THRA Orchestrates Myocardial Protection Against Hypothyroidism-Induced Ferroptosis via the GATA4-GPX4 Transcriptional Cascade

Abstract

Aims:

Hypothyroidism frequently causes myocardial injury, but the role of thyroid hormone receptor alpha (THRA) remains unclear. This study investigated the function and mechanism of THRA in hypothyroidism-associated cardiac damage.

Methods:

A propylthiouracil (PTU)-induced hypothyroid mouse model was utilized, incorporating wild-type and THRA-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. THRA 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 glutathione peroxidase 4 (GPX4), compared with group M. Mechanistically, we identified GATA binding protein 4 (GATA4) as an upstream transcriptional activator of THRA. Furthermore, THRA itself directly bound to the GPX4 promoter and transactivated its expression. This GATA4-THRA-GPX4 axis was essential for cardioprotection, alongside modulation of the phosphoinositide 3-kinase/protein kinase B signaling pathway.

Conclusion:

This study defines the GATA4-THRA-GPX4 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. Antioxid. Redox Signal. 44, 236–250.