Regulating SLC7A11/GSH/GPX4 axis by glucose dyshomeostasis to simultaneously promote disulfidptosis, cuproptosis and ferroptosis

As one of the key targets of tumor metabolic therapy, glucose dyshomeostasis by disrupting glucose metabolism possesses the potential to reverse therapeutic resistance of a variety of regulated cell deaths (RCDs), but the functional pathways are not fully revealed and employed. Herein, we demonstrate that the intervention on SLC7A11/GSH/GPX4 antioxidant axis by glucose dyshomeostasis can simultaneously promote disulfidptosis, cuproptosis and ferroptosis, which is verified by employing glucose oxidase (GOx)-modified copper-apigenin (CuAp) network nanoshuttles (CuAp@GOx NSs) in ovarian tumor therapy. Ap and GOx can jointly induce glucose dyshomeostasis respectively by inhibiting glucose transporter 1-mediated glucose uptake upstream, and consuming massive glucose downstream. As a result of glucose dyshomeostasis, the NADPH supplement is downregulated, which further disrupts SLC7A11/GSH/GPX4 antioxidant axis. This simultaneously boosts disulfidptosis by facilitating cystine accumulation, cuproptosis by attenuating GSH-mediated Cu⁺ inactivation, and ferroptosis by downregulating GPX4 expression. Owing to the combination of disulfidptosis, cuproptosis and ferroptosis, CuAp@GOx NSs exhibit good efficacy in treating ovarian tumor model. This work proposes an alternative strategy for tumor therapy based on glucose dyshomeostasis, which mainly targets the RCDs relating to SLC7A11/GSH/GPX4 axis.