The study shows that a protein called EVA1A keeps liver fat in check. When EVA1A levels drop (as seen in fatty liver disease), the liver takes up more fat because another protein, CD36, becomes more abundant and more “palmitoylated,” which pushes it to the cell surface. Boosting EVA1A in mice reduces liver fat, suggesting EVA1A helps balance fat intake and burning in the liver.

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 &#x3b2;-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)-PPAR&#x3b3;2 (peroxisome proliferator-activated receptor &#x3b3;2) 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 &#x3b2;-oxidation. Collectively, these results establish EVA1A as an essential regulator of hepatic lipid homeostasis, coordinating fatty acid uptake and &#x3b2;-oxidation by modulating CD36 expression and palmitoylation. Therefore, targeting the EVA1A-CD36 axis represents a promising therapeutic strategy for MASLD.