Ferroptosis is a novel form of iron-dependent cell death characterized by lipid peroxidation. While the importance and disease relevance of ferroptosis is gaining recognition

much remains unknown about various genetic and non-genetic determinants of ferroptosis. Hippo signaling pathway is an evolutionarily conserved pathway that responds to various environmental cues and controls organ size

cell proliferation

death

and self-renewal capacity. In cancer biology

Hippo pathway is a potent tumor suppressing mechanism and its dysregulation contributes to apoptosis evasion

cancer development

metastasis

and treatment resistance. Hippo dysregulation leads to aberrant activation of YAP and TAZ

the two major transcription co-activators of TEADs

that induce the expression of genes triggering tumor-promoting phenotypes

including enhanced cell proliferation

self-renewal and apoptosis inhibition. The Hippo pathway is regulated by the cell-cell contact and cellular density/confluence. Recently

ferroptosis has also been found being regulated by the cellular contact and density. The YAP/TAZ activation under low density

while confers apoptosis resistance

renders cancer cells sensitivity to ferroptosis. These findings establish YAP/TAZ and Hippo pathways as novel determinants of ferroptosis. Therefore

inducing ferroptosis may have therapeutic potential for YAP/TAZ-activated chemo-resistant and metastatic tumor cells. Reciprocally

various YAP/TAZ-targeting treatments under clinical development may confer ferroptosis resistance

limiting the therapeutic efficacy.