Study on the Mechanism of Action of Hippuric Acid Targeting the UGDH/FOXK1/CD36 Signaling Axis in Regulating Metabolic Dysfunction-AssociatedSteatotic Liver Diseases

Metabolic dysfunction-associated steatotic liver diseases (MASLD) is the most prevalent chronic liver disease globally, and the systemic metabolic disorders it triggers have become a serious public health concern. The endogenous metabolite hippuric acid (HA) is closely associated with a variety of metabolic disorders, but its molecular mechanisms in the progression of MASLD are not yet clear. Preliminary studies of this project have found that serum HA levels are significantly reduced in obese individuals and animals, and exogenous HA supplementation can alleviate body weight and liver fat accumulation in obese mice. It was also discovered that HA can reduce intracellular lipid deposition in hepatocytes by inhibiting CD36 expression. Mechanistic studies have revealed that HA can target UGDH, enhancing its binding with the transcription factor FOXK1, and inhibiting FOXK1 expression significantly reduces the transcription level of CD36. Therefore, the scientific hypothesis is proposed: HA inhibits liver fat accumulation by regulating the UGDH/FOXK1/CD36 signaling axis. This project will combine clinical sample analysis with in vitro and in vivo experiments to systematically elucidate the molecular mechanisms by which HA targets UGDH to inhibit nuclear expression of FOXK1, thereby regulating CD36 transcription. This will enhance our understanding of HA's role in lipid metabolism regulation and the development of MASLD and lay a theoretical foundation for uncovering effective therapeutic targets for MASLD.