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Here, we report the discovery of a nitroxyl radical\u2010conjugated Rh(III) complex (\n                    <jats:bold>OG\u2010Rh<\/jats:bold>\n                    ) that triggers dual disulfidptosis and apoptosis via synergistic metabolic sabotage and redox catalysis.\n                    <jats:bold>OG\u2010Rh<\/jats:bold>\n                    inhibited glucose uptake, depleted NADPH, and induced disulfidptosis, a novel disulfide\u2010stress\u2010mediated death, by inducing actin cytoskeleton collapse via pathogenic disulfide over\u2010crosslinking. Simultaneously, its tumor\u2010selective superoxide dismutase\/peroxidase (SOD)\/(POD) mimetic activity converted endogenous O\n                    <jats:sub>2<\/jats:sub>\n                    \u2022\n                    <jats:sup>\u2212<\/jats:sup>\n                    and H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    into \u2022OH, resulting in redox attacks that suppressed AP\u20101 via Mitogen\u2010activated protein kinases (MAPK)\u2010SIRT1 and amplified disulfide stress. This dual pathway mechanism overcomes apoptosis resistance and catalytic therapy limitations. In vitro,\n                    <jats:bold>OG\u2010Rh<\/jats:bold>\n                    showed potent cytotoxicity (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u00a0=\u00a01.0 \u00b5M in BEL\u20107402 cells) and selectivity (&gt;10\u2010fold versus normal cells). In vivo, it suppressed tumor growth by 60.9% without systemic toxicity. This work pioneered a strategy via \u201cmetabolic sabotage\u2010redox storm\u201d achieved by a small\u2010molecule metallodrug, offering a paradigm\u2010shifting approach against refractory HCC.\n                  <\/jats:p>","DOI":"10.1002\/anie.202517864","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T07:01:12Z","timestamp":1764054072000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Rhodium(III)\u2010Nitroxyl Radical Complex Triggers Dual\u2010Pronged Disulfidptosis\u2010Apoptosis in Hepatocellular Carcinoma via Metabolic Sabotage and Redox Catalysis"],"prefix":"10.1002","volume":"65","author":[{"given":"Hui\u2010Chao","family":"Lin","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen\u2010Ying","family":"Shen","sequence":"additional","affiliation":[{"name":"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"},{"name":"Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy Guilin Medical University  Guilin 541199 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian\u2010Hua","family":"Wei","sequence":"additional","affiliation":[{"name":"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"},{"name":"Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy Guilin Medical University  Guilin 541199 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu\u2010Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun\u2010Peng","family":"Jia","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zu\u2010Yu.","family":"Mo","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li\u2010Xia","family":"Wang","sequence":"additional","affiliation":[{"name":"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 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