2. Academic Validation
  3. Brazilin alleviates acute lung injury via inhibition of ferroptosis through the SIRT3/GPX4 pathway

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

  • Apoptosis. 2024 Dec 25. doi: 10.1007/s10495-024-02058-w.
Xiaopei Yan # 1,  Li Xu # 1,  Chang Qi # 2,  Yiling Chang # 3,  Juanjuan Zhang 1,  Ning Li 1,  Baoyu Shi 1,  Bo Guan 4,  Siming Hu 1,  Chao Huang 5,  Hui Wang 1,  Ying Chen 1,  Xiao Xu 1,  Jian Lu 6,  Guopeng Xu 1,  Chao Chen 7,  Su Li 8,  Yuqiong Chen 9
Affiliations

Affiliations

  • 1 Department of Respiratory Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China.
  • 2 Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 3 The Affiliated Taizhou People's Hospital of Nanjing Medical University, Jiangsu, China.
  • 4 Department of Geriatrics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China.
  • 5 Ministry of Science and Technology, Public Experimental Department, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China.
  • 6 Department of Emergency, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China.
  • 7 Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215000, Jiangsu, China. chenchao120218@163.com.
  • 8 Department of Cardiology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China. li.su@zs-hospital.sh.cn.
  • 9 Department of Cardiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, 215000, Jiangsu, China. cosmoscyq@163.com.
  • # Contributed equally.
PMID: 39720978 DOI: 10.1007/s10495-024-02058-w
Abstract

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.

Keywords

Acetylation; Acute lung injury; Brazilin; Ferroptosis; GPX4; SIRT3.

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