Small peptides derived from goat milk products regulate hepatic lipid metabolism by activating CTCF

• Goat milk and fermented goat milk improve hepatic metabolic homeostasis during metabolic dysfunction • From CTCF CUT TAG-seq data, goat milk decreased CTCF peak signal of upstream of the transcription start site (TSS) was enriched in HFD liver. • The transcription factor CTCF as an important mediator of goat milk peptides in the regulation of hepatic lipid metabolism . • Fermented goat milk may improve HFD-induced hepatic cholestasis through altering fecal microbial structure and increasing beneficial bacteria Milk products have emerged as a promising strategy for addressing metabolic syndromes. Nonetheless, the ameliorative effects of goat milk products on lipid disorders and their associated molecular mechanism remain uncertain. We constructed a high-fat murine model and detected the hepatic metabolic homeostasis in liver tissue via H&E staining, serum biochemical assay, RNA sequencing analysis, and CUT TAG-seq. Results showed that goat milk can regulate lipid accumulation in the liver by reducing fat deposition and increasing TBIL, IBIL, and CAT level. The CUT TAG-seq results revealed that reduced CTCF activity suppressed expression of the downstream genes Egr1 and Fabp5 by direct binding to their promoter regions. Furthermore, in vitro tests revealed that anti-digestion peptides, such as peptide B, peptide T, and peptide G, in goat milk were capable of binding to CTCF and activating its expression. Our results provide new insights into the role of goat milk-derived functional peptides in lipid metabolism regulation and demonstrate their therapeutic potential in alleviating metabolic syndromes.