Oxysterol-sensing by Liver X receptor counteracts ferroptosis via lipid remodeling

Ferroptosis, an iron-dependent form of regulated cell death, is controlled by cellular metabolism. Nutrients and metabolites determine cell states that render cells sensitive or resistant to ferroptosis. Nuclear receptors can act as cellular sensors for distinct metabolites and nutrients to regulate ferroptosis. We performed a chemical genetics screen using a nuclear receptor small molecule library to identify novel regulators of ferroptosis. We find that activating or overexpressing the liver X receptor (LXR) suppresses ferroptosis in various cell models, including ex vivo primary mouse hepatocytes. Interestingly, hepatocellular carcinoma with high levels of LXR shows poorer survival outcomes. In cells, activation of LXR by the endogenous oxysterol 24(S),25-epoxycholesterol or synthetic agonists reduces lipid peroxidation and ferroptotic cell death. Mechanistically, LXR activation drives a selective transcriptional program upregulating SREBP-1c, SCD1 and ACSL3, key enzymes involved in the synthesis of monounsaturated fatty acid-containing phospholipids (MUFA-PLs). Lipidomic analysis reveals that this lipid remodeling enriches cellular membranes with MUFA-PLs, reducing their susceptibility to peroxidation and thereby counteracting ferroptosis. Together, we identify LXR as an oxysterol-sensing endogenous suppressor of ferroptosis coupling oxysterol sensing to the adaptive remodeling of cellular membrane lipid composition to limit lipid peroxidation.