Glycyrrhetinic acid alleviates LPS-induced acute lung injury and is associated with modulation of Keap1-Nrf2 signaling and ferroptosis.

Glycyrrhetinic acid, a substance extracted from licorice, has several pharmacological activities, such as anti-inflammatory and antioxidant effects and antiviral properties. Acute lung injury (ALI) represents a significant contributor to morbidity and mortality associated with respiratory disorders, marked by the presence of lung edema, interstitial neutrophilic infiltration, and dysfunction of intravascular and endothelial barriers, ultimately leading to respiratory failure. The present study aimed to investigate the effects of glycyrrhetinic acid on LPS-induced ALI. Glycyrrhetinic acid pretreatment significantly attenuated LPS-induced pulmonary edema, inflammatory cell infiltration, and alveolar wall thickening, while reducing proinflammatory cytokines (TNF-α, IL-1β) in BALF and serum. The transcriptomics analysis predicted that the ferroptosis pathways might be involved in the underlying mechanism of glycyrrhetinic acid against ALI, with validation experiments demonstrating glycyrrhetinic acid-mediated restoration of ferroptosis markers. Mechanistically, glycyrrhetinic acid suppressed Keap1 expression and activated Nrf2, enhancing antioxidant responses and inhibiting lipid peroxidation. These findings suggest that glycyrrhetinic acid may modulate inflammation and ferroptosis, with Keap1-Nrf2 signaling potentially contributing to its protective effects. The study suggests that targeting ferroptosis may represent a potential strategy for ALI management, with glycyrrhetinic acid emerging as a promising pharmacological candidate.