Ferritinophagy activation states determine the susceptibility to ferroptosis of macrophages in bone marrow and spleen.

Macrophages exhibit heterogeneity due to their presence in different tissues that have distinct cell fates. Ferroptosis is one type of cellular fate, but the sensitivity of different types of macrophages to ferroptosis and the associated molecular mechanisms are not clear. This study explored the ferroptosis sensitivity of bone marrow and splenic macrophage, focusing on the contribution of ferritinophagy. We found that bone marrow M2 macrophages were more susceptible to ferroptosis, which was attributed to their lower solute carrier family 40 member 1 (SLC40A1) and ferritin heavy/light chain (FTH/L) expression and higher labile iron levels compared to those of splenic macrophages. Further, ferritinophagy activation, particularly in M2 macrophages, was identified as the primary cause of increased labile iron levels, as evidenced by experiments using autophagic flux modifiers and RAW264.7 cells with autophagy related 5 (ATG5) and nuclear receptor coactivator 4 (NCOA4) knockdown and NCOA4 knockout. These results provide a new direction for further understanding the heterogeneity and functionality of macrophages, and offers innovative treatments for a variety of health issues in which macrophage regulation plays a critical role.