Deciphering the Lipid Oxygen Radical Defense (LORD) Pathway in Oxidative Stress, Physiology, and Disease

Ziel

How does a cell control the quality of its components and respond to damage? Life on Earth depends on oxygen, yet its reactivity makes oxidative damage inevitable. While DNA and proteins have been the primary focus of damage response studies, lipids are equally vulnerable—and when lipid peroxides accumulate, they can trigger ferroptosis, a regulated form of cell death with implications in cancer, inflammation, neurodegeneration, and aging. Although much is known about redox homeostasis and oxidative stress responses, how cells detect lipid damage and activate protective gene expression programs is not well understood.
We recently discovered the LORD (Lipid Oxygen Radical Defense) pathway, an epigenetically controlled stress response triggered by lipid peroxides that induces a broad antioxidant gene network. This foundational work defines a new regulatory pathway and highlights a key role for S-acylation–via the S-acyltransferase ZDHHC20–in lipid quality control and ferroptosis prevention. The goal of ExpLORD is to define how the LORD pathway and ZDHHC20 contribute to safeguarding membrane integrity and redox homeostasis in mammals.
Our multidisciplinary research will:
1. Unravel the molecular mechanisms governing repression and activation of LORD;
2. Define the regulation of LORD effector proteins—including the acyltransferase ZDHHC20L and its substrate GPX4—and how they maintain redox homeostasis;
3. Explore the LORD pathway at the organoid and animal levels, including in disease-relevant settings.
To achieve these aims, we will integrate time-resolved RNA-seq, ChIP-seq, proximity proteomics, live-cell imaging, biochemistry, metabolic engineering approaches, molecular dynamics simulations, and mathematical modeling.
ExpLORD builds on foundational discoveries, strong preliminary data, and established collaborations. It aims to break new ground in oxidative stress biology by defining how cells sense, respond to, and recover from lipid oxidative damage.