Ru3: a novel ruthenium-based compound overcomes cisplatin resistance in non-small cell lung cancer via the E2F2-IGFBP3-GPX4 pathway

Abstract Cisplatin resistance remains a major hurdle in non-small cell lung cancer (NSCLC) treatment. Here, we designed and synthesized a novel ruthenium-based compound, which selectively kills cisplatin-resistant NSCLC cells while sparing parental cells. Mechanistically, Ru3 triggers mitochondrial damage and reactive oxygen species (ROS) accumulation. In addition, it upregulates the transcription factor E2F2, which directly represses IGFBP3 expression. IGFBP3 normally scavenges ROS via the GPX4 system; thus, E2F2-mediated IGFBP3 suppression disrupts this antioxidant defense, exacerbating ROS levels and cell death. Notably, cisplatin-resistant cells exhibit elevated GPX4 and IGFBP3 expression, making them particularly vulnerable to Ru3. This study elucidates the E2F2-IGFBP3-GPX4 axis as a novel therapeutic vulnerability and highlights Ru3 as a promising agent for refractory NSCLC. Graphical abstract Ru3's Mechanism of Action on Cisplatin Resistant Lung Cancer Cells Ru3 induces mitochondrial damage, which promotes the accumulation of ROS and ultimately triggers cell death. Ru3 upregulates E2F2, enabling it to directly bind to the IGFBP3 promoter and suppress IGFBP3 expression, which inhibits GPX4 expression and further exacerbating lethal ROS accumulation . Treatment with Ru3 resulted in significant cell death in cisplatin-resistant lung cancer cells, yet had a minimal impact on parental lung cancer cells, which attributed to the suppression of the TRX antioxidant system in cisplatin-resistant cells, coupled with an increase in the activity of the GSH antioxidant system.