[Research advancements on the role of nuclear factor E2-related factor 2 and its related pathways in sepsis-induced...

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, characterized by high morbidity and mortality. Acute lung injury (ALI) is one of the earliest and most frequent complications of sepsis. Inflammatory response, oxidative stress, and ferroptosis are important pathogenic mechanisms in sepsis-induced ALI. Nuclear factor E2-related factor 2 (Nrf2), an essential antioxidant transcription factor, plays a pivotal role in alleviating lung injury by regulating multiple signaling pathways. This review systematically elaborates on the structure of Nrf2 and its protective role in sepsis-induced ALI, with a focus on how the Nrf2/heme oxygenase-1 (HO-1), Kelch-like ECH-associated protein 1 (Keap1)/Nrf2, silent information regulator 1 (Sirt1)/Nrf2, and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/Nrf2 pathways collaboratively alleviate oxidative stress, suppress the release of inflammatory factors, and inhibit ferroptosis by regulating downstream target genes such as HO-1, glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11). Furthermore, the article summarizes the lung-protective effects demonstrated by various agents, including β-globin, curcumin, and hyperoside, through the specific activation of these pathways, providing a solid experimental basis for optimizing related treatment strategies and developing new drugs. This review aims to offer a deeper understanding of the biological significance of Nrf2 in sepsis-induced ALI and to provide theoretical support and research insights for future targeted clinical therapies.