YBX1/CD36 positive feedback loop-mediated lipid accumulation drives metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver disorder mainly caused by an imbalance in lipid homeostasis. Y-box binding protein 1 (YBX1) participates in multiple pathophysiological processes, including embryonic development, tissue repair, liver disorders, and energy metabolism. The objective of this study is to investigate the mechanisms underlying MASLD and characterize the role of YBX1 in MASLD. A positive correlation between hepatic YBX1 expression and MASLD using single-cell sequencing data and human liver samples was observed. Hepatocyte-specific YBX1 deficiency ameliorates MASLD in a mouse model generated by subjecting YBX1-KO(hep) and LOXP mice to a high-fat-cholesterol and high-fructose diet. Subsequently, the role of YBX1 in the hepatic lipid deposit was assessed by using primary hepatocytes and by performing transmission electron microscopy and biological and histological analyses. Mechanistically, the elevated YBX1 expression enhances the CD36 expression and its membrane localization by directly binding to the promoter of CD36. Furthermore, CD36 promotes the expression of YBX1 under lipid stimulation. The YBX1/CD36 positive feedback loop facilitates hepatic lipid accumulation. The up-regulation of CD36 attenuated the reduction of hepatic steatosis mediated by hepatic YBX1 deficiency in MASLD mouse models. These findings suggest that YBX1 is essential for hepatic lipid homeostasis. This study reveals a novel mechanism of liver steatosis and shows that targeting YBX1 may represent a potential approach for MASLD treatment.