# Hic-5 promotes the progression of nonalcoholic steatohepatitis by regulating hepatocellular fatty acid metabolism through the PTEN/PGE2/EP4 axis

## TL;DR

This study shows that Hic-5, a protein in liver cells, worsens nonalcoholic liver disease by altering fat metabolism and inflammation.

## Contribution

The study identifies Hic-5 as a novel regulator of fatty acid metabolism in NASH through the PTEN/PGE2/EP4 signaling axis.

## Key findings

- Hic-5 deficiency reduces fatty acid levels and hepatic steatosis in NASH models.
- Hic-5 promotes fatty acid synthesis in hepatocytes via PGE2 secretion from HSCs.
- Pharmacological inhibition of EP4 reduces NASH progression in Hic-5 overexpressing mice.

## Abstract

Nonalcoholic steatohepatitis (NASH) is a metabolic disease characterized by hepatic steatosis and inflammation among other features. Dysregulated lipid metabolism is crucial in the pathogenesis of NASH. However, its regulatory mechanisms remain intricate and poorly elucidated. Hepatic stellate cells (HSCs) have been reported to contribute to hepatocellular lipid metabolism dysregulation and aggravate NASH progression. However, the potential mechanisms remain unclear. Here, we demonstrate that hydrogen peroxide-inducible clone 5 (Hic-5), which is highly expressed in HSCs within the liver, is elevated in NASH patients and mouse models. Hic-5 deficiency alleviates hepatic steatosis, and liver metabolomics revealed reduced fatty acid levels. Meanwhile, RNA-sequencing revealed that Hic-5 deficiency increases AMPK phosphorylation. Additionally, HSC-specific overexpression of Hic-5 exacerbates NASH severity. Co-culture experiments indicated that Hic-5 increases hepatocellular fatty acid synthesis. Cellular transcriptomic analysis and validation revealed that prostaglandin E2 (PGE2), secreted by HSCs, mediates hepatocellular fatty acid synthesis. Mechanistically, the N-terminal domain of Hic-5 binds c-Src, leading to phosphorylation of PTEN, which is bound to the C-terminal domain. This event subsequently induces phosphorylation and nuclear translocation of the transcription factor SP1, ultimately increasing PGE2 secretion. Finally, Hic-5 promotes hepatocellular fatty acid synthesis by activating the PGE2-EP4 axis. Pharmacological inhibition of EP4 in HSC-specific Hic-5 overexpression mice fed with HFD diet (HFD) significantly attenuated NASH progression. These findings increase our understanding of molecular mechanisms linking hepatic lipid metabolism dysregulation and may offer therapeutic potential for treating NASH.

The online version contains supplementary material available at 10.1186/s43556-026-00409-4.