MDM2 Alters Cellular Iron Homeostasis by Promoting the Degradation of Proteins Involved in Iron Storage and Iron Export

The intracellular iron levels are tightly controlled by the coordinated action of specialized proteins that regulate iron uptake, storage, and export pathways in response to iron availability. For example, Ferroportin serves as the sole mammalian iron exporter; whereas ferritin acts as the primary intracellular iron storage complex. Although both Ferroportin and ferritin are reported to be primarily degraded through lysosomal pathways, it is possible that these proteins can also be regulated through the proteasomal pathway, which may provide a more rapid mechanism to modulate intracellular iron availability. Here, we identify MDM2 as a previously unrecognized regulator of cellular iron homeostasis. We found that MDM2 is required to maintain intracellular labile iron. Mechanistically, we found that MDM2 interacts with and promotes the degradation of both Ferroportin and ferritin heavy chain. Consequently, MDM2 exerts a critical role in modulating cellular iron retention by simultaneously suppressing iron storage and iron export pathways. These findings expand the biological functions of MDM2 beyond its established role as a p53 E3 ubiquitin ligase, revealing a previously unappreciated link between MDM2 signaling and iron metabolism.