Department of Neurology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.
School of Basic Medical Sciences, Wannan Medical College, Wuhu, China.
J Cell Mol Med. 2024 Sep;28(17):e70018. doi: 10.1111/jcmm.70018.
Ferroptosis, an iron-dependent form of cell death, plays a crucial role in the progression of liver injury in Wilson's disease (WD). Gandouling (GDL) has emerged as a potential therapeutic agent for preventing and treating liver injury in WD. However, the precise mechanisms by which GDL mitigates ferroptosis in WD liver injury remain unclear. In this study, we discovered that treating Toxic Milk (TX) mice with GDL effectively decreased liver copper content, corrected iron homeostasis imbalances, and lowered lipid peroxidation levels, thereby preventing ferroptosis and improving liver injury. Bioinformatics analysis and machine learning algorithms identified Hspb1 as a pivotal regulator of ferroptosis. GDL treatment significantly upregulated the expression of HSPB1 and its upstream regulatory factor HSF1, thereby activating the HSF1/HSPB1 pathway. Importantly, inhibition of this pathway by NXP800 reversed the protective effects of GDL on ferroptosis in the liver of TX mice. In conclusion, GDL shows promise in alleviating liver injury in WD by inhibiting ferroptosis through modulation of the HSF1/HSPB1 pathway, suggesting its potential as a novel therapeutic agent for treating liver ferroptosis in WD.
铁死亡是一种依赖铁的细胞死亡形式，在威尔逊病 (WD) 肝损伤的进展中起着关键作用。肝豆灵 (GDL) 已成为预防和治疗 WD 肝损伤的潜在治疗药物。然而，GDL 减轻 WD 肝损伤中铁死亡的确切机制尚不清楚。在这项研究中，我们发现用 GDL 治疗 Toxic Milk (TX) 小鼠可有效降低肝铜含量，纠正铁平衡失调，并降低脂质过氧化水平，从而防止铁死亡并改善肝损伤。生物信息学分析和机器学习算法确定 Hspb1 是铁死亡的关键调节因子。GDL 处理显著上调 HSPB1 及其上游调节因子 HSF1 的表达，从而激活 HSF1/HSPB1 通路。重要的是，通过 NXP800 抑制该途径可逆转 GDL 对 TX 小鼠肝铁死亡的保护作用。总之，GDL 通过调节 HSF1/HSPB1 通路抑制铁死亡缓解 WD 中的肝损伤，表明其作为治疗 WD 肝铁死亡的新型治疗药物的潜力。
