The Potentials of Stem Cell-Derived Exosomal MicroRNAs in Ferroptosis Modulation: Molecular Insights into Hepatoprotection, Neuroprotection, Cardioprotection, Renoprotection and Pulmonoprotection.

Ferroptosis is an iron-dependent, regulated form of cell death characterized by lipid peroxidation and disrupted redox homeostasis. This process plays a role in the development of various organ injuries. Stem cell-derived exosomes carrying microRNAs (miRNAs) have recently emerged as a promising therapeutic approach for modulating ferroptosis and providing organ protection. This review summarizes the core molecular mechanisms of ferroptosis, including iron metabolism, lipid peroxidation, the glutathione/GPX4 axis, and regulatory networks involving non-coding RNAs. The biological hallmarks of stem cells, particularly mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cell derivatives (iPSCs), as well as the biogenesis and cargo sorting of exosomal miRNAs, are outlined. Evidence comprehensively shows that stem cell-derived exosomal miRNAs can influence ferroptosis. They provide protective effects in the lungs, liver, nervous system, kidneys, and heart. The review highlights how various exosomal miRNAs target ferroptotic regulators such as SLC7A11, GPX4, and ACSL4, as well as upstream signaling pathways. By tackling the current translational barriers, such as improving exosome engineering, increasing miRNA encapsulation efficiency, ensuring organ-specific delivery, enhancing biosafety, and conducting thorough in vivo validation, stem cell-derived exosomal miRNAs could become a clinically useful and reliable method for precise ferroptosis modulation and multi-organ protection.