Abstract：
Chemotherapy agents for lung cancer often cause apoptotic resistance in cells, leading to suboptimal therapeutic outcomes. FIN56 can be a potential treatment for lung cancer as it induces non-apoptotic cell death, namely ferroptosis. However, a bottleneck exists in FIN56-induced ferroptosis treatment; specifically, FIN56 fails to induce sufficient oxidative stress and may even trigger the defense system against ferroptosis, resulting in poor therapeutic efficacy. To overcome this, this study proposed a strategy of co-delivering FIN56 and piperlongumine to enhance the ferroptosis treatment effect by increasing oxidative stress and connecting with the autophagy pathway. FIN56 and piperlongumine were encapsulated into silk fibroin-based nano-disruptors, named FP@SFN. Characterization results showed that the particle size of FP@SFN was in the nanometer range and the distribution was uniform. Both in vivo and in vitro studies demonstrated that FP@SFN could effectively eliminate A549 cells and inhibit subcutaneous lung cancer tumors. Notably, ferroptosis and autophagy were identified as the main cell death pathways through which the nano-disruptors increased oxidative stress and facilitated cell membrane rupture. In conclusion, nano-disruptors can effectively enhance the therapeutic effect of ferroptosis treatment for lung cancer through the ferroptosis-autophagy synergy mechanism, providing a reference for the development of related therapeutics.
摘要：
肺癌的化疗药物通常会导致细胞凋亡抵抗，导致次优的治疗结果。FIN56可能是肺癌的潜在治疗方法，因为它诱导非凋亡性细胞死亡。即铁性。然而,FIN56诱导的铁中毒治疗存在瓶颈；特别是，FIN56无法诱导足够的氧化应激，甚至可能触发防御系统对抗铁凋亡，导致治疗效果不佳。为了克服这一点，这项研究提出了一种联合递送FIN56和胡椒隆胺的策略，通过增加氧化应激并与自噬途径连接来增强铁凋亡治疗效果。FIN56和胡椒隆胺被封装到基于丝素蛋白的纳米破坏剂中，名为FP@SFN。表征结果表明，FP@SFN的粒径在纳米范围内，分布均匀。体内和体外研究均表明FP@SFN可以有效清除A549细胞并抑制皮下肺癌肿瘤。值得注意的是,铁凋亡和自噬被确定为主要的细胞死亡途径，通过这些途径，纳米破坏剂增加氧化应激并促进细胞膜破裂。总之,纳米干扰物通过铁凋亡-自噬协同机制,可有效增强铁凋亡治疗肺癌的疗效,为相关疗法的发展提供参考。
