Advanced nitric oxide-activated calcium overload and zinc ion-amplified oxidative imbalance in ferroptosis/apoptosis

Ferroptosis, a programmed cell death driven by lipid peroxidation, relies on an oxidative imbalance. However, tumor cells counteract the effects of oxidative imbalance through adaptive defense mechanisms and metabolic reprogramming, thereby limiting the therapeutic efficacy of ferroptosis. An antitumor strategy was designed to synergistically induce ferroptosis and apoptosis by targeting the release of nitric oxide (NO) and zinc ions (Zn 2+ ), effectively disrupting the redox homeostasis and antioxidant capacity of tumor cells. ZIF-8 degradation in tumor cells triggers Zn 2+ -mediated mitochondrial electron transport chain inhibition and nicotinamide adenine dinucleotide phosphate oxidase 1 activation, significantly increasing endogenous reactive oxygen species (ROS) levels. NO-derived reactive nitrogen species exhibit strong oxidative activity, amplifying ROS-mediated oxidative imbalance, and promoting lipid peroxidation by depleting glutathione and inhibiting glutathione peroxidase 4 activity, inducing ferroptosis and apoptosis. Furthermore, NO disrupts intracellular redox equilibrium by activating endoplasmic reticulum stress and inhibiting the mitochondrial electron transport chain, resulting in calcium overload and mitochondrial malfunction. Multi-pathway disruption of intracellular adaptive defense mechanisms and metabolic reprogramming homeostasis can be achieved via NO synergistic Zn 2+ , offering the potential for developing highly effective combined ferroptosis and apoptosis antitumor therapies.