In the present study, we verified that portal hypertension induces FADDosome formation on the epithelial mitochondrial membrane to enhance Drp1-dependent mitochondrial fission and dysfunction and alter glycolysis profile; the FADDosome also promotes transforming growth factor-β-activated kinase 1 (TAK1)/NF-κBp65/NOX2 signaling to strengthen Drp1-dependent mitochondrial fission, alter glycolysis process and enhance mtROS production; consequently, the enhanced mtROS generation triggers NLRP3 inflammasome activation and results in gastric epithelial pyroptosis and mucosal injury in PHG. This evidence concerns the gene DNM1L and portal hypertension.