Rhodium(III)-Nitroxyl Radical Complex Triggers Dual-Pronged Disulfidptosis-Apoptosis in Hepatocellular Carcinoma via...

Area of Science:

• Medicinal Chemistry
• Oncology
• Biochemistry

Background:

• Hepatocellular carcinoma (HCC) exhibits resistance to apoptosis-targeting treatments.
• There is a critical need for novel therapeutic agents targeting alternative cell death pathways in HCC.

Purpose of the Study:

• To discover and characterize a novel nitroxyl radical-conjugated Rh(III) complex (OG-Rh) for treating HCC.
• To investigate the dual mechanism of action of OG-Rh, involving disulfidptosis and apoptosis.

Main Methods:

• Synthesis and characterization of the OG-Rh complex.
• In vitro cytotoxicity assays and selectivity evaluation against normal cells.
• In vivo tumor growth suppression studies and toxicity assessments.
• Analysis of metabolic sabotage (glucose uptake, NADPH depletion) and redox catalysis (SOD/POD mimetic activity).

Main Results:

• OG-Rh effectively inhibits glucose uptake and depletes NADPH, inducing disulfidptosis via actin cytoskeleton collapse.
• The complex exhibits tumor-selective superoxide dismutase/peroxidase mimetic activity, generating hydroxyl radicals (•OH) and amplifying disulfide stress.
• OG-Rh demonstrates potent in vitro cytotoxicity (IC50 = 1.0 µM) and selectivity (>10-fold) against HCC cells.
• In vivo studies show significant tumor growth suppression (60.9%) without systemic toxicity.

Conclusions:

• The OG-Rh complex represents a novel metallodrug strategy employing "metabolic sabotage-redox storm" for HCC treatment.
• This dual-pathway mechanism effectively overcomes apoptosis resistance and limitations of catalytic therapies.
• The findings offer a paradigm-shifting approach for refractory hepatocellular carcinoma.