Plant sterol ester of α-linolenic acid protects against ferroptosis in metabolic dysfunction-associated fatty liver disease via activating the Nrf2 signaling pathway

Increasing evidence indicates that ferroptosis contributes to the occurrence and development of metabolic dysfunction-associated fatty liver disease (MAFLD). This study aimed to investigate the improvement effect of plant sterol ester of α-linolenic acid (PS-ALA) on ferroptosis in hepatocytes and further elucidate the underlying molecular mechanism, focusing on the regulation of Nrf2 signaling. We found that PS-ALA ameliorated liver iron overload and reduced ROS generation and lipid peroxides (MDA and 4-HNE) production both in mice fed a high-fat diet and HepG2 cells induced by oleic acid/erastin. In addition, our data revealed the ability of PS-ALA to protect against ferroptosis as evidenced by diminished PI staining positive cells, enhanced SLC7A11/GPX4 antioxidant system, and decreased protein expression of the key enzymes catalyzing lipid peroxidation (ACSL4, ALOX5ap, and PTGS2). Mechanistically, PS-ALA promoted the nuclear translocation of Nrf2 and enhanced the protein expression of HO-1 and NQO1. Silence of Nrf2 by siRNA markedly weakened the protected effect of PS-ALA on ferroptosis. Our findings indicate that inhibition of ferroptosis via activating the Nrf2 signal pathway is involved in the protective role of PS-ALA on MAFLD and highlight the potential of PS-ALA as a prevention and treatment strategy for MAFLD.