Nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma and liver disorders have become the leading causes for the need of liver transplantation in developed countries. Lipotoxicity plays a central role in NASH progression by causing endoplasmic reticulum stress and disrupting protein homeostasis. To identify key molecules that mitigate the detrimental consequences of lipotoxicity, we performed integrative multiomics analysis and identified the E3 ligase tripartite motif 16 (TRIM16) as a candidate molecule. In particular, we found that lipid accumulation and inflammation in a mouse NASH model is mitigated by TRIM16 overexpression but aggravated by its depletion. Multiomics analysis showed that TRIM16 suppressed NASH progression by attenuating the activation of the mitogen-activated protein kinase (MAPK) signaling pathway; specifically, by preferentially interacting with phospho-TAK1 to promote its degradation. Together, these results identify TRIM16 as a promising therapeutic target for the treatment of NASH.