The Intersection of DNA Damage Response and Ferroptosis-A Rationale for Combination Therapeutics

Ferroptosis is a novel form of iron-dependent cell death characterized by lipid peroxidation. While the importance and disease relevance of ferroptosis are gaining recognition, much remains unknown about its interaction with other biological processes and pathways. Recently, several studies have identified intricate and complicated interplay between ferroptosis, ionizing radiation (IR), ATM (ataxia-telangiectasia mutated)/ATR (ATM and Rad3-related), and tumor suppressor p53, which signifies the participation of the DNA damage response (DDR) in iron-related cell death. DDR is an evolutionarily conserved response triggered by various DNA insults to attenuate proliferation, enable DNA repairs, and dispose of cells with damaged DNA to maintain genome integrity. Deficiency in proper DDR in many genetic disorders or tumors also highlights the importance of this pathway. In this review, we will focus on the biological crosstalk between DDR and ferroptosis, which is mediated mostly via noncanonical mechanisms. For clinical applications, we also discuss the potential of combining ionizing radiation and ferroptosis-inducers for synergistic effects. At last, various ATM/ATR inhibitors under clinical development may protect ferroptosis and treat many ferroptosis-related diseases to prevent cell death, delay disease progression, and improve clinical outcomes.