Ferritinophagy: A novel insight into the double-edged sword in ferritinophagy-ferroptosis axis and human diseases

Nuclear receptor coactive 4 (NCOA4), which functions as a selective cargo receptor, is a critical regulator of the particularly autophagic degradation of ferritin, a process known as ferritinophagy. Mechanistically, NCOA4-mediated ferritinophagy performs an increasingly vital role in the maintenance of intracellular iron homeostasis by promoting ferritin transport and iron release as needed. Ferritinophagy is not only involved in iron-dependent responses but also in the pathogenesis and progression of various human diseases, including metabolism-related, neurodegenerative, cardiovascular and infectious diseases. Therefore, ferritinophagy is of great importance in maintaining cell viability and function and represents a potential therapeutic target. Recent studies indicated that ferritinophagy regulates the signalling pathway associated with ferroptosis, a newly discovered type of cell death characterised by iron-dependent lipid peroxidation. Although accumulating evidence clearly demonstrates the importance of the interplay between dysfunction in iron metabolism and ferroptosis, a deeper understanding of the double-edged sword effect of ferritinophagy in ferroptosis has remained elusive. Details of the mechanisms underlying the ferritinophagy-ferroptosis axis in regulating relevant human diseases remain to be elucidated. In this review, we discuss the latest research findings regarding the mechanisms that regulate the biological function of NCOA4-mediated ferritinophagy and its contribution to the pathophysiology of ferroptosis. The important role of the ferritinophagy-ferroptosis axis in human diseases will be discussed in detail, highlighting the great potential of targeting ferritinophagy in the treatment of diseases. Nuclear receptor coactive 4 (NCOA4), served as a selective cargo receptor, is critically responsible for the mediation of autophagic degradation of ferritin that is defined as ferrinnophagy. Mechanically, NCOA4-mediated ferritinophagy is considered as a pre-requisite for maintenance of intracellular iron homeostasis by promoting ferritin transport and iron release in accordance with requirements. Therefore, ferritinophagy is of great importance in safeguarding the viability and functionality of cells, and might be a potential therapeutic target for various diseases. In this review, we conclude the latest research findings and regulated mechanisms covering the biological function of NCOA4-mediated ferritinophagy and its contribution to the pathophysiology of ferroptosis. Moreover, the pivotal role of ferritinophagy-ferroptosis axis in human diseases will be discussed in details, proposing to attract attention on the great potential of ferritinophagy in the treatment of various diseases. image