# NCOA4 and ferritinophagy in hematological malignancies: a double-edged regulator of iron metabolism and cell fate

## TL;DR

This paper reviews how NCOA4 and ferritinophagy regulate iron metabolism in blood cancers, particularly acute myeloid leukemia, and their potential as therapeutic targets.

## Contribution

The paper provides a comprehensive review of NCOA4 and ferritinophagy's dual role in iron metabolism and cancer cell fate in hematological malignancies.

## Key findings

- Ferritinophagy supports mitochondrial metabolism in some cancers but promotes ferroptosis in others.
- AML cells may depend on ferritinophagy for iron-driven metabolism, suggesting a potential therapeutic strategy.
- NCOA4 regulation and its role in AML remain areas requiring further investigation.

## Abstract

Ferritinophagy, a selective autophagic process mediated by NCOA4, plays a central role in cellular iron homeostasis by mobilizing iron from ferritin to sustain mitochondrial metabolism and redox balance. In cancer, ferritinophagy’s effects vary with context: it can support metabolic fitness in some settings while promoting ferroptotic vulnerability in others. In acute myeloid leukemia (AML), evidence suggests that leukemic stem cells rely more heavily on iron-driven mitochondrial metabolism, making ferritinophagy a potential therapeutic target. This review summarizes current knowledge of NCOA4 regulation and ferritinophagy, discusses their relevance in hematologic malignancies, and highlights therapeutic opportunities and unresolved questions in AML.