Brazilin alleviates acute lung injury via inhibition of ferroptosis through the SIRT3/GPX4 pathway

Dec 25, 2024Apoptosis : an international journal on programmed cell death

Brazilin reduces acute lung injury by blocking cell death through the SIRT3/GPX4 protective pathway

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Abstract

Brazilin pretreatment significantly mitigated LPS-induced lung injury and inflammation.

Ferroptosis, a type of cell death linked to iron, is associated with acute lung injury.
Brazilin may inhibit mitochondrial oxidative stress and ferroptosis in lung tissues.
Sirtuin 3 (SIRT3) is identified as a key target of brazilin in reducing lung injury.
Overexpression of SIRT3 reproduced the protective effects of brazilin against lung inflammation.
SIRT3 enhances the function of glutathione peroxidase 4 (GPX4) by promoting its mitochondrial movement and reducing its acetylation.
Mutating a specific acetylation site on GPX4 decreases oxidative stress and ferroptosis, potentially alleviating lung injury.

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Ferroptosis is a novel type of programmed cell death dependent on iron and is characterized by the accumulation of lipid peroxides, which is involved in acute lung injury (ALI). Brazilin, an organic compound known for its potent antioxidant and anti-inflammatory properties, has not been thoroughly studied for its potential impact on lipopolysaccharide (LPS)-induced ALI. Here, we found that pretreatment of brazilin mitigated LPS-induced lung injury and inflammation by inhibiting mitochondrial oxidative stress and ferroptosis, both in vivo and in vitro. Sirtuin 3 (SIRT3) was identified as a downstream target of brazilin, and overexpression of SIRT3 mirrored the protective effects of brazilin against LPS-induced ALI. Additionally, SIRT3 contributed to the upregulation, mitochondrial translocation and deacetylation of glutathione peroxidase 4 (GPX4). Through screening potential acetylation sites on GPX4, we identified lysine 148 (K148) as the residue deacetylated by SIRT3. Mutating the acetylation site of GPX4 within mitochondria (mitoGPX4-K148R) reduced LPS or SIRT3 knockdown-induced GPX4 acetylation, oxidative stress, and ferroptosis, ultimately ameliorating ALI. In conclusion, our study demonstrates the beneficial effects of brazilin in treating LPS-induced ALI. Brazilin enhances SIRT3 expression, which in turn deacetylates and facilitates the mitochondrial translocation of GPX4, thereby reducing mitochondrial oxidative stress and ferroptosis. These findings suggest that the SIRT3/GPX4 pathway may represent a critical mechanism, and brazilin emerges as a promising therapeutic candidate for ALI.

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Brazilin alleviates acute lung injury via inhibition of ferroptosis through the SIRT3/GPX4 pathway

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