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

作者：Hongmei Zhou, Yujia Liang, Lijuan Liu, Yulin Liang, Jiaying Tang, He Ding, Shufang Ning, Piaoping Yang, Chen Wang · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03793-1 · 被引用次数：5 · 研究领域：Ferroptosis and cancer prognosis、Nitric Oxide and Endothelin Effects、Trace Elements in Health

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 (Zn2+), effectively disrupting the redox homeostasis and antioxidant capacity of tumor cells. ZIF-8 degradation in tumor cells triggers Zn2+-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 Zn2+, offering the potential for developing highly effective combined ferroptosis and apopto...