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 demonstrate that Sox9(+)HNF4α(+) hepatocytes, generated by transition from mature hepatocytes, play an important role in the initial phase after partial hepatectomy (PHx). Additionally, knocking down the expression of Sox9 suppresses hepatocyte proliferation and blocks the recovery of lost hepatic tissue. In vitro and in vivo assays demonstrated that Bcl3, activated by LPS, promotes hepatocyte conversion and liver regeneration. Mechanistically, Bcl3 forms a complex with and deubiquitinates YAP1 and further induces YAP1 to translocate into the nucleus, resulting in Sox9 upregulation and mature hepatocyte conversion. We demonstrate that Bcl3 promotes Sox9(+)HNF4α(+) hepatocytes to participate in liver regeneration, and might therefore be a potential target for enhancing regeneration after liver injury.