MicroRNA-mediated regulation of ferroptosis via GPX4: mechanisms and therapeutic opportunities

Ferroptosis is a type of regulated cell death that depends on iron and lipid peroxidation and is considered a key pathological mechanism in a continuum of pathologies, including oncogenic, neurodegenerative, cardiovascular, and metabolic diseases. GPX4 serves as the regulator of ferroptosis, reducing the toxic lipid hydroperoxides to non-toxic lipid alcohols using the glutathione-dependent reaction and maintaining membrane integrity and cellular viability. MicroRNAs, short non-coding RNAs that regulate gene expression in a post-transcriptional manner, have been reported to play an important role in regulating both GPX4 expression and ferroptotic processes. This narrative review specifically focuses on microRNA-mediated regulation of GPX4, a central antioxidant regulator of ferroptosis, and explores the current evidence on miRNAs that modulate GPX4 expression across diverse disease contexts. This follows the miRNAs that directly target GPX4 through binding its 3'UTR, including hsa-miR-214-3p, hsa-miR-188-3p, hsa-miR-1909-5p, hsa-miR-761, hsa-miR-3619-5p, hsa-miR-15, and hsa-miR-324-3p, alongside miRNAs that indirectly modulate GPX4 via intermediate pathways such as Keap1/Nrf2, SLC7A11, and ACSL4. These microRNAs have demonstrated to have both pro-ferroptotic and anti-ferroptotic effects across a variety of disease models through in-silico predictions and experimental validation in each case, depending on the dynamics of their expression. Therapeutic interventions using microRNA-mimics, antagomirs, and adjunct therapeutic methods utilising natural compounds show the potential to control ferroptosis by regulating GPX4, thus providing new opportunities for the treatment of ferroptosis-related diseases.