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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. This work proposes the glucose dyshomeostasis-disrupted SLC7A11/GSH/GPX4 antioxidant axis as an efficient target for simultaneously evoking disulfidptosis, cuproptosis and ferroptosis in tumor therapy by employing the advantages of drug assemblies. [Display omitted] •SLC7A11/GSH/GPX4 axis is a target to regulate multi-mode regulated cell deaths.•Disulfidptosis, cuproptosis and ferroptosis can be evoked synchronously.•Glucose dyshomeostasis is efficient to regulate SLC7A11/GSH/GPX4 axis.•Drug assemblies are robust to direct metabolic modulation for tumor therapy.

Diabetic cardiomyopathy (DCM) is a severe complication of diabetes, in which ferroptosis is a key pathogenic mechanism. This study examines how alpha-linolenic acid (ALA), a plant-derived omega-3 polyunsaturated fatty acid, protects against damage from ferroptosis in DCM. Using an in vitro model of H9C2 cardiomyocytes treated with high glucose/palmitate, combined with a high-fat diet and mouse model of low-dose streptozotocin (STZ)-induced diabetes, this research demonstrates for the first time that ALA significantly alleviates cardiac dysfunction and prevents ferroptosis. Mechanistically, ALA inhibits STAT3 phosphorylation by activating the AMPK signaling pathway, thereby reducing NCOA4-mediated ferritinophagy and mitigating mitochondrial iron overload and reactive oxygen species accumulation. It also enhances the function of the SLC7A11/GSH/GPX4 axis, reducing lipid peroxidation (LPO)-induced ferroptosis. Collectively, these findings indicate that ALA protects against diabetic cardiomyopathy by coordinating the regulation of ferritinophagy and antioxidant defense through the AMPK-STAT3 pathway, offering a potential therapeutic strategy for disease management.