靶向FDX1的冬凌草甲素触发铜死亡并抑制鼻咽癌肿瘤进展

文献信息

中文摘要

鼻咽癌（NPC）是一种侵袭性恶性肿瘤，治疗选择有限，凸显了对新型抗肿瘤药物的迫切需求。冬凌草甲素是一种来源于碎米桠（Isodon rubescens）的生物活性二萜类化合物，已显示出广谱抗癌活性。然而，其在鼻咽癌中的确切作用在很大程度上仍未明确。本研究探讨了冬凌草甲素的抗鼻咽癌作用及其潜在机制。在体外，冬凌草甲素显著抑制鼻咽癌细胞增殖和迁移，同时增强对铜离子载体诱导的细胞死亡的敏感性。在机制上，转录组分析及后续验证表明，冬凌草甲素在转录水平上调FDX1——铜死亡的关键调节因子，并以高亲和力直接结合FDX1。FDX1敲低显著削弱了冬凌草甲素诱导的铜死亡，表现为DLAT寡聚化/聚集减少（提示脂酰化DLAT聚集减少）以及对铜离子载体的耐药性，证实FDX1是冬凌草甲素的关键下游效应因子。在体内，冬凌草甲素显著抑制异种移植模型中的肿瘤生长，并伴随瘤内铜水平升高以及FDX1和DLAT表达增加。总之，这些发现表明冬凌草甲素通过靶向FDX1诱导铜死亡而发挥抗鼻咽癌活性，凸显冬凌草甲素作为鼻咽癌治疗的有前景的候选药物。

英文摘要

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with limited therapeutic options, highlighting the urgent need for novel anti-tumor agents. Oridonin, a bioactive diterpenoid derived from Isodon rubescens, has demonstrated broad-spectrum anticancer activities. However, its precise role in NPC remains largely undefined. This study investigated the anti-NPC effects of oridonin and its underlying mechanisms. In vitro, oridonin significantly inhibited NPC cell proliferation and migration, while enhancing sensitivity to copper ionophore-induced cell death. Mechanistically, transcriptomic analysis and subsequent validation revealed that oridonin transcriptionally upregulates FDX1, a key regulator of cuproptosis, and directly binds to FDX1 with high affinity. FDX1 knockdown substantially abrogated oridonin-induced cuproptosis, as evidenced by reduced DLAT oligomerization/aggregation (indicative of reduced lipoylated DLAT aggregation) and resistance to copper ionophores, confirming that FDX1 is a critical downstream effector of oridonin. In vivo, oridonin significantly suppressed tumor growth in xenograft models, accompanied by elevated intra-tumoral copper levels and increased FDX1 and DLAT expression. Collectively, these findings demonstrate that oridonin exerts anti-NPC activity by targeting FDX1 to induce cuproptosis, highlighting oridonin as a promising therapeutic candidate for NPC treatment.