LPS/Bcl3/YAP1 Signaling Promotes Sox9+HNF4α+ Hepatocyte-Mediated Liver Regeneration after Hepatectomy

Recent reports have demonstrated that Sox9+HNF4α+ hepatocytes are involved in liver regeneration after chronic liver injury; however, little is known about the origin of Sox9+HNF4α+ hepatocytes and the regulatory mechanism. Employing a combination of chimeric lineage tracing, immunofluorescence, and immunohistochemistry, we revealed that Sox9+HNF4α+ hepatocytes that transition from mature hepatocytes played an essential role in the initial phase after PHx. Additionally, knocking down the expression of Sox9 suppressed hepatocyte proliferation and blocked the recovery of lost hepatic tissue. In vitro and in vivo assays demonstrated that Bcl3, activated by LPS, promoted hepatocyte conversion and liver regeneration. Mechanistically, Bcl3 formed a complex with and deubiquitinated YAP1 and further induced YAP1 to translocate into the nucleus, resulting in Sox9 upregulation and mature hepatocyte conversion. Our findings demonstrated that Bcl3 promoted Sox9+HNF4α+ hepatocytes to participate in liver regeneration, which might be a potential target for promoting regeneration after liver injury.