In brief, we, for the first time, found that ROS-mediated DUSP22 degradation participated in the setting and progression of fatty liver, contributing to the etiopathogenesis of NASH and associated HCC via promoting the phosphorylation of FAK at Y397 and Y576 + Y577 residues and thereafter aggravating its downstream ERK1/2 and NF-κB signaling cascade. Here, PTK2 is linked to fatty liver disease.