ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Stem Cell Research
Dynamic Activation and Dual Roles of SOX9⁺ Hepatocytes in Liver Regeneration under acute and chronic injuryand Chronic Disease Revealed by Single-Cell Transcriptomics
1. University of Oxford, Bee Research Laboratory, Oxford, United Kingdom
2. Peking Union Medical College Hospital, Beijing, China
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Abstract
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: Public scRNA-seq datasets from mouse liver models were analyzed, including partial hepatectomy (PHx), acetaminophen-induced acute injury (APAP), and nonalcoholic fatty liver disease (NAFLD). 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).Differential expression and pathway enrichment were assessed by MAST and 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. Under PHx, SOX9⁺ hepatocytes undergo transient metabolic activation to support early recovery with proliferation. In APAP, they show biphasic activation, responding to early stress and cytokine signals before restoring metabolic balance. During NAFLD progression, they expand progressively and acquire inflammatory and wound-healing phenotypes. Conclusions: 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. Our findings uncover the dual nature of SOX9⁺ hepatocytes, which act as protective metabolic responders during regeneration but shift toward maladaptive, pro-fibrotic states under chronic injury, identifying them as a potential therapeutic target in liver disease.
Summary
Keywords
liver Liver injuryfibrosis, Liver Regeneration, Partial hepatectomy, single-cell RNA-seq, SOX9⁺ hepatocytes
Received
10 November 2025
Accepted
30 January 2026
Copyright
© 2026 Zhang, Xu and Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Junwei Zhang
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