Fucoxanthin Prevents Lipopolysaccharide-Induced Acute Lung Injury by Inhibiting Ferroptosis via Nrf2/STAT3 and Glutathione Pathways.

Abstract

Fucoxanthin, sourced from marine brown algae, diatoms, and microalgae, is known to possess strong anti-inflammatory activity. To explore its intrinsic mechanism, we investigated its effects on acute lung injury (ALI) with an experiment using lipopolysaccharide (LPS)-induced RAW264.7 inflammatory cells and an ALI animal model. Fucoxanthin was observed to suppress the inflammatory response in vitro by reducing the levels of inflammatory markers such as PTGS2, iNOS, and TNF-α. Network pharmacology analysis revealed that fucoxanthin could potentially inhibit ferroptosis through 10 targets, including PTGS2. This was further confirmed by the dose-dependent increase in lipid peroxidation and Fe[Formula: see text] levels caused by fucoxanthin, as well as the regulation of ferroptosis-associated proteins ACSL4, SLC7A11, GPX4, and FTH1. Furthermore, fucoxanthin was found to significantly reduce the inflammatory response and ferroptosis in a mouse model of LPS-induced ALI. Further research revealed that fucoxanthin could raise the levels of [Formula: see text]-Glu-Cys and carbamyl glycine, which are intermediate metabolites of glutathione synthesis, in RAW264.7 cells. This implies that fucoxanthin can inhibit ferroptosis by regulating the [Formula: see text]-glutamyl cycle. Our research demonstrated that fucoxanthin is capable of activating phosphorylated STAT3 and raising the expression of Nrf2 and HO-1, implying that fucoxanthin may be able to prevent LPS-induced ferroptosis in ALI through the Nrf2/STAT3 pathway.