Yan Xiaopei, Xu Li, Qi Chang, Chang Yiling, Zhang Juanjuan, Li Ning, Shi Baoyu, Guan Bo, Hu Siming, Huang Chao, Wang Hui, Chen Ying, Xu Xiao, Lu Jian, Xu Guopeng, Chen Chao, Li Su, Chen Yuqiong
Department of Respiratory Medicine, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China.
Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Apoptosis. 2025 Apr;30(3-4):768-783. doi: 10.1007/s10495-024-02058-w. Epub 2024 Dec 25.
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.
铁死亡是一种新型的程序性细胞死亡，依赖于铁，其特征是脂质过氧化物的积累，它参与急性肺损伤（ALI）。巴西苏木素是一种以其强大的抗氧化和抗炎特性而闻名的有机化合物，其对脂多糖（LPS）诱导的ALI的潜在影响尚未得到充分研究。在这里，我们发现巴西苏木素预处理通过在体内和体外抑制线粒体氧化应激和铁死亡，减轻了LPS诱导的肺损伤和炎症。沉默调节蛋白3（SIRT3）被确定为巴西苏木素的下游靶点，SIRT3的过表达反映了巴西苏木素对LPS诱导的ALI的保护作用。此外，SIRT3有助于谷胱甘肽过氧化物酶4（GPX4）的上调、线粒体易位和去乙酰化。通过筛选GPX4上潜在的乙酰化位点，我们确定赖氨酸148（K148）是被SIRT3去乙酰化的残基。在线粒体内突变GPX4的乙酰化位点（mitoGPX4-K148R）可降低LPS或SIRT3敲低诱导的GPX4乙酰化、氧化应激和铁死亡，最终改善ALI。总之，我们的研究证明了巴西苏木素在治疗LPS诱导的ALI中的有益作用。巴西苏木素增强SIRT3表达，进而使GPX4去乙酰化并促进其线粒体易位，从而减少线粒体氧化应激和铁死亡。这些发现表明，SIRT3/GPX4途径可能是一个关键机制，巴西苏木素有望成为治疗ALI的候选药物。
