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

Oct 30, 2025Inflammation research : official journal of the European Histamine Research Society ... [et al.]

Astilbin may reduce acute lung injury by preventing lung cell death through activating NRF2 at the Val608 site

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Abstract

Astilbin (ATB) significantly alleviated acute lung injury in a mouse model.

ATB decreased inflammation caused by lipopolysaccharide (LPS) in acute lung injury.
The compound inhibited ferroptosis in epithelial cells by increasing the expression of GPX4 and xCT.
ATB promoted the movement of NRF2 into the nucleus in LPS-treated cells.
Inhibition of NRF2 reversed the protective effects of ATB on ferroptosis and inflammation.
NRF2 knockout in mice eliminated the protective effects of ATB against acute lung injury.
ATB binds to the Val608 amino acid of NRF2, enhancing its activity.

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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.

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

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