Effects of Bound Polyphenols on Lipid Metabolism in HepG2 Cells and Glucose-Induced C. elegans Models

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent liver disease associated with insulin resistance and hepatic lipid accumulation. Polyphenols have attracted considerable attention for their hepatoprotective and lipid-lowering activities. Our previous studies characterized a bound polyphenol extracted from the inner shell of foxtail millet (BPIS) and identified its major active components. In the present study, we investigated the molecular mechanisms underlying its biological activity using HepG2 cells and Caenorhabditis elegans. BPIS activated AMPK signaling, normalized intracellular glutathione (GSH) levels, and upregulated SLC7A11 and GPX4, suggesting modulation of ferroptosis-related pathways and improved cellular redox homeostasis. BPIS also alleviated endoplasmic reticulum stress by increasing GRP78 expression, inhibiting DRAK2, and regulating the ERK pathway, thereby improving the regulation of key lipid-metabolism-related signaling pathways, including SREBP1c, SCD1, CD36, FASN, and CPT1A. Consistent with these findings, BPIS reduced glucose- and free fatty acid-induced lipid accumulation and improved lipid-related phenotypes in C. elegans. Overall, BPIS attenuated hepatic steatosis through modulation of ferroptosis-related markers, endoplasmic reticulum stress, and lipid metabolism. These findings provide new mechanistic insights into the biological activities of BPIS and support its potential application as a nutraceutical ingredient for the prevention and management of MASLD.