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

Journal article

Background: 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. Methods: 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). Results: 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. Conclusion: 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.

Authors: Zhang, J; Xu, Y; Lu, X

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Frontiers Media
• Journal: Frontiers in Cell and Developmental Biology
• Volume: 14
• Article number: 1743286
• Publication date: 2026-02-18
• Acceptance date: 2026-01-30
• DOI: 10.3389/fcell.2026.1743286
• EISSN: 2296-634X
• ISSN: 2296-634X
• Language: English
• Keywords: partial hepatectomy; liver injury; liver regeneration; single-cell RNA sequencing; SOX9-positive hepatocytes