New insights on iron overload-mediated lysosomal membrane rupture in liver regeneration following acetaminophen-induced liver injury.

Acetaminophen (APAP) overdose is a leading cause of liver failure in Western countries and a major clinical challenge because effective treatment options remain limited for patients who present after the optimal early therapeutic window. Iron is distributed among several subcellular compartments, such as cytosol, mitochondria, ferritin, and endosomes/lysosomes. Emerging evidence indicates that intracellular iron homeostasis and organelle function may be critical during the regeneration phase for repairing liver damage. Our recent work identified the metalloreductase six-transmembrane epithelial antigen of the prostate 4 (STEAP4) as a critical regulator of lysosomal iron homeostasis and membrane integrity during the regeneration phase following APAP overdose. Hepatic STEAP4 deficiency promoted lysosomal iron accumulation and impaired hepatocyte proliferation, whereas deferiprone-mediated iron chelation restored lysosomal function and promoted liver regeneration. In this perspective, we discuss the potential of targeting lysosomal iron to promote liver repair after APAP overdose-induced liver injury, as well as the limitations and challenges.