# ETS1 suppresses hepatic stellate cell activation and liver fibrosis

## TL;DR

ETS1 helps prevent liver fibrosis by keeping hepatic stellate cells inactive and promoting recovery after liver damage.

## Contribution

This study reveals ETS1 as a key regulator of hepatic stellate cell quiescence and fibrosis regression.

## Key findings

- ETS1 deficiency in hepatic stellate cells worsens liver fibrosis in mice.
- ETS1 knockdown in human cells increases fibrogenic gene expression and prevents fibrosis regression.
- ETS1 regulates quiescent hepatic stellate cells via the CRTC2/PGC1α/PPARγ pathway.

## Abstract

Chronic liver injury results in activation of quiescent hepatic stellate cells (HSCs) into collagen type I–producing activated HSCs that make the liver fibrotic. We identified ETS1 and ETS2 (ETS1/2) as lineage-specific transcription factors regulating HSC phenotypes. Here, we investigated the role of ETS1/2 in HSCs in liver fibrosis using toxic liver injury models and 3D human liver spheroids. Liver fibrosis was induced in WT and HSC-specific Ets1-KO (Ets1ΔHSC) and Ets2-KO (Ets2ΔHSC) mice by administration of CCl4 for 6 weeks, followed by cessation of liver injury for 2 weeks. Liver fibrosis was more severe in Ets1ΔHSC and to a lesser extent Ets2ΔHSC mice compared with WT mice. Regression of liver fibrosis was suppressed only in Ets1ΔHSC mice, indicating Ets1 is the predominant isoform maintaining a quiescent-like phenotype in HSCs. Similar results were obtained in a metabolic dysfunction–associated steatohepatitis (MASH) model using 3D human liver spheroids. Knockdown of ETS1 in human HSCs caused upregulation of fibrogenic genes in MASH human liver spheroids and prevented fibrosis regression. ETS1 regulated the quiescent HSC phenotype via the CREB-regulated transcription coactivator 2 (CRTC2)/PGC1α/PPARγ pathway. Knockdown of CRTC2 abrogated PPARγ responses and facilitated HSC activation. These findings suggest that ETS1 may represent a therapeutic target for antifibrotic therapy.

ETS1 maintains quiescent phenotype of Hepatic Stellate Cells, suppresses liver fibrosis and facilitates fibrosis regression.