Curcumin-Loaded Liposomes (hPLipo/Cur) with Liver-Targeting Properties for Efficient NAFLD Treatment by Alleviating Mitochondrial ROS-Mediated Ferroptosis via NRF2 Pathway

NAFLD is a rising health problem worldwide with unsatisfied therapies. Curcumin has an ameliorative but limited effect on NAFLD due to its low water solubility. In this study, we innovatively establish the high-PC-content liposome-loaded curcumin (hPLipo/Cur) with liver-targeting properties for NAFLD therapy. hPLipo/Cur, composed of DSPC, cholesterol, and DSPE-PEG₂₀₀₀, has better biocompatibility and water solubility and is loaded with curcumin with high efficiency. hPLipo/Cur is superior to curcumin in improving hepatic histology, as evidenced by reducing lipid deposition and macrophage infiltration in steatohepatitis. Mechanistically, hPLipo/Cur reduces NRF2 degradation and promotes the nuclear translocation of NRF2, as well as the expression of downstream antioxidant genes. The activated NRF2 pathway reduces cellular oxidative stress and the generation of mitochondrial ROS, thereby reducing the accumulation of lipid peroxides and inhibiting ferroptosis in steatohepatitis. In conclusion, hPLipo/Cur reduces mitochondrial ROS-mediated ferroptosis by enhancing the NRF2 pathway to alleviate steatohepatitis, providing a promising strategy for NAFLD treatment.