We found that PGE2-EP4-mTOR signaling promotes Lyso-ER cholesterol transport via NPC1 and aggravates ER stress-induced macrophage M1-type polarization through the ERO1α-mediated disturbance of ER redox in HBx-related NASH. The gene discussed is PTGER4; the disease is metabolic dysfunction-associated steatohepatitis.