Photoinduction of Ferroptosis and cGAS-STING Activation by a H2S-Responsive Iridium(III) Complex for Cancer-Specific Therapy

  • J Med Chem. 2024 Sep 26;67(18):16235-16247. doi: 10.1021/acs.jmedchem.4c01065.
Yi Li  1 ,  Ben Liu  1  2 ,  Yue Zheng  3 ,  Meng Hu  1  2 ,  Liu-Yi Liu  3 ,  Cai-Rong Li  2 ,  Wei Zhang  2 ,  Yu-Xiao Lai  2 ,  Zong-Wan Mao  3
Affiliations
  • 1. Key Laboratory of Theoretical Organic Chemistry and Function Molecule, Ministry of Education, School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201, P. R. China.
  • 2. Centre for Translational Medicine Research & Development, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, P. R. China.
  • 3. MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, IGCME, Sun Yat-Sen University, Guangzhou 510275, P. R. China.
PMID: 39250558 DOI: 10.1021/acs.jmedchem.4c01065
Abstract

Triggering Ferroptosis represents a promising Anticancer therapeutic strategy, but the development of a selective Ferroptosis inducer for cancer-specific therapy remains a great challenge. Herein, a H2S-responsive iridium(III) complex NA-Ir has been well-designed as a Ferroptosis inducer. NA-Ir could selectively light up H2S-rich Cancer cells, primarily localize in mitochondria, intercalate into mitochondrial DNA (mtDNA), and induce mtDNA damage, exhibiting higher Anticancer activity under light irradiation. Mechanistic studies showed that NA-Ir-mediated PDT triggered lipid peroxidation and Glutathione Peroxidase 4 downregulation through ROS production and GSH depletion, resulting in Ferroptosis through multiple pathways. Moreover, the intense mtDNA damage can activate the cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) pathway, leading to ferritinophagy and further Ferroptosis. RNA-sequencing analysis showed that NA-Ir-mediated PDT mainly affects the expression of genes related to Ferroptosis, Autophagy, and Cancer immunity. This study demonstrates the first cancer-specific example with Ferroptosis and cGAS-STING activation, which provides a new strategy for multimodal synergistic therapy.

Products