Diabetic patients are considered as the high risk population to develop critical limb ischemia (CLI), a peripheral vascular disease (PVD) resulted from atherosclerosis. Cuproptosis is a novel copper-dependent cell death that has shown the regulatory role in diabetes, while its effect on diabetic CLI has not been explored yet. In this study, Diabetic CLI mice was induced by femoral artery ligation (FAL) on diabetic mice. Endothelial injury in diabetic CLI was mimicked in human microvascular endothelial cells (HMEC-1) via the induction with high glucose (HG) and nutrient deprivation (ND). Besides, copper chelator Ammonium Tetrathiomolybdate (TM), which has shown the anti-cuproptosis property, was administrated to explore its potential effects on diabetic CLI mice and HG/ND-induced HMEC-1 cells. Strikingly, obvious cuproptosis was found in the gastrocnemius muscles of diabetic CLI mice and HG/ND-induced HMEC-1 cells, as evidenced by the copper overload and dysregulated cuproptosis-related proteins (such as Fe-S cluster proteins, copper exporter ATP7A, and copper importer SLC31A1). More importantly, TM protected against the hindlimb ischemic damages in diabetic CLI mice and alleviated cuproptosis-associated cell deaths in HG/ND-induced HMEC-1 cells. In summary, this study indicates the involvements of cuproptosis in diabetic CLI, and provides novel insights into copper chelator TM on diabetic CLI therapy.
The notably heightened copper levels found in cancer underscore the critical involvement of copper ions in tumor progression and metastasis. Consequently, disrupting tumor copper homeostasis is emerging as a novel strategy for cancer treatment. Here, LTMP was constructed using PEG-modified mesoporous polydopamine (MP) loaded with lonidamine (LND, a glycolysis inhibitor) and tetrathiomolybdate (TM, a copper chelator). The utilization of TM as a copper chelator led to a substantial reduction in copper content and inhibited the activity of copper-dependent enzymes, thereby suppressing the oxidative phosphorylation (OXPHOS) process in tumor cells. However, the inhibition of OXPHOS lead to compensatory upregulation of glycolysis, enhancing cellular drug resistance. Therefore, the combination of LND and TM could effectively achieve dual inhibition of glycolysis and OXPHOS, resulting in a substantial enhancement of tumor cell apoptosis. Furthermore, LTMP was found to inhibit the activities of matrix metalloproteinases and lysyl oxidase, thereby impeding the epithelial-mesenchymal transition process and significantly reducing lung tumor metastasis. Additionally, LTMP-based photothermal therapy combined with chemotherapy effectively regulated the tumor microenvironment by reducing immunosuppressive cells and enhancing T lymphocyte infiltration. This work provided new insights for the design of intricate anti-tumor strategies.
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