Metabolic Dysfunction-Associated Steatotic Liver Disease（MASLD） is characterized by excessive accumulation of lipids in hepatocytes and is closely associated with the rapid rise in insulin resistance, obesity, and diabetes prevalence, making it one of the most common chronic liver diseases worldwide. Fatty liver can lead to systemic metabolic dysfunction and further progress to steatohepatitis, hepatic fibrosis, cirrhosis, and even hepatocellular carcinoma. However, current clinical interventions are limited to lifestyle and dietary modifications, with no effective drugs or therapies available for MASLD. Hepatic lipid metabolism dysregulation, caused by an imbalance between lipid acquisition and utilization, is a primary driver of MASLD, with fatty acid uptake being a critical step facilitated by fatty acid transporters such as CD36. CD36 can undergo various modifications, including palmitoylation, and dynamic palmitoylation directly regulates fatty acid uptake by altering its membrane localization and endocytic processes. Nevertheless, the specific molecular mechanisms regulating CD36 expression and its palmitoylation in the liver remain unclear.

Recently, a study revealed that CD36 expression and palmitoylation are regulated by the tumor suppressor gene EVA1A in hepatocellular carcinoma, making it a key regulator of hepatic lipid metabolism. The elucidated EVA1A-CD36 axis presents a novel pathogenic mechanism and a promising therapeutic target for MASLD. This study was conducted by the team of Associate Professor Ning Li at Qingdao University. Their core findings are as follows：

Downregulation of EVA1A in Fatty Liver Disease
In liver tissue from patients with hepatocellular carcinoma (HCC) and concomitant fatty liver disease, the expression of the tumor suppressor gene EVA1A was significantly downregulated. Liver-specific Eva1a knockout mice, generated using the Cre/Loxp recombination system, developed marked hepatic steatosis and exhibited disordered fat and fatty acid metabolism, indicating a direct causal role for EVA1A deficiency in hepatic lipid dysregulation.

Restoration of EVA1A Ameliorates Steatosis
In genetically obese ob/ob mice (a model of hereditary obesity and fatty liver), specific restoration of hepatic Eva1a expression via tail-vein injection of an adeno-associated virus (AAV-Eva1a) significantly improved liver steatosis. This therapeutic intervention led to the suppression of the fatty acid transporter CD36 in the liver.

Mechanistic Insight: Dual Regulation of CD36 by EVA1A
Transcriptional Level: Downregulation of EVA1A activates the mTORC1-PPARγ2 signaling pathway, thereby upregulating the transcription of CD36.
Post-translational Modification Level: EVA1A downregulation inhibits the transcription of the depalmitoylation enzyme APT1 while enhancing the transcription of palmitoyl acyltransferases ZDHHC4/5. This shift promotes the palmitoylation of CD36.
Consequence – Altered CD36 Localization: Palmitoylation drives CD36 localization to the plasma membrane, increasing fatty acid uptake. Concurrently, it reduces CD36 distribution on mitochondria, impairing fatty acid β-oxidation.

The complete study is accessible via DOI:10.34133/research.1001