Macrophages produce PGE2 to promote hepatic stellate cell autophagy and liver fibrosis

The pathogenesis of liver fibrosis in nonalcoholic fatty liver disease (NAFLD) remains unclear and the effective treatments have not been explored yet. The activation of hepatic stellate cells (HSCs) is the most critical factor in the progression of liver fibrosis. Macroautophagy/autophagy has recently been identified as a new mechanism to regulate HSC activation. In a recent study, we found that type 2 (M2) macrophages promote HSC autophagy by secreting prostaglandin E2 (PGE2) to bind its receptor PTGER4/EP4 on HSCs, consequently activating the MAPK/ERK pathway to promote autophagy and activation of HSCs. A specific PGE2-PTGER4 antagonist, E7046, significantly inhibits HSC autophagy and improves liver fibrosis and histopathology in NAFLD mice. Our findings provide novel mechanistic insights into liver fibrosis and suggest E7046 as a promising therapy to prevent NASH progression.