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

IF 9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Apoptosis Pub Date : 2026-10-03 DOI:10.1007/s10495-026-02447-3

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

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引用次数: 0

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

1.
Ru3 induces mitochondrial damage, which promotes the accumulation of ROS and ultimately triggers cell death.
2.
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 .
3.
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.

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Ru3：一种新型钌基化合物通过E2F2-IGFBP3-GPX4途径克服非小细胞肺癌的顺铂耐药。

顺铂耐药仍然是非小细胞肺癌（NSCLC）治疗的主要障碍。在这里，我们设计并合成了一种新的钌基化合物，它可以选择性地杀死顺铂耐药的NSCLC细胞，同时保留亲代细胞。从机制上讲，Ru3触发线粒体损伤和活性氧（ROS）积累。此外，它上调转录因子E2F2，直接抑制IGFBP3的表达。IGFBP3通常通过GPX4系统清除ROS；因此，e2f2介导的IGFBP3抑制破坏了这种抗氧化防御，加剧了ROS水平和细胞死亡。值得注意的是，顺铂耐药细胞表现出GPX4和IGFBP3表达升高，使它们特别容易受到Ru3的影响。本研究阐明了E2F2-IGFBP3-GPX4轴是一种新的治疗易损，并强调Ru3是治疗难治性NSCLC的一种有前景的药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Apoptosis 生物-生化与分子生物学

CiteScore

9.10

自引率

4.20%

发文量

审稿时长

1 months

期刊介绍： Apoptosis, a monthly international peer-reviewed journal, focuses on the rapid publication of innovative investigations into programmed cell death. The journal aims to stimulate research on the mechanisms and role of apoptosis in various human diseases, such as cancer, autoimmune disease, viral infection, AIDS, cardiovascular disease, neurodegenerative disorders, osteoporosis, and aging. The Editor-In-Chief acknowledges the importance of advancing clinical therapies for apoptosis-related diseases. Apoptosis considers Original Articles, Reviews, Short Communications, Letters to the Editor, and Book Reviews for publication.