ROLE OF COPPER DEATH MARKERS ATP7A/ATP7B IN REGULATING ANTIOXIDANTS GSH AND SOD IN THE PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)
Keywords:
ATP7A, ATP7B, GSH, SOD, COPDAbstract
Objective: To investigate the underlying mechanisms by which cuproptosis-related markers ATP7A/ATP7B, together with the antioxidant regulators GSH and SOD, contribute to the pathogenesis of COPD. Methods: A retrospective study was conducted using clinical data from 102 patients diagnosed with COPD and enrolled between March 2021 and December 2024, who constituted the study population.Sixty Wholesome subjects receiving medical screenings in the identical timeframe were chosen as the reference group. Multiplex concurrent fluorimetric signal quantitative PCR and WB were used to detect ATP7A, ATP7B, SLC31A1, FDX1, and DLAT in all participants. Baseline data, routine laboratory tests, COPD assessment test (CAT) scores, and pulmonary function indicators were also collected. Results: In the study group, ATP7A, ATP7B, FDX1, and DLAT expression levels were significantly lower, while SLC31A1 was considerably elevated relative to the reference group (P<0.05). No notable discrepancies were found in sex or alcohol history. However, the study group had significantly higher age, rates of diabetes and hypertension, smoking history, CRP, LTB4, ICAM-1, TNF-α, MDA, CAT scores, and airway resistance (Raw), and significantly lower GSH, SOD, FEV1, FVC, and PEFR levels (P<0.05). All these factors, including the gene expressions and clinical indicators, were significantly correlated with COPD (P<0.05). ROC analysis showed that age, CRP, IL-6, IL-8, IL-10, IL-17, LTB4, ICAM-1, TNF-α, MDA, CAT, and Raw had strong predictive value (AUC > 0.8), with a combined diagnostic AUC of 1. Conclusion: ATP7A/ATP7B, GSH, and SOD may reduce cuproptosis and inhibit the onset and progression of COPD. However, their individual predictive value is limited, and other indicators should be combined in clinical diagnosis.References
[1] Parsanathan R. Copper's dual role: unravelling the link between copper homeostasis, cuproptosis, and cardiovascular diseases. Hypertension Research, 2024, 47(5): 1440-1442.
[2] Wang Y, Feng LS, Xu A, et al. Copper ions: the invisible killer of cardiovascular disease (Review). Molecular Medicine Reports, 2024, 30(5): 210.
[3] Gao W, Huang Z, Duan J, et al. Elesclomol induces copper-dependent ferroptosis in colorectal cancer cells via degradation of ATP7A. Molecular Oncology, 2021, 15(12): 3527-3544.
[4] Arnold PK, Jackson BT, Paras KI, et al. A non-canonical tricarboxylic acid cycle underlies cellular identity. Nature, 2002, 6037901: 477-481.
[5] Yan C, Liu Y, Zhao G, et al. Inhalable metal-organic framework-mediated cuproptosis combined with PD-L1 checkpoint blockade for lung metastasis synergistic immunotherapy. Acta Pharmaceutica Sinica B, 2024, 14(5): 2281-2297.
[6] Christenson SA, Smith BM, Bafadhel M, et al. Chronic obstructive pulmonary disease. The Lancet, 2022, 399(10342): 2227-2242.
[7] Qi W, Liu L, Zeng Q, et al. Contribution of cuproptosis and Cu metabolism-associated genes to chronic obstructive pulmonary disease. Journal of Cellular and Molecular Medicine, 2023, 27(24): 4034-4044.
[8] Han L, Zhu W, Qi H, et al. The cuproptosis-related gene glutaminase promotes alveolar macrophage copper ion accumulation in chronic obstructive pulmonary disease. International Immunopharmacology, 2024, 129: 111585.
[9] Ma L, Zhang D, Ma G, et al. Intervention effects of drugs on GSH and SOD enzyme activity of rats kidney acutely poisoned by nickel carbonyl. Chinese Journal of Occupational Diseases and Occupational Hazards, 2022, 40(12): 888-892.
[10] Rosa A, Bruni N, Meineri G, et al. Strategies to expand the therapeutic potential of superoxide dismutase by exploiting delivery approaches. International Journal of Biological Macromolecules, 2021, 168: 846-865.
[11] Dunaevskaya SS, Sergeeva EY, Titova NM, et al. Rol' superoksiddismutazy pri razvitii ostrogo pankreatita: ot antioksidantnoi zashchity do regulyatsii aktivnosti genov [Role of superoxide dismutase in acute pancreatitis: from antioxidant protection to gene regulation]. Khirurgiia (Mosk), 2024(4): 112-117.
[12] Du T, Yao Y, Meng Y. Research progress on copper death prediction of lung adenocarcinoma prognosis and guidance of immunotherapy. Anhui Medical Journal, 2024, 45(8): 1055-1059.
[13] Li Y, Xie F, Chu X, et al. Analysis of copper death CDKN2A gene and potential traditional Chinese medicine prediction in lung adenocarcinoma based on bioinformatics. Journal of Traditional Medicine, 2024, 51(6): 1-4.
[14] Qin Y, Liu Y, Xiang X, et al. Cuproptosis correlates with immunosuppressive tumor microenvironment based on pan-cancer multiomics and single-cell sequencing analysis. Molecular Cancer, 2023, 22(1): 59.
[15] Yang L, Yang P, Lip G, et al. Copper homeostasis and cuproptosis in cardiovascular disease therapeutics. Trends in Pharmacological Sciences, 2023, 44(9): 573-585.
[16] Liu W, Lin W, Yan L, et al. Copper homeostasis and cuproptosis in cancer immunity and therapy. Immunological Reviews, 2024, 321(1): 211-227.
[17] Singh S, Verma SK, Kumar S, et al. Evaluation of oxidative stress and antioxidant status in chronic obstructive pulmonary disease. Scandinavian Journal of Immunology, 2017, 85(2): 130-137.
[18] Lu J, Ling X, Sun Y, et al. FDX1 enhances endometriosis cell cuproptosis via G6PD-mediated redox homeostasis. Apoptosis, 2023, 28(7-8): 1128-1140.
[19] Wang C, Guo J, Zhang Y, et al. Cuproptosis-related gene FDX1 suppresses the growth and progression of colorectal cancer by retarding EMT progress. Biochemical Genetics, 2025, 63(1): 775-788.
[20] Zhang Y, Zhou Q, Lu L, et al. Copper induces cognitive impairment in mice via modulation of cuproptosis and CREB signaling. Nutrients, 2023, 15(4): 972.
[21] Zhao R, Sukocheva O, Tse E, et al. Cuproptosis, the novel type of oxidation-induced cell death in thoracic cancers: can it enhance the success of immunotherapy? Cellular Communication and Signaling, 2024, 22(1): 379.
[22] Luo D, Liu S, Luo J, et al. Characterization of cuproptosis identified immune microenvironment and prognosis in acute myeloid leukemia. Clinical and Translational Oncology, 2023, 25(8): 2393-2407.
[23] Ti H, Zhou Y, Liang X, et al. Targeted treatments for Chronic Obstructive Pulmonary Disease (COPD) using Low-Molecular-Weight Drugs (LMWDs). Journal of Medicinal Chemistry, 2019, 62(13): 5944-5978.
[24] Schmidt K, Ralle M, Schaffer T, et al. ATP7A and ATP7B copper transporters have distinct functions in the regulation of neuronal dopamine-β-hydroxylase. Journal of Biological Chemistry, 2018, 293(52): 20085-20098.
[25] Wu X, Mandigers PJJ, Watson AL, et al. Association of the canine ATP7A and ATP7B with hepatic copper accumulation in Dobermann dogs. Journal of Veterinary Internal Medicine, 2019, 33(4): 1646-1652.
[26] Liu Z, Zeng H, Zhang H. Association of the oxidation balance score with the prevalence of chronic obstructive pulmonary disease from the NHANES 2007-2012: A large-scale cross-sectional study. Heart & Lung, 2024, 65: 84-92.
[27] He X, Lin X, He B, et al. Association between oxidative balance score and frailty in chronic obstructive pulmonary disease. Heliyon, 2024, 10(4): e25750.
[28] Huo S, Wang Q, Shi W, et al. ATF3/SPI1/SLC31A1 signaling promotes cuproptosis induced by advanced glycosylation end products in diabetic myocardial injury. International Journal of Molecular Sciences, 2023, 24(2): 1667.
[29] Jiang J, Zhao C, Han T, et al. Advanced glycation end products, bone health, and diabetes mellitus. Experimental and Clinical Endocrinology & Diabetes, 2022, 130(10): 671-677.
[30] Saedi S, Tan Y, Watson SE, et al. Potential pathogenic roles of ferroptosis and cuproptosis in cadmium-induced or exacerbated cardiovascular complications in individuals with diabetes. Frontiers in Endocrinology, 2024, 15: 1461171.
[31] Yu Y, Li H, Yang X, et al. Elesclomol-Cu induces cuproptosis in human acute myeloid leukemia cells. Chinese Journal of Experimental Hematology, 2024, 32(2): 389-394.
[32] Zhang P, Zhou C, Ren X, et al. Inhibiting the compensatory elevation of xCT collaborates with disulfiram/copper-induced GSH consumption for cascade ferroptosis and cuproptosis. Redox Biology, 2024, 69: 103007.
[33] Xu Y, Liu S, Zeng L, et al. An enzyme-engineered nonporous copper(I) coordination polymer nanoplatform for cuproptosis-based synergistic cancer therapy. Advanced Materials, 2022, 34(43): e2204733.
[34] Fu L, Wan Y, Qi C, et al. Nanocatalytic theranostics with glutathione depletion and enhanced reactive oxygen species generation for efficient cancer therapy. Advanced Materials, 2021, 33(7): e2006892.
[35] Wang Z, Liu B, Sun Q, et al. Fusiform-like copper (II)-based metal-organic framework through relief hypoxia and GSH-depletion co-enhanced starvation and chemodynamic synergetic cancer therapy. ACS Applied Materials & Interfaces, 2020, 12(15): 17254-17267.
[36] Lee B, Afshari NA, Shaw PX. Oxidative stress and antioxidants in cataract development. Current Opinion in Ophthalmology, 2024, 35(1): 57-63.
[37] Rondanelli M, Faliva MA, Peroni G, et al. Food Pyramid for subjects with chronic obstructive pulmonary diseases. International Journal of Chronic Obstructive Pulmonary Disease, 2020, 15: 1435-1448.