and mitophagy-related pathways. Mitophagy inhibitors reversed the promotion of mitophagy and ferroptosis and the inhibition of cell proliferation conferred by TFB2M knockdown. In animal experiments, they weakened the inhibition of mitophagy and the alleviation of LUAD progression induced by TFB2M knockdown. TFB2M contributes to ferroptosis resistance in LUAD by suppressing mitophagy.