Citation: Zhengqi SHEN, Hanxue LIU, Lin HOU, Meng REN, Xiangyu DAI, Yating ZHANG, Zhi SU, Chao GE, Xuling XUE, Hongke LIU. A dual-pathway synergistic inhibition strategy based on ruthenium/iridium metal complexes targeting GPX4 and DHODH: Mechanism of directly activating ferroptosis in leukemia cells[J]. Chinese Journal of Inorganic Chemistry, ;2026, 42(2): 271-283. doi: 10.11862/CJIC.20250230 shu

A dual-pathway synergistic inhibition strategy based on ruthenium/iridium metal complexes targeting GPX4 and DHODH: Mechanism of directly activating ferroptosis in leukemia cells

Zhengqi SHEN ¹ ,
Hanxue LIU ¹ ,
Lin HOU ¹ ,
Meng REN ¹ ,
Xiangyu DAI ¹ ,
Yating ZHANG ¹ ,
Zhi SU ¹ ,
Chao GE ² ,
Xuling XUE ^{1, 3,,} ,
Hongke LIU ^{1, 3,,}

1.
School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
2.
School of Chemistry and Environmental Engineering, Yancheng Teachers University, Yancheng, Jiangsu 224007, China
3.
State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210023, China

Corresponding author: Xuling XUE, xuexuling87@163.com Hongke LIU, liuhongke@njnu.edu.cn
Received Date: 14 July 2025
Revised Date: 7 November 2025

Figures(7)

Developing metal-based drugs that exhibit tumor selectivity, exert anti-proliferative effects, and minimize physiological toxicity remains a major challenge in leukemia therapy. In this study, two novel ruthenium- and iridium-based complexes (CS2-Ru and CS2-Ir) were synthesized by conjugating ruthenium/iridium metal precursors with the DHODH (dihydroorotate dehydrogenase) inhibitor CS2. CS2-Ru and CS2-Ir disrupt the intracellular redox balance in human acute promyelocytic leukemia cells (NB-4 cells) by elevating the levels of reactive oxygen species (ROS) and inducing mitochondrial membrane depolarization. In addition to these effects, the complexes also exert a dual-pathway inhibition (GPX4/DHODH) (GPX4=glutathione peroxidase 4), which leads to the abnormal accumulation of lipid peroxides to a lethal threshold and increases the sensitivity of NB-4 cells to ferroptosis.
- ruthenium/iridium complex,
- ferroptosis,
- leukemia treatment,
- DHODH inhibitor
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