Targeting FDX1 with oridonin triggers cuproptosis and inhibits tumor progression in nasopharyngeal carcinoma.

Abstract

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.