# Dynamic activation and dual roles of SOX9+ hepatocytes in liver regeneration under acute and chronic injury by single-cell transcriptomics

## TL;DR

This study explores how SOX9+ liver cells respond to different types of liver injury, showing their roles in regeneration and chronic disease.

## Contribution

The study reveals the dynamic and context-specific roles of SOX9+ hepatocytes in liver regeneration and chronic injury using single-cell transcriptomics.

## Key findings

- SOX9+ hepatocytes show transient metabolic activation during acute liver regeneration.
- In chronic injury, SOX9+ hepatocytes expand and adopt inflammatory and wound-healing programs.
- SOX9+ hepatocytes display biphasic activation in response to acute stress and recovery.

## Abstract

SOX9+ hepatocytes, marked by progenitor-like features, have been implicated in both liver regeneration and fibrosis. This study systematically characterized the temporal and contextual roles of SOX9+ hepatocytes during acute and chronic liver injury using integrated single-cell transcriptomics.

Publicly available single-cell RNA sequencing (scRNA-seq) datasets derived from mouse liver models of partial hepatectomy (PHx) and acetaminophen-induced acute liver injury (APAP), as well as human liver tissues with nonalcoholic fatty liver disease (NAFLD), were analyzed. Data were processed using Seurat and Harmony for batch correction. Pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA).

Under PHx, SOX9+ hepatocytes exhibit transient metabolic activation associated with early regenerative responses and hepatocyte proliferation. In the APAP model, SOX9+ hepatocytes display a biphasic activation pattern, characterized by an early response to stress- and cytokine-associated signals followed by restoration of metabolic balance. During NAFLD progression, SOX9+ hepatocytes progressively expand and acquire transcriptional programs associated with inflammatory signaling and wound-healing processes.

Our findings highlight SOX9+ hepatocytes as a dynamic and context-dependent hepatocyte subpopulation associated with adaptive metabolic responses during regeneration and altered inflammatory and wound-healing–related programs under chronic injury.