EVA1A Regulates Hepatic Lipid Homeostasis by Modulating CD36 Expression and Its Palmitoylation

Hepatic lipid dysregulation drives metabolic dysfunction-associated steatotic liver disease (MASLD); nonetheless, the precise regulatory mechanisms remain incompletely elucidated. In this study, we examine the function of EVA1A, a known hepatocellular carcinoma tumor suppressor, in hepatic lipid metabolism. Hepatic EVA1A was markedly down-regulated in individuals diagnosed with MASLD, as well as in mice subjected to a high-fat diet. Hepatocyte-specific knockout of <i>Eva1a</i> in mice resulted in significant hepatic steatosis, accompanied by disrupted fatty acid metabolism, marked by increased fatty acid uptake and compromised β-oxidation, while hepatic Eva1a overexpression reversed these metabolic changes and largely alleviated fatty liver in ob/ob mice. Mechanistically, EVA1A deficiency activates mTORC1 (mechanistic target of rapamycin complex 1)-PPARγ2 (peroxisome proliferator-activated receptor γ2) signaling to up-regulate CD36 transcription. Concurrently, it transcriptionally represses the S-depalmitoylase APT1 while enhancing palmitoyl acyltransferases ZDHHC4/5, boosting CD36 palmitoylation. This dual action promotes CD36 plasma membrane localization for fatty acid uptake, reducing its mitochondrial distribution and impairing β-oxidation. Collectively, these results establish EVA1A as an essential regulator of hepatic lipid homeostasis, coordinating fatty acid uptake and β-oxidation by modulating CD36 expression and palmitoylation. Therefore, targeting the EVA1A-CD36 axis represents a promising therapeutic strategy for MASLD.