Goat Whey Protein Hydrolysate Mitigates High-Fructose Corn Syrup-Induced Hepatic Steatosis in a Murine Model.

: Hepatic steatosis, characterized by abnormal fat accumulation in the liver, is a major health concern with limited effective treatments. Goat milk whey proteins have demonstrated various therapeutic benefits. This study aimed to evaluate the hepatoprotective effects of goat whey protein hydrolysate (GWPH) on high-fructose corn syrup (HFCS)-induced hepatic steatosis in a murine model. : The GWPH was prepared through enzymatic hydrolysis using Alcalase and divided into fractions: GWPH03 (<3 kDa), GWPH0310 (3-10 kDa), GWPH1030 (10-30 kDa), and GWPH30 (>30 kDa). These fractions were administered to respective GWPH treatment groups at 200 mg/kg b.w/day via intragastric gavage for 8 weeks, with HFCS provided to all groups except the Naïve group. After dietary intervention, an oral glucose tolerance test (OGTT) was performed, and the mice were then sacrificed for further analysis. : Our results demonstrate that GWPH mitigates HFCS-induced hepatic steatosis, reduces body weight gain, improves glucose homeostasis, alleviates liver injury, and regulates hepatic lipid metabolism. Notably, GWPH treatment significantly suppressed hepatic fatty acid synthase (FASN) expressions, indicating reduced de novo lipogenesis (DNL). Molecular docking of the identified peptides from GWPH-particularly PFNVYNVV, which showed strong binding affinity for KHK-suggests that it has potential as a competitive inhibitor of fructose metabolism. : Collectively, our findings suggest that GWPH and its derived peptides could be promising candidates for managing hepatic steatosis and related metabolic abnormalities.