Hepatic STEAP4 promotes liver regeneration by regulating lysosomal iron homeostasis and membrane integrity in acetaminophen-induced liver injury

BACKGROUND AND AIMS: Understanding the mechanisms behind liver repair in acetaminophen (APAP)-induced liver injury (AILI) is crucial for developing effective treatments. Six-transmembrane epithelial antigen of the prostate 4 (STEAP4) is a metalloreductase involved in iron regulation. The roles of STEAP4 and endolysosomal iron in liver regeneration in AILI remain unclear. APPROACH AND RESULTS: Alb-Cre- Steap4flox/flox and liver-specific STEAP4 knockout (Alb-Cre+ Steap4flox/flox , L-STEAP4 KO) mice were given APAP for different periods. Deferiprone (DFP) was administered with or after APAP. Biochemical and histological analyses were performed to examine iron homeostasis and liver injury. STEAP4 expression decreased in human AILI livers. APAP treatment lowered hepatic STEAP4 expression in mice. L-STEAP4 KO mice showed similar hepatocyte death and serum ALT levels between 6 and 24 hours, but experienced delayed liver recovery at 48 hours after APAP compared with wild-type mice. Loss of STEAP4 led to iron buildup in endolysosomes, lysosomal membrane damage, and the release of cathepsin B following APAP treatment, which was correlated with lower hepatic mTOR activity, impaired mitophagy, and reduced hepatocyte proliferation 48 hours after APAP. DFP restored mitochondrial and lysosomal functions, providing protection against AILI. Overexpressing STEAP4 or TFEB (a key regulator of lysosomal biogenesis) or post-treatment with DFP repaired lysosomal membranes and inhibited AILI in both wild-type and L-STEAP4 KO mice. CONCLUSIONS: STEAP4 is not essential during the early injury phase but plays a critical role in liver regeneration by maintaining lysosomal iron homeostasis and function after APAP overdose. Targeting STEAP4-mediated endolysosomal iron overload may open new therapeutic avenues for AILI.