Oxidative damage to membrane lipids poses a serious threat to cellular integrity and can lead to ferroptosis, a form of cell death implicated in chronic diseases such as neurodegeneration, but also in cancer, where it could be exploited to kill tumor cells. Surprisingly, the mechanisms that couple lipid damage to gene regulation remain largely unknown. The newly discovered lipid quality control pathway, LORD (Lipid Oxygen Radical Defense) links lipid peroxidation to epigenetically gated gene expression and membrane repair. LORD is repressed at baseline by a ZNF354A-centered chromatin complex and activated through a lipid peroxide-dependent MAP kinase phospho-switch triggering complex disassembly and coordinated control of antioxidant gene expression, glutathione metabolism, selenoprotein synthesis, and GPX4 activity. LORD differs from canonical oxidative stress responses and connects epigenetic regulation to membrane biology, in particular through the control of S-acylation, the only reversible lipid post-translational modification of proteins.