Yan Liang, Feng Qi, Sun Yong, Zeng Bo-Ning, Sun Chuan-Chuan, Zha Qing-Bing, Zhang Xing-Wang, Zhu Shi-Ping
Guangdong Provincial Key Laboratory of Spine and Spinal Cord Reconstruction, The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan 517000, China.
Department of Chinese Traditional Medicine, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
Biomater Res. 2025 Aug 12;29:0236. doi: 10.34133/bmr.0236. eCollection 2025.
Ferroptosis, a form of lipid peroxidation-mediated cell death, plays a critical role in acute kidney injury (AKI) progression. Tripterine is an active component isolated from traditional medicinal herbs and exhibits diverse biological and pharmacological activities. However, poor bioavailability and cytotoxicity of tripterine has limited its further clinical application, and the underlying action mechanism of tripterine against AKI remains largely unknown. This study aimed to overcome these shortcomings by formulating tripterine into selenized phytosomes and to investigate the therapeutic effects of selenized tripterine phytosomes (Se@Tri-PTs) on ferroptosis-associated AKI. The data showed that Se@Tri-PTs improved the antioxidant capacity of tripterine while reducing its cytotoxicity. Upon erastin or RSL3 stimulation, Se@Tri-PTs maintained intracellular glutathione levels, decreased lipid ROS generation, and suppressed ferroptosis. Mechanistically, Se@Tri-PTs blocked autophagy-mediated degradation of glutathione peroxidase 4 (GPX4), thereby suppressing ferroptosis. Furthermore, Se@Tri-PTs maintained dual-specificity protein phosphatase 1 (DUSP1) protein levels in erastin-stimulated cells, and knockdown reversed Se@Tri-PTs-mediated inhibition of autophagy and ferroptosis. In line with in vitro results, Se@Tri-PTs administration obviously attenuated folic acid-induced AKI and autophagy-dependent ferroptosis in mice. Collectively, these results indicated that Se@Tri-PTs ameliorated ferroptosis and AKI by preserving DUSP1 levels to block autophagy-mediated degradation of GPX4, highlighting their potential in treating ferroptosis-related diseases.
铁死亡是一种脂质过氧化介导的细胞死亡形式，在急性肾损伤（AKI）进展中起关键作用。雷公藤红素是从传统草药中分离出的一种活性成分，具有多种生物学和药理活性。然而，雷公藤红素的低生物利用度和细胞毒性限制了其进一步的临床应用，雷公藤红素抗AKI的潜在作用机制仍不清楚。本研究旨在通过将雷公藤红素制成硒化植物脂质体来克服这些缺点，并研究硒化雷公藤红素植物脂质体（Se@Tri-PTs）对铁死亡相关AKI的治疗作用。数据显示，Se@Tri-PTs提高了雷公藤红素的抗氧化能力，同时降低了其细胞毒性。在erastin或RSL3刺激下，Se@Tri-PTs维持细胞内谷胱甘肽水平，减少脂质ROS生成，并抑制铁死亡。机制上，Se@Tri-PTs阻断自噬介导的谷胱甘肽过氧化物酶4（GPX4）降解，从而抑制铁死亡。此外，Se@Tri-PTs维持erastin刺激细胞中双特异性蛋白磷酸酶1（DUSP1）的蛋白水平，敲低DUSP1可逆转Se@Tri-PTs介导的自噬和铁死亡抑制。与体外结果一致，给予Se@Tri-PTs可明显减轻小鼠叶酸诱导的AKI和自噬依赖性铁死亡。总的来说，这些结果表明，Se@Tri-PTs通过维持DUSP1水平来阻断自噬介导的GPX4降解，从而改善铁死亡和AKI，突出了它们在治疗铁死亡相关疾病中的潜力。
