Sailer, J. | bioRxiv Science

bioRxiv2026

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.

cell biology↗

bioRxiv2025

IRP1 deficiency alters mitochondrial metabolism and protects against metabolic syndrome pathologies

Iron regulatory protein 1 (IRP1) is a post-transcriptional regulator of cellular iron metabolism. In mice, loss of IRP1 causes polycythemia through translational de-repression of hypoxia-inducible factor 2 (HIF2) mRNA, which increases renal erythropoietin production. Here we show that Irp1-/- mice develop fasting hypoglycemia and are protected against high-fat diet-induced hyperglycemia and hepatic steatosis. Discovery-based proteomics of Irp1-/- livers revealed a mitochondrial dysfunction signature. Seahorse flux analysis in primary hepatocytes and differentiated skeletal muscle myotubes confirmed impaired respiratory capacity, with a shift from oxidative phosphorylation to glycolytic ATP production. This metabolic rewiring was associated with enhanced insulin sensitivity and increased glucose uptake in skeletal muscle. Under metabolic stress, IRP1 deficiency altered the redox balance of mitochondrial iron, resulting in inefficient energy production and accumulation of amino acids and metabolites in skeletal muscle, rendering them unavailable for hepatic gluconeogenesis. These findings identify IRP1 as a critical regulator of systemic energy homeostasis.

pathology↗