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

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.