GPX4-Targeting Phenolato ZrIV Complexes Induce Ferroptosis and Lysosome-Dependent Cell Death for Immunotherapy of Chemoresistant Cancer

  • J Med Chem. 2026 Jul 9;69(13):15974-15995. doi: 10.1021/acs.jmedchem.6c01164.
Tiankun Zhao  1 ,  Jialiu Zhao  1 ,  Jing Ma  1 ,  Dongyu Mei  1 ,  Yinan Ding  1 ,  Qi-Pin Qin  2  3 ,  Isabel Correia  4 ,  Hong Liang  3
Affiliations
  • 1. School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou 730050, China.
  • 2. Guangxi Key Laboratory of Agricultural Resources Chemistry and Biotechnology, School of Chemistry and Food Science, Yulin Normal University, Yulin 537000, China.
  • 3. State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, P. R. China.
  • 4. Centro de Química Estrutural and Departamento de Engenharia Química, Institute of Molecular Sciences, Instituto Superior Técnico, Universidade de Lisboa, Avenida Rovisco Pais 1, 1049-001 Lisboa, Portugal.
PMID: 42350927 DOI: 10.1021/acs.jmedchem.6c01164
Abstract

Here, we report three classes of dipicolinic acid (Dipic)-stabilized diaminobis(phenolato) ZrIV bis-chelates with high aqueous stability and potent antiproliferative activity. Among them, complex 1t exhibited strong cytotoxicity against multiple Cancer cell lines, including cisplatin-resistant Hep G2/DDP cells, while showing low toxicity toward normal LO2 cells. Mechanistic studies demonstrated that 1t preferentially accumulates in mitochondria and lysosomes, leading to excessive ROS generation, lipid peroxidation, mitochondrial membrane depolarization, and GPX4 downregulation, consistent with Ferroptosis induction. Concurrently, lysosomal iron accumulation, membrane permeabilization, and CTSB/Caspase-8 activation indicated the involvement of lysosome-dependent cell death, further exacerbating oxidative stress. Moreover, 1t triggered immunogenic cell death and activated cGAS-STING signaling. In vivo, 1t significantly suppressed tumor growth in a Hep G2/DDP xenograft model with minimal systemic toxicity, highlighting Dipic-stabilized ZrIV bis-chelates as promising candidates for the treatment of chemoresistant cancers.

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