# Sexually Dimorphic Response to Hepatic Injury in Newborn Suffering from Intrauterine Growth Restriction

## TL;DR

Newborns with IUGR show sex-specific liver injury responses, with females adapting better and males suffering more severe damage.

## Contribution

This study reveals sexually dimorphic mechanisms in hepatic injury and identifies APOA4 as a novel biomarker in IUGR males.

## Key findings

- IUGR females show immune-adapted T cell conversion that reduces inflammation and promotes liver regeneration.
- IUGR males experience severe hepatic injury due to disrupted lipid metabolism and prolonged inflammation.
- APOA4 upregulation in IUGR males protects against hypoxia-induced liver damage.

## Abstract

Intrauterine growth restriction (IUGR), when a fetus does not grow as expected, is associated with a reduction in hepatic functionality and a higher risk for chronic liver disease in adulthood. Utilizing early developmental plasticity to reverse the outcome of poor fetal programming remains an unexplored area. Focusing on the biochemical profiles of neonates and previous transcriptome findings, piglets from the same fetus are selected as models for studying IUGR. The cellular landscape of the liver is created by scRNA‐seq to reveal sex‐dependent patterns in IUGR‐induced hepatic injury. One week after birth, IUGR piglets experience hypoxic stress. IUGR females exhibit fibroblast‐driven T cell conversion into an immune‐adapted phenotype, which effectively alleviates inflammation and fosters hepatic regeneration. In contrast, males experience even more severe hepatic injury. Prolonged inflammation due to disrupted lipid metabolism hinders intercellular communication among non‐immune cells, which ultimately impairs liver regeneration even into adulthood. Additionally, Apolipoprotein A4 (APOA4) is explored as a novel biomarker by reducing hepatic triglyceride deposition as a protective response against hypoxia in IUGR males. PPARα activation can mitigate hepatic damage and meanwhile restore over‐expressed APOA4 to normal in IUGR males. The pioneering study offers valuable insights into the sexually dimorphic responses to hepatic injury during IUGR.

Intrauterine growth restriction (IUGR) induced by hypoxia leads to sex‐specific liver injury. In IUGR females, a slight inflammatory response occurs due to fibroblast‐driven T cells converting to an immune‐adapted phenotype. In IUGR males, excessive inflammation driven by macrophages is caused by triglyceride deposition. The protective upregulation of apolipoprotein apolipoprotein A4 (APOA4) in hepatocytes helps IUGR males survive.