Black Sesame Pigment Ameliorates Non-Alcoholic Fatty Liver Disease via Modulation of the Gut–Liver Axis and HIF-1 Signaling Pathway

Black sesame pigment (BSP), a key macromolecular component of the traditional food–medicine black sesame, holds potential for improving non-alcoholic fatty liver disease (NAFLD), but its mechanisms remain unclear. We evaluated BSP and fired black sesame pigment (FBSP) in a high-fat diet/streptozotocin-induced NAFLD mouse model. An integrated multi-omics strategy—encompassing network pharmacology, urinary metabolomics, and 16S rRNA sequencing—was employed to identify potential targets and pathways. Key findings were subsequently validated in a human liver organoid model of NAFLD. FBSP treatment significantly alleviated hepatic steatosis and dysfunction in mice. Multi-omics analysis revealed that FBSP reshaped the gut microbiota (increasing Lactobacillus and Bacteroides) and influenced host glycolysis/gluconeogenesis metabolism. Both omics predictions converged on the HIF-1 signaling pathway. In human liver organoids, FBSP reduced lipid accumulation and inflammation, and modulated the expression of core HIF-1 pathway genes. This study demonstrates that FBSP ameliorates NAFLD, potentially through a gut–liver axis mechanism that involves microbiota remodeling and subsequent modulation of the hepatic HIF-1 signaling pathway. Our findings position FBSP as a promising food-derived candidate for NAFLD intervention.