A Biomimetic Manganese Complex Synergistically Disables Antioxidant Defenses and Amplifies Oxidative Stress to Potentiate Ferroptosis in Hepatocellular Carcinoma

ABSTRACT Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options in advanced stages. Here, we report a biomimetic manganese‐based complex (MSM) engineered to selectively target HCC cells and potently induce ferroptosis through a dual mechanism: disabling cellular antioxidant defenses and amplifying oxidative stress. The complex undergoes glutathione (GSH)‐triggered disassembly within tumor cells, releasing Mn 2+ ions and sulfasalazine (SAS). Mn 2+ catalyzes a Fenton‐like reaction, generating a burst of reactive oxygen species (ROS), while SAS inhibits the System Xc − /GSH/GPX4 axis, blocking both de novo GSH synthesis and redox homeostasis. This synergistic action depletes intracellular GSH, promotes lethal lipid peroxidation, and drives robust ferroptosis. Furthermore, the GSH‐responsive release of Mn 2+ enables activatable T 1 ‐weighted magnetic resonance imaging, allowing real‐time monitoring of treatment response. Our work presents an integrated theranostic strategy that combines precise ferroptosis induction with non‐invasive imaging, offering a promising approach for the management of advanced HCC.