Liver-specific Bcl3 Knockout Alleviates Acetaminophen-induced Liver Injury by Activating Nrf2 Pathway in Male Mice

Acetaminophen (APAP) overdose is the leading cause of acute liver failure, with oxidative stress being a critical factor in this process. Glutathione (GSH) plays a vital defensive role. Activation of nuclear factor erythroid 2 like 2 (Nrf2) pathway mitigates APAP-induced liver damage by promoting GSH biosynthesis and enhancing drug detoxification. Although the role of B cell leukemia/lymphoma 3 (Bcl3) in regulating inflammatory responses, cellular oncogenesis, and immune balance is well-documented, its function in APAP-induced liver injury remains unclear.

We employed liver-specific Bcl3 knockout (Bcl3^hep-/-) mice and adeno-associated virus (AAV)-8-mediated Bcl3 overexpression (AAV-Bcl3) mice to model APAP-induced liver injury. Liver damage was assessed through hematoxylin and eosin staining and serum alanine aminotransferase and aspartate aminotransferase measurements. The interaction between Bcl3 and Nrf2 was examined using immunofluorescence and co-immunoprecipitation assays.

Our study reveals a significant upregulation of Bcl3 expression in the livers of male mice following APAP administration, suggesting Bcl3's potential involvement in this pathological process. In Bcl3^hep-/- mice, a reduced severity of liver damage was observed at both 6 and 24 hours post-APAP treatment compared with controls. Notably, Bcl3-deficient mice exhibited accelerated GSH replenishment due to the rapid induction of Gclc and Gclm genes following 6 hours of APAP exposure. Through immunofluorescence and co-immunoprecipitation analyses, we identified an interaction between Bcl3 and Nrf2. The loss of Bcl3 enhanced Nrf2 translocation upon APAP challenge, leading to the upregulation of antioxidant gene expression. These findings suggest that Bcl3 knockout alleviates oxidative stress resulting from APAP overdose.

We uncovered a previously uncharacterized role of Bcl3 in APAP-induced liver injury, emphasizing the role of the Bcl3-Nrf2 axis in oxidative stress-related liver damage.