Acute Pericentral Liver Injury Induces a Novel Transient Hepatocyte Population

The liver exhibits robust regenerative capacity in response to injury, a property shaped by its essential metabolic and detoxification roles. While the mechanisms of regeneration following chronic liver injury have been extensively studied, the response during the early phases of acute injury remains poorly understood. Here, we employed a pericentral model of acute liver injury using carbon tetrachloride (CCl4) to investigate the initial hepatocyte response to damage. Through integration of single-nucleus multiome-sequencing, lineage tracing, spatial transcriptomics, and immunostaining, we identified a novel, transient population of damage-responsive SOX9+ pericentral hepatocytes. This population does not exhibit progenitor-like behavior but instead potentially mediates key aspects of early tissue repair. Specifically, SOX9+ pericentral hepatocytes engage in interactions with hepatic stellate cells and display migratory features associated with wound closure. Moreover, these cells exhibit an immune-related transcriptional signature and colocalize with liver macrophages at injury sites, suggesting a role in modulating immune responses. Our findings highlight a previously underappreciated function of SOX9 as a stress-responsive regulator of hepatocyte behavior and intercellular crosstalk during the early stages of acute liver injury.