Astaxanthin attenuates ferroptosis via Keap1-Nrf2/HO-1 signaling pathways in LPS-induced acute lung injury

Ferroptosis is a form of regulated nonapoptotic cell death associated with iron-dependent lipid peroxidation. Previous studies have shown that ferroptosis is involved in the occurrence and development of acute lung injury (ALI). In this study, a systems pharmacology approach was performed through the overall process of target acquisition, network construction, and further analysis. Then, the effects of astaxanthin on LPS-induced inflammation and ferroptosis were investigated in RAW264.7 cells induced by LPS in vitro and ALI mice induced by LPS in vivo. The enrichment analysis of astaxanthin-target gene is closely related to the occurrence and development mechanism of ferroptosis. GO and KEGG enrichment analysis of astaxanthin acting on ALI found that these intersection genes are associated with ALI inflammatory pathway. In addition, astaxanthin can effectively inhibit LPS-induced production of pro-inflammatory cytokines and ferroptosis in RAW264.7 cells. Consistently, administration of astaxanthin protected mice against LPS-induced ALI and significantly decreased the extent of lung edema, inflammatory cells infiltration, and ferroptosis in vivo, and Keap1-Nrf2/HO-1 pathway is involved in astaxanthin inhibits LPS-induced ALI and ferroptosis. Taken together, these results demonstrate that astaxanthin inhibit inflammation and ferroptosis by regulating Keap1-Nrf2/HO-1 pathway to reduce LPS-induced ALI.