Identification of the Lipid Oxygen Radical Defense pathway and its epigenetic control

Membrane phospholipids are vulnerable to oxidative radicals, and uncontrolled lipid peroxidation can compromise cell viability. To mitigate lipid damage, cells have evolved defense mechanisms, the genetic regulation of which is not fully understood. Here, we identify the Lipid Oxygen Radical Defense (LORD) pathway. Under normal conditions, the pathway is epigenetically repressed by a complex comprising the KRAB-zinc finger protein ZNF354A, the scaffold protein KAP1/TRIM28, the histone methyltransferase SETDB1, and the transcriptional activator ATF2. In response to lipid peroxide accumulation, ATF2, KAP1, and ZNF354A undergo p38- and JNK-dependent phosphorylation, and the repressive complex disassembles, releasing ZNF354A from specific DNA loci. A protective gene network is subsequently activated, comprising targets of the major redox regulator NRF2 and modulating cellular sensitivity to oxidative stress and ferroptosis. These findings reveal a novel layer of epigenetic regulation in the cellular defense against lipid damage but also position the LORD pathway as a promising therapeutic target for diseases linked to chronic inflammation, neurodegeneration and cancer.