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

Authors

Yiting Lu, Shiming Wu, Ying Jiang, Meishu Wang, Xinyu Liao, Jian Zhang, Junqi Xiang, Hua Yang, Min Yu, Jiang Min, Chen Fu, Yunlong Lei

Published in

Apoptosis : an international journal on programmed cell death. Volume 31. Issue 10. Oct 03, 2026. Epub Oct 03, 2026.

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.

PMID:
42829402
Bibliographic data and abstract were imported from PubMed on 04 Oct 2026.

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