PPARγ signaling in hepatocarcinogenesis: Mechanistic insights for cellular reprogramming and therapeutic implications

Liver cancer or hepatocellular carcinoma (HCC) is leading cause of cancer-related mortalities globally. The therapeutic approaches for chronic liver diseases-associated liver cancers aimed at modulating immune check-points and peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway during multistep process of hepatocarcinogenesis that played a dispensable role in immunopathogenesis and outcomes of disease. Herein, the review highlights PPARγ-induced effects in balancing inflammatory (tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1) and anti-inflammatory cytokines (IL-10, transforming growth factor beta (TGF-β), and interplay of PPARγ, hepatic stellate cells and fibrogenic niche in cell-intrinsic and -extrinsic crosstalk of hepatocarcinogenesis. PPARγ-mediated effects in pre-malignant microenvironment promote growth arrest, cell senescence and cell clearance in liver cancer pathophysiology. Furthermore, PPARγ-immune cell axis of liver microenvironment exhibits an immunomodulation strategy of resident immune cells of the liver (macrophages, natural killer cells, and dendritic cells) in concomitance with current clinical guidelines of the European Association for Study of Liver Diseases (EASL) for several liver diseases. Thus, mechanistic insights of PPARγ-associated high value targets and canonical signaling suggest PPARγ as a possible therapeutic target in reprogramming of hepatocarcinogenesis to decrease burden of liver cancers, worldwide.