EPG5 controls iron storage by regulating two steps in the breakdown of large iron-storage complexes

EPG5 deficiency leads to a unique decrease in hemosiderin and an increase in the labile iron pool.

• EPG5 is involved in the regulation of iron compartmentalization through autophagy and ferritinophagy.
• Loss of EPG5 disrupts the maturation of autophagosomes and endocytic trafficking, causing iron transporters to accumulate in abnormal structures.
• Compensatory activation of TBK1 occurs in response to EPG5 loss.
• TBK1 phosphorylates TAX1BP1 and interacts with ferritinophagy receptors, which may inhibit receptor clustering and affect ferritinophagic activity.
• These findings suggest that EPG5 plays a critical role in maintaining iron homeostasis and responding to related stress.

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