Peroxisome Proliferator-Activated Receptor-γ Modulation of Hepatic Stellate Cell-Hepatocyte Crosstalk Enhances Liver Regeneration Postradiation Injury via Interleukin 6 and Hepatocyte Growth Factor Signaling.

Abstract

Radiation-induced liver disease is a common complication of liver cancer radiation therapy, affecting treatment outcomes and patient quality of life. Although liver regeneration is critical after radiation injury, the molecular mechanisms remain unclear. This study investigates the role of peroxisome proliferator-activated receptor (PPAR)γ in liver regeneration following radiation-induced injury and evaluates its potential as a therapeutic target to enhance liver proliferation and recovery. Liver regeneration was evaluated in both clinical practice and animal models using radiation-sparing liver protection zones. Proteomics analysis, alongside in vivo and in vitro rescue experiments, was conducted to examine PPARγ's role in liver regeneration and its impact on hepatocyte proliferation. Clinical and animal studies indicate that radiation-sparing liver protection zones successfully preserve the regenerative capacity of nonirradiated liver tissue. This process is mediated by PPARγ's modulation of hepatic stellate cell-hepatocyte crosstalk, which enhances liver regeneration postradiation injury through IL-6 and HGF signaling pathways. Furthermore, in an Sprague-Dawley rat radiation model, PPARγ agonists were observed to suppress hepatocyte proliferation, whereas PPARγ antagonists promoted liver regeneration. Implementing radiation-sparing liver protection zones in clinical practice helps preserve the regenerative capacity of nonirradiated liver tissue. Targeting PPARγ presents a promising therapeutic approach, because it plays a central role in mediating the interaction between hepatic stellate cells and hepatocytes during liver regeneration.