Nuclear Receptor Coactivator 4-mediated Ferritinophagy Drives Proliferation of Dental Pulp Stem Cells in Hypoxia

Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy has been implicated in the ferroptosis in cancer cells and hematopoiesis in the bone marrow. However, the role of iron metabolism, especially NCOA4-mediated degradation of ferritin, has not been explored in the proliferation of mesenchymal stem cells. The present study was designed to explore the role of NCOA4-mediated ferritinophagy in hypoxia-treated dental pulp stem cells (DPSCs). Hypoxia treatment increased ROS generation, boosted cytosolic labile iron pool, increased expression of transferrin receptor 1 and NCOA4. Moreover, colocalization of LC3B with NCOA4 and ferritin was observed in hypoxia-treated DPSCs, indicating the development of ferritinophagy. Hypoxia promoted the proliferation of DPSCs, but not ferroptosis, under normal serum supplement and serum deprivation. NCOA4 knock-down reduced ferritin degradation and inhibited proliferation of DPSCs under hypoxia. Furthermore, the activation of hypoxia inducible factor 1α and p38 mitogen-activated protein kinase signaling pathway was involved in the upregulation of NCOA4 in hypoxia. Therefore, our present study suggested that NCOA4-mediated ferritinophagy promoted the level of labile iron pool, leading to enhanced iron availability and elevated cell proliferation of DPSCs. Our present study uncovered a physiological role of ferritinophagy in the proliferation and growth of mesenchymal stem cells under hypoxia.