A novel anti-acute lung injury mechanism of astilbin: inhibition of epithelial cells ferroptosis by targeting NRF2 activation via binding Val608 site of NRF2.

OBJECTIVE AND DESIGN: Astilbin (ATB) is a newly discovered natural compound with anti-inflammatory and immunomodulatory effects. However, its effects and underlying mechanisms in acute lung injury (ALI) remain unclear.

MATERIAL OR SUBJECTS: An ALI model was established by intratracheal injection of lipopolysaccharide (LPS) into the trachea of C57BL/6 mice. In vitro, MLE-12 cells were stimulated with LPS. ATB was administered as a pretreatment to C57BL/6 mice and MLE-12 cells.

RESULTS: ATB significantly alleviated ALI and suppressed the inflammatory response induced by LPS. Further data suggested that ATB inhibited LPS-induced ferroptosis in epithelial cells by increasing GPX4 and xCT expression. Moreover, ATB promoted NRF2 nuclear translocation in the LPS-treated group, while NRF2 inhibition significantly reversed the protective effects of ATB on ferroptosis and inflammation. NRF2 knockout in vivo abolished the protective effects of ATB against ALI and epithelial cell ferroptosis. Mechanistically, ATB increased NRF2 activity by binding to the Val608 amino acid of NRF2. The effect of ATB in improving ALI and ferroptosis was significantly reduced in NRF2 Val608 mutant mice.

CONCLUSION: ATB mitigated ALI by suppressing epithelial cell ferroptosis and activating the NRF2 pathway via binding to Val608 of NRF2.