LEAP2 deficiency does not impair essential iron-dependent functions in zebrafish.

Abstract

LEAP2 is a blood-derived antimicrobial peptide predominantly expressed in the liver. As the first identified liver-derived blood antimicrobial peptide, LEAP1/hepcidin is a key regulator of iron metabolism. Although LEAP2 shares gene structure and tissue distribution patterns with LEAP1/hepcidin, its metabolic role remains controversial. This study systematically investigated the effects of LEAP2 deficiency on metabolism in zebrafish for the first time, utilizing a previously established LEAP2 knockout model. Comprehensive analyses included tissue iron content, larval hemoglobin levels, adult erythrocyte counts, and ferritin expression. The results revealed that homozygous LEAP2 knockout zebrafish embryos exhibited developmental retardation compared with controls. Systemic assessment of iron metabolism showed no significant alterations in hemoglobin content of mutant larvae, red blood cell counts in adult fish, or tissue iron levels. Only liver ferritin showed a specific increase, while intestinal ferritin was specifically decreased. Upon Aeromonas hydrophila infection, liver ferritin content was significantly reduced. Taken together, these findings indicate that while LEAP2 deficiency does not markedly disrupt systemic iron homeostasis in zebrafish, it may exacerbate ferroptosis by modulating ferritin metabolism under bacterial infection conditions. This study provides new experimental evidence elucidating the biological function of LEAP2.