RNF90 promotes hepatic steatosis by degrading CPT1α to suppress fatty acid oxidation.

Hepatic fatty acid oxidation (FAO) is crucial for maintaining hepatic lipid homeostasis, and dysregulation of hepatic lipid metabolism is closely associated with metabolic dysfunction-associated fatty liver disease. However, the molecular mechanisms governing FAO in hepatocytes remain incompletely understood. Here, we demonstrate that RNF90 is essential for FAO regulation, with its expression significantly upregulated in fatty liver. Further investigation revealed that RNF90 is transcriptionally activated by KLF5 and functions as an E3 ubiquitin ligase to promote the ubiquitin-dependent proteasomal degradation of carnitine palmitoyltransferase 1α (CPT1α), a rate-limiting enzyme in mitochondrial FAO. Hepatocyte-specific RNF90 knockout significantly increased CPT1α protein expression, enhanced FAO activity, and alleviated hepatic steatosis, as evidenced by reduced hepatic lipid accumulation and triglyceride levels. Conversely, overexpression of wildtype RNF90 (but not its E3 ligase-deficient mutant) exerted the opposite effects. Function rescue experiments further confirm that CPT1α is indispensable for RNF90-mediated regulation of FAO and protection against hepatic steatosis. Collectively, our study establishes RNF90 as a critical regulator of hepatic lipid metabolism and identifies the KLF5/RNF90/CPT1α axis as a potential therapeutic target for metabolic dysfunction-associated fatty liver disease.