Rhodium(III)-Nitroxyl Radical Complex Triggers Dual-Pronged Disulfidptosis-Apoptosis in Hepatocellular Carcinoma via Metabolic Sabotage and Redox Catalysis.

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• and HO 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 = 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.