IRS1 and Insulin resistance: Acutely activated Rhbdf2–MAP3K7 signaling with dysfunctional Trim31 further increases downstream events, including JNK-IRS1-related insulin signaling, the IκBα-NF-κB-c-Jun pathway, suppression of AKT-GSK3β-FOXO1 phosphorylation levels, and CTGF-TIMP1 cascades, promoting the occurrence of impaired insulin signaling (insulin resistance), chronic inflammation, abnormal glucose metabolic disorder, and collagen deposition in the liver, accordingly aggravating abnormal lipid metabolism and the consequential liver steatosis and NASH phenotype (Fig. 8k).