THRA Orchestrates Myocardial Protection Against Hypothyroidism-Induced Ferroptosisthe GATA4-GPX4 Transcriptional Cascade.

Abstract

AIMS: Hypothyroidism frequently causes myocardial injury, but the role of() remains unclear. This study investigated the function and mechanism ofin hypothyroidism-associated cardiac damage. METHODS: A propylthiouracil (PTU)-induced hypothyroid mouse model was utilized, incorporating wild-type and-knockout (KO) groups with or without thyroxine (T4) treatment. Systemic parameters, cardiac injury, histopathology, and molecular pathways were analyzed using enzyme-linked immunosorbent assay, immunohistochemistry, Western blot, quantitative polymerase chain reaction, RNA sequencing, chromatin immunoprecipitation, and dual-luciferase reporter assays. RESULTS: PTU-induced hypothyroidism significantly reduced body weight, impaired cardiac function, and dysregulated thyroid hormones.KO exacerbated these effects and completely abolished the therapeutic response to T4. Crucially, group KO-M markedly elevated markers of ferroptosis, including iron overload, malondialdehyde, and reactive oxygen species, while suppressing the reduced-to-oxidized glutathione ratio (GSH/GSSG) and key antiferroptotic proteins like(), compared with group M. Mechanistically, we identified() as an upstream transcriptional activator of. Furthermore,itself directly bound to thepromoter and transactivated its expression. This--axis was essential for cardioprotection, alongside modulation of the/signaling pathway. CONCLUSION: This study defines the--transcriptional axis as a crucial mechanism that protects the heart from hypothyroidism-driven ferroptosis, uncovering a previously unrecognized transcriptional axis that is crucial for cardioprotection during hypothyroidism.44, 236-250.