The role of estrogen and its receptors in the regulation of ferroptosis and autophagy

Ferroptosis is a distinct form of regulated cell death characterized by iron-dependent lipid peroxidation and the accumulation of reactive oxygen species (ROS), distinguishing it from apoptosis, necroptosis, and pyroptosis, and playing a vital role in maintaining physiological balance under stress by supporting organismal development and eliminating unnecessary or potentially harmful cells. Emerging evidence links ferroptosis to estrogen signaling, revealing interactions between estrogen receptors (ERα, ERβ, and GPER) and key regulatory pathways, including Nrf2, PI3K, AMPK, and p53. Intriguingly, many genes and pathways governing ferroptosis also regulate autophagy, and autophagy can drive ferroptotic cell death, giving rise to autophagy-dependent ferroptosis. This review summarizes recent findings on the interplay between estrogen signaling, autophagy, and ferroptosis, highlighting their potential impact on human health. By integrating knowledge of estrogen-regulated autophagy and ferroptosis, we aim to advance understanding of their physiological roles and their contribution to the pathogenesis of cancer, hormonal disorders, and neurodegenerative diseases. Understanding the molecular mechanisms controlling autophagy and ferroptotic sensitivity — including hormone-dependent signaling pathways — may ultimately enable the development of novel therapeutic strategies in both oncology and neurodegeneration.