Rhodium(III)‐Nitroxyl Radical Complex Triggers Dual‐Pronged Disulfidptosis‐Apoptosis in Hepatocellular Carcinoma via Metabolic Sabotage and Redox Catalysis
Abstract
Abstract Hepatocellular carcinoma (HCC) resists apoptosis‐targeting therapies, necessitating the development of agents targeting alternative cell death pathways. Here, we report the discovery of a nitroxyl radical‐conjugated Rh(III) complex ( OG‐Rh ) that triggers dual disulfidptosis and apoptosis via synergistic metabolic sabotage and redox catalysis. OG‐Rh inhibited glucose uptake, depleted NADPH, and induced disulfidptosis, a novel disulfide‐stress‐mediated death, by inducing actin cytoskeleton collapse via pathogenic disulfide over‐crosslinking. Simultaneously, its tumor‐selective superoxide dismutase/peroxidase (SOD)/(POD) mimetic activity converted endogenous O 2 • − and H 2 O 2 into •OH, resulting in redox attacks that suppressed AP‐1 via Mitogen‐activated protein kinases (MAPK)‐SIRT1 and amplified disulfide stress. This dual pathway mechanism overcomes apoptosis resistance and catalytic therapy limitations. In vitro, OG‐Rh showed potent cytotoxicity (IC 50 = 1.0 µM in BEL‐7402 cells) and selectivity (>10‐fold versus normal cells). In vivo, it suppressed tumor growth by 60.9% without systemic toxicity. This work pioneered a strategy via “metabolic sabotage‐redox storm” achieved by a small‐molecule metallodrug, offering a paradigm‐shifting approach against refractory HCC.
Article Details
Authors (12)
Hui‐Chao Lin
Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences Guangxi Normal University Guilin 541004 China
Wen‐Ying Shen
Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences Guangxi Normal University Guilin 541004 China
Jian‐Hua Wei
Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences Guangxi Normal University Guilin 541004 China
Liu‐Lin Chen
Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences Guangxi Normal University Guilin 541004 China
Chun‐Peng Jia
Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences Guangxi Normal University Guilin 541004 China
Zu‐Yu. Mo
Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences Guangxi Normal University Guilin 541004 China
Li‐Xia Wang
Huairou Research Center of Institute of Chemistry Chinese Academy of Sciences Beijing China
Cheng Hou
Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences Guangxi Normal University Guilin 541004 China
Yang‐Han Liu
Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences Guangxi Normal University Guilin 541004 China
Jihu Su
CAS Key Laboratory of Microscale Magnetic Resonance and Department of Physics, School of Physical Sciences
Hong Liang
Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences
Zhen‐Feng Chen
Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences Guangxi Normal University Guilin 541004 China