Mutation of TP53 confers ferroptosis resistance in lung cancer through the FOXM1/MEF2C axis

Ferroptosis is a highly regulated tumor suppressor process. Loss or mutation of TP53 can cause changes in sensitivity to ferroptosis. Our previous study found that mutations in TP53 may be associated with the "malignant" or "indolent" progression of ground glass nodules (GGO) in early lung cancer, so we wondered whether ferroptosis may also be involved in determining this biological process. Here, using in vivo and in vitro gain- and loss-of-function approaches, clinical tissue for mutation analysis and pathological research, we identified wild-type TP53 inhibits the expression of FOXM1 by binding to PGC1α, maintaining the mitochondrial function and thus affecting the sensitivity to ferroptosis, whereas this function is absent in mutant cells, resulting in overexpression of FOXM1 and feeeptosis resistance. Mechanistically, FOXM1 can activate the transcription level of MEF2C in MAPK signaling pathway, leading to stress protection when exposed to ferroptosis inducers. This study provides new insights into the mechanism of association between TP53 mutation and ferroptosis tolerance, which can help to deeply understand the role of TP53 in the malignant progression of lung cancer.