Research progress on copper death mechanism in metabolic associated fatty liver disease_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Ningjing , LI Beibei , SONG Shuxian , ZHENG Kepu ,  RAN Jianghua

Department of Hepatobiliary Pancreatic Surgery, First People's Hospital of Kunming/The Affiliated Calmette Hospital of Kunming Medical University, Kunming 650100, P. R. China;

Corresponding author：

RAN Jianghua, Email: ranjianghua@kmmu.edu.cn

Keywords：

copper; cuproptosis; metabolic associated fatty liver disease

DOI：

10.7507/1007-9424.202505092

Video：

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Objective Objective To summarize the latest research progress on the copper death mechanism in metabolic associated fatty liver disease (MAFLD) and to provide new avenues for the treatment of MAFLD. Methods We reviewed recent domestic and international research on copper and copper death in MAFLD, and summarized the role of copper death mechanisms in the pathogenesis of MAFLD and related treatments. Results Copper death is primarily caused by abnormal intracellular copper accumulation binding to acylated proteins in the tricarboxylic acid cycle, leading to protein oligomerization, downregulation of iron-sulfur cluster protein expression, triggering a toxic stress response, and ultimately cell death. The occurrence and progression of MAFLD are closely associated with genes associated with the copper death pathway. Imbalanced copper metabolism can lead to insulin resistance, causing abnormalities in blood glucose and lipid metabolism, promoting fat accumulation in the liver, and ultimately contributing to the development of MAFLD. Targeting genes involved in the copper death pathway can delay the progression of MAFLD. Conclusion The occurrence and progression of MAFLD are closely linked to the copper death signaling pathway, with copper metabolism imbalance as a core component. This pathway not only directly leads to hepatocyte death but also triggers insulin resistance and abnormal lipid metabolism, jointly driving the progression of MAFLD. Therefore, targeted regulation of the copper death pathway is a novel therapeutic strategy to slow the progression of MAFLD.

1.	Tsvetkov P, Coy S, Petrova B, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science, 2022, 375(6586): 1254-1261.
2.	Younossi ZM, Wong G, Anstee QM, et al. The global burden of liver disease. Clin Gastroenterol Hepatol, 2023, 21(8): 1978-1991.
3.	Tang D, Chen X, Kroemer G. Cuproptosis: a copper-triggered modality of mitochondrial cell death. Cell Res, 2022, 32(5): 417-418.
4.	Tutunchi H, Saghafi-Asl M, Asghari-Jafarabadi M, et al. The relationship between severity of liver steatosis and metabolic parameters in a sample of Iranian adults. BMC Res Notes, 2020, 13(1): 218. doi: 10.1186/s13104-020-05059-5.
5.	Subramanian P, Hampe J, Tacke F, et al. Fibrogenic pathways in metabolic dysfunction associated fatty liver disease (MAFLD). Int J Mol Sci, 2022, 23(13): 6996. doi: 10.3390/ijms23136996.
6.	Saito T, Tsuchishima M, Tsutsumi M, et al. Molecular pathogenesis of metabolic dysfunction-associated steatotic liver disease, steatohepatitis, hepatic fibrosis and liver cirrhosis. J Cell Mol Med, 2024, 28(12): e18491. doi: 10.1111/jcmm.18491.
7.	Kaya E, Yilmaz Y. Metabolic-associated fatty liver disease (MAFLD): a multi-systemic disease beyond the liver. J Clin Transl Hepatol, 2022, 10(2): 329-338.
8.	Ye Q, Zou B, Yeo YH, et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol, 2020, 5(8): 739-752.
9.	Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol, 2020, 73(1): 202-209.
10.	Nováková B. Metabolic dysfunction-associated fatty liver disease (MAFLD) as a more accurate name for NAFLD - common aspects of pathogenesis. Cas Lek Cesk, 2022, 161(2): 65-71.
11.	Pierson H, Yang H, Lutsenko S. Copper transport and disease: what can we learn from organoids?. Annu Rev Nutr, 2019, 39: 75-94.
12.	Gao L, Zhang A. Copper-instigated modulatory cell mortality mechanisms and progress in oncological treatment investigations. Front Immunol, 2023, 14: 1236063. doi: 10.3389/fimmu.2023.1236063.
13.	Tang D, Kang R, Berghe TV, et al. The molecular machinery of regulated cell death. Cell Res, 2019, 29(5): 347-364.
14.	Cheng F, Peng G, Lu Y, et al. Relationship between copper and immunity: the potential role of copper in tumor immunity. Front Oncol, 2022, 12: 1019153. doi: 10.3389/fonc.2022.1019153.
15.	Ge EJ, Bush AI, Casini A, et al. Connecting copper and cancer: from transition metal signalling to metalloplasia. Nat Rev Cancer, 2022, 22(2): 102-113.
16.	Tsvetkov P, Detappe A, Cai K, et al. Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol, 2019, 15(7): 681-689.
17.	Yang Z, Su W, Wei X, et al. Hypoxia inducible factor-1α drives cancer resistance to cuproptosis. Cancer Cell, 2025, 43(5): 937-954.
18.	Han X, Zhang X, Liu Z, et al. Copper-based nanotubes that enhance starvation therapy through cuproptosis for synergistic cancer treatment. Adv Sci (Weinh), 2025, e04121. doi: 10.1002/advs.202504121.
19.	邢中旭, 许筱炎, 焦旸, 等. 铜及铜死亡在恶性肿瘤辐射抵抗中的研究现状. 中华放射肿瘤学杂志, 2025, 34(3): 305-309.
20.	Wang Y, Zhang L, Zhou F. Cuproptosis: a new form of programmed cell death. Cell Mol Immunol, 2022, 19(8): 867-868.
21.	Malis CD, Bonventre JV. Mechanism of calcium potentiation of oxygen free radical injury to renal mitochondria. A model for post-ischemic and toxic mitochondrial damage. J Biol Chem, 1986, 261(30): 14201-14208.
22.	Tian H, Sun S, Qiu X, et al. Diallyl trisulfide from garlic regulates RAB18 phase separation to inhibit lipophagy and induce cuproptosis in hepatic stellate cells for antifibrotic effects. Adv Sci (Weinh), 2025, 12(21): e2415325. doi: 10.1002/advs.202415325.
23.	Rowland EA, Snowden CK, Cristea IM. Protein lipoylation: an evolutionarily conserved metabolic regulator of health and disease. Curr Opin Chem Biol, 2018, 42: 76-85.
24.	张开航, 孙浩, 高宁. 铜死亡的发生机制及其在肿瘤治疗中的研究进展. 遵义医科大学学报, 2025, 48(3): 307-317.
25.	任黎蕾, 赵小波, 高砚春, 等. 铜死亡与乳腺癌相关性的研究进展. 中国普外基础与临床杂志, 2024, 31(2): 250-256.
26.	Cao S, Wang Q, Sun Z, et al. Role of cuproptosis in understanding diseases. Hum Cell, 2023, 36(4): 1244-1252.
27.	Pouwels S, Sakran N, Graham Y, et al. Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss. BMC Endocr Disord, 2022, 22(1): 63. doi: 10.1186/s12902-022-00980-1.
28.	Eslam M, Sarin SK, Wong VW, et al. The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol Int, 2020, 14(6): 889-919.
29.	Ma C, Han L, Zhu Z, et al. Mineral metabolism and ferroptosis in non-alcoholic fatty liver diseases. Biochem Pharmacol, 2022, 205: 115242. doi: 10.1016/j.bcp.2022.115242.
30.	Toktogulova N, Breidert M, Eschbach J, et al. Energy metabolism in residents in the low and moderate altitude regions of central Asia with MAFLD and type 2 diabetes mellitus. Horm Metab Res, 2024, 56(4): 294-299.
31.	Morrell A, Tallino S, Yu L, et al. The role of insufficient copper in lipid synthesis and fatty-liver disease. IUBMB Life, 2017, 69(4): 263-270.
32.	Yang H, Liu CN, Wolf RM, et al. Obesity is associated with copper elevation in serum and tissues. Metallomics, 2019, 11(8): 1363-1371.
33.	Zhang C, Yang M. Current options and future directions for NAFLD and NASH treatment. Int J Mol Sci, 2021, 22(14): 7571. doi: 10.3390/ijms22147571.
34.	Pan Z, Deng C, Shui L, et al. Copper deficiency induces oxidative stress in liver of mice by blocking the Nrf2 pathway. Biol Trace Elem Res, 2024, 202(4): 1603-1611.
35.	Chen L, Min J, Wang F. Copper homeostasis and cuproptosis in health and disease. Signal Transduct Target Ther, 2022, 7(1): 378. doi: 10.1038/s41392-022-01229-y.
36.	Barber TM, Kabisch S, Pfeiffer AFH, et al. Metabolic-associated fatty liver disease and insulin resistance: a review of complex interlinks. Metabolites, 2023, 13(6): 757. doi: 10.3390/metabo13060757.
37.	Sakurai Y, Kubota N, Yamauchi T, et al. Role of insulin resistance in MAFLD. Int J Mol Sci, 2021, 22(8): 4156. doi: 10.3390/ijms22084156.
38.	Song M, Vos MB, McClain CJ. Copper-Fructose Interactions: A Novel Mechanism in the Pathogenesis of NAFLD. Nutrients, 2018, 10(11): 1815. doi: 10.3390/nu10111815.
39.	van den Berghe PV, Klomp LW. New developments in the regulation of intestinal copper absorption. Nutr Rev, 2009, 67(11): 658-672.
40.	Nose Y, Kim BE, Thiele DJ. Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. Cell Metab, 2006, 4(3): 235-244.
41.	Horn N, Wittung-Stafshede P. ATP7A-regulated enzyme metalation and trafficking in the menkes disease puzzle. Biomedicines, 2021, 9(4): 391. doi: 10.3390/biomedicines9040391.
42.	Horn N, Møller LB, Nurchi VM, et al. Chelating principles in Menkes and Wilson diseases: choosing the right compounds in the right combinations at the right time. J Inorg Biochem, 2019, 190: 98-112.
43.	Nunes VS, Andrade AR, Guedes ALV, et al. Distinct phenotype of non-alcoholic fatty liver disease in patients with low levels of free copper and of ceruloplasmin. Arq Gastroenterol, 2020, 57(3): 249-253.
44.	Hilário-Souza E, Cuillel M, Mintz E, et al. Modulation of hepatic copper-ATPase activity by insulin and glucagon involves protein kinase A (PKA) signaling pathway. Biochim Biophys Acta, 2016, 1862(11): 2086-2097.
45.	Xie L, Yuan Y, Xu S, et al. Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex. Cell Rep, 2022, 41(3): 111498. doi: 10.1016/j.celrep.2022.111498.
46.	Klevay LM, Inman L, Johnson LK, et al. Increased cholesterol in plasma in a young man during experimental copper depletion. Metabolism, 1984, 33(12): 1112-1118.
47.	Aigner E, Strasser M, Haufe H, et al. A role for low hepatic copper concentrations in nonalcoholic fatty liver disease. Am J Gastroenterol, 2010, 105(9): 1978-1985.
48.	Song M, Schuschke DA, Zhou Z, et al. Modest fructose beverage intake causes liver injury and fat accumulation in marginal copper deficient rats. Obesity (Silver Spring), 2013, 21(8): 1669-1675.
49.	Tallino S, Duffy M, Ralle M, et al. Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease. J Nutr Biochem, 2015, 26(10): 996-1006.
50.	Stättermayer AF, Traussnigg S, Aigner E, et al. Low hepatic copper content and PNPLA3 polymorphism in non-alcoholic fatty liver disease in patients without metabolic syndrome. J Trace Elem Med Biol, 2017, 39: 100-107.
51.	Gatiatulina ER, Popova EV, Polyakova VS, et al. Evaluation of tissue metal and trace element content in a rat model of non-alcoholic fatty liver disease using ICP-DRC-MS. J Trace Elem Med Biol, 2017, 39: 91-99.
52.	Song M, Schuschke DA, Zhou Z, et al. High fructose feeding induces copper deficiency in Sprague-Dawley rats: a novel mechanism for obesity related fatty liver. J Hepatol, 2012, 56(2): 433-440.
53.	Blades B, Ayton S, Hung YH, et al. Copper and lipid metabolism: a reciprocal relationship. Biochim Biophys Acta Gen Subj, 2021, 1865(11): 129979. doi: 10.1016/j.bbagen.2021.129979.
54.	Lan Y, Wu S, Wang Y, et al. Association between blood copper and nonalcoholic fatty liver disease according to sex. Clin Nutr, 2021, 40(4): 2045-2052.
55.	Arefhosseini S, Pouretedal Z, Tutunchi H, et al. Serum copper, ceruloplasmin, and their relations to metabolic factors in nonalcoholic fatty liver disease: a cross-sectional study. Eur J Gastroenterol Hepatol, 2022, 34(4): 443-448.
56.	Xue Q, Yan D, Chen X, et al. Copper-dependent autophagic degradation of GPX4 drives ferroptosis. Autophagy, 2023, 19(7): 1982-1996.
57.	Vargas JNS, Hamasaki M, Kawabata T, et al. The mechanisms and roles of selective autophagy in mammals. Nat Rev Mol Cell Biol, 2023, 24(3): 167-185.
58.	Corradini E, Buzzetti E, Dongiovanni P, et al. Ceruloplasmin gene variants are associated with hyperferritinemia and increased liver iron in patients with NAFLD. J Hepatol, 2021, 75(3): 506-513.
59.	Cheli VT, Sekhar M, Santiago González DA, et al. The expression of ceruloplasmin in astrocytes is essential for postnatal myelination and myelin maintenance in the adult brain. Glia, 2023, 71(10): 2323-2342.
60.	Kolarova H, Tan J, Strom TM, et al. Lifetime risk of autosomal recessive neurodegeneration with brain iron accumulation (NBIA) disorders calculated from genetic databases. EBioMedicine, 2022, 77: 103869. doi: 10.1016/j.ebiom.2022.103869.
61.	Pelucchi S, Ravasi G, Piperno A. Ceruloplasmin variants might have different effects in different iron overload disorders. J Hepatol, 2021, 75(4): 1003-1004.
62.	Mitrofanova A, Merscher S, Fornoni A. Kidney lipid dysmetabolism and lipid droplet accumulation in chronic kidney disease. Nat Rev Nephrol, 2023, 19(10): 629-645.
63.	Dai W, Shu R, Yang F, et al. Engineered bio-heterojunction confers extra- and intracellular bacterial ferroptosis and hunger-triggered cell protection for diabetic wound repair. Adv Mater, 2024, 36(9): e2305277. doi: 10.1002/adma.202305277.
64.	Pope LE, Dixon SJ. Regulation of ferroptosis by lipid metabolism. Trends Cell Biol, 2023, 33(12): 1077-1087.

1. Tsvetkov P, Coy S, Petrova B, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science, 2022, 375(6586): 1254-1261.
2. Younossi ZM, Wong G, Anstee QM, et al. The global burden of liver disease. Clin Gastroenterol Hepatol, 2023, 21(8): 1978-1991.
3. Tang D, Chen X, Kroemer G. Cuproptosis: a copper-triggered modality of mitochondrial cell death. Cell Res, 2022, 32(5): 417-418.
4. Tutunchi H, Saghafi-Asl M, Asghari-Jafarabadi M, et al. The relationship between severity of liver steatosis and metabolic parameters in a sample of Iranian adults. BMC Res Notes, 2020, 13(1): 218. doi: 10.1186/s13104-020-05059-5.
5. Subramanian P, Hampe J, Tacke F, et al. Fibrogenic pathways in metabolic dysfunction associated fatty liver disease (MAFLD). Int J Mol Sci, 2022, 23(13): 6996. doi: 10.3390/ijms23136996.
6. Saito T, Tsuchishima M, Tsutsumi M, et al. Molecular pathogenesis of metabolic dysfunction-associated steatotic liver disease, steatohepatitis, hepatic fibrosis and liver cirrhosis. J Cell Mol Med, 2024, 28(12): e18491. doi: 10.1111/jcmm.18491.
7. Kaya E, Yilmaz Y. Metabolic-associated fatty liver disease (MAFLD): a multi-systemic disease beyond the liver. J Clin Transl Hepatol, 2022, 10(2): 329-338.
8. Ye Q, Zou B, Yeo YH, et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol, 2020, 5(8): 739-752.
9. Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol, 2020, 73(1): 202-209.
10. Nováková B. Metabolic dysfunction-associated fatty liver disease (MAFLD) as a more accurate name for NAFLD - common aspects of pathogenesis. Cas Lek Cesk, 2022, 161(2): 65-71.
11. Pierson H, Yang H, Lutsenko S. Copper transport and disease: what can we learn from organoids?. Annu Rev Nutr, 2019, 39: 75-94.
12. Gao L, Zhang A. Copper-instigated modulatory cell mortality mechanisms and progress in oncological treatment investigations. Front Immunol, 2023, 14: 1236063. doi: 10.3389/fimmu.2023.1236063.
13. Tang D, Kang R, Berghe TV, et al. The molecular machinery of regulated cell death. Cell Res, 2019, 29(5): 347-364.
14. Cheng F, Peng G, Lu Y, et al. Relationship between copper and immunity: the potential role of copper in tumor immunity. Front Oncol, 2022, 12: 1019153. doi: 10.3389/fonc.2022.1019153.
15. Ge EJ, Bush AI, Casini A, et al. Connecting copper and cancer: from transition metal signalling to metalloplasia. Nat Rev Cancer, 2022, 22(2): 102-113.
16. Tsvetkov P, Detappe A, Cai K, et al. Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol, 2019, 15(7): 681-689.
17. Yang Z, Su W, Wei X, et al. Hypoxia inducible factor-1α drives cancer resistance to cuproptosis. Cancer Cell, 2025, 43(5): 937-954.
18. Han X, Zhang X, Liu Z, et al. Copper-based nanotubes that enhance starvation therapy through cuproptosis for synergistic cancer treatment. Adv Sci (Weinh), 2025, e04121. doi: 10.1002/advs.202504121.
19. 邢中旭, 许筱炎, 焦旸, 等. 铜及铜死亡在恶性肿瘤辐射抵抗中的研究现状. 中华放射肿瘤学杂志, 2025, 34(3): 305-309.
20. Wang Y, Zhang L, Zhou F. Cuproptosis: a new form of programmed cell death. Cell Mol Immunol, 2022, 19(8): 867-868.
21. Malis CD, Bonventre JV. Mechanism of calcium potentiation of oxygen free radical injury to renal mitochondria. A model for post-ischemic and toxic mitochondrial damage. J Biol Chem, 1986, 261(30): 14201-14208.
22. Tian H, Sun S, Qiu X, et al. Diallyl trisulfide from garlic regulates RAB18 phase separation to inhibit lipophagy and induce cuproptosis in hepatic stellate cells for antifibrotic effects. Adv Sci (Weinh), 2025, 12(21): e2415325. doi: 10.1002/advs.202415325.
23. Rowland EA, Snowden CK, Cristea IM. Protein lipoylation: an evolutionarily conserved metabolic regulator of health and disease. Curr Opin Chem Biol, 2018, 42: 76-85.
24. 张开航, 孙浩, 高宁. 铜死亡的发生机制及其在肿瘤治疗中的研究进展. 遵义医科大学学报, 2025, 48(3): 307-317.
25. 任黎蕾, 赵小波, 高砚春, 等. 铜死亡与乳腺癌相关性的研究进展. 中国普外基础与临床杂志, 2024, 31(2): 250-256.
26. Cao S, Wang Q, Sun Z, et al. Role of cuproptosis in understanding diseases. Hum Cell, 2023, 36(4): 1244-1252.
27. Pouwels S, Sakran N, Graham Y, et al. Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss. BMC Endocr Disord, 2022, 22(1): 63. doi: 10.1186/s12902-022-00980-1.
28. Eslam M, Sarin SK, Wong VW, et al. The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol Int, 2020, 14(6): 889-919.
29. Ma C, Han L, Zhu Z, et al. Mineral metabolism and ferroptosis in non-alcoholic fatty liver diseases. Biochem Pharmacol, 2022, 205: 115242. doi: 10.1016/j.bcp.2022.115242.
30. Toktogulova N, Breidert M, Eschbach J, et al. Energy metabolism in residents in the low and moderate altitude regions of central Asia with MAFLD and type 2 diabetes mellitus. Horm Metab Res, 2024, 56(4): 294-299.
31. Morrell A, Tallino S, Yu L, et al. The role of insufficient copper in lipid synthesis and fatty-liver disease. IUBMB Life, 2017, 69(4): 263-270.
32. Yang H, Liu CN, Wolf RM, et al. Obesity is associated with copper elevation in serum and tissues. Metallomics, 2019, 11(8): 1363-1371.
33. Zhang C, Yang M. Current options and future directions for NAFLD and NASH treatment. Int J Mol Sci, 2021, 22(14): 7571. doi: 10.3390/ijms22147571.
34. Pan Z, Deng C, Shui L, et al. Copper deficiency induces oxidative stress in liver of mice by blocking the Nrf2 pathway. Biol Trace Elem Res, 2024, 202(4): 1603-1611.
35. Chen L, Min J, Wang F. Copper homeostasis and cuproptosis in health and disease. Signal Transduct Target Ther, 2022, 7(1): 378. doi: 10.1038/s41392-022-01229-y.
36. Barber TM, Kabisch S, Pfeiffer AFH, et al. Metabolic-associated fatty liver disease and insulin resistance: a review of complex interlinks. Metabolites, 2023, 13(6): 757. doi: 10.3390/metabo13060757.
37. Sakurai Y, Kubota N, Yamauchi T, et al. Role of insulin resistance in MAFLD. Int J Mol Sci, 2021, 22(8): 4156. doi: 10.3390/ijms22084156.
38. Song M, Vos MB, McClain CJ. Copper-Fructose Interactions: A Novel Mechanism in the Pathogenesis of NAFLD. Nutrients, 2018, 10(11): 1815. doi: 10.3390/nu10111815.
39. van den Berghe PV, Klomp LW. New developments in the regulation of intestinal copper absorption. Nutr Rev, 2009, 67(11): 658-672.
40. Nose Y, Kim BE, Thiele DJ. Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. Cell Metab, 2006, 4(3): 235-244.
41. Horn N, Wittung-Stafshede P. ATP7A-regulated enzyme metalation and trafficking in the menkes disease puzzle. Biomedicines, 2021, 9(4): 391. doi: 10.3390/biomedicines9040391.
42. Horn N, Møller LB, Nurchi VM, et al. Chelating principles in Menkes and Wilson diseases: choosing the right compounds in the right combinations at the right time. J Inorg Biochem, 2019, 190: 98-112.
43. Nunes VS, Andrade AR, Guedes ALV, et al. Distinct phenotype of non-alcoholic fatty liver disease in patients with low levels of free copper and of ceruloplasmin. Arq Gastroenterol, 2020, 57(3): 249-253.
44. Hilário-Souza E, Cuillel M, Mintz E, et al. Modulation of hepatic copper-ATPase activity by insulin and glucagon involves protein kinase A (PKA) signaling pathway. Biochim Biophys Acta, 2016, 1862(11): 2086-2097.
45. Xie L, Yuan Y, Xu S, et al. Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex. Cell Rep, 2022, 41(3): 111498. doi: 10.1016/j.celrep.2022.111498.
46. Klevay LM, Inman L, Johnson LK, et al. Increased cholesterol in plasma in a young man during experimental copper depletion. Metabolism, 1984, 33(12): 1112-1118.
47. Aigner E, Strasser M, Haufe H, et al. A role for low hepatic copper concentrations in nonalcoholic fatty liver disease. Am J Gastroenterol, 2010, 105(9): 1978-1985.
48. Song M, Schuschke DA, Zhou Z, et al. Modest fructose beverage intake causes liver injury and fat accumulation in marginal copper deficient rats. Obesity (Silver Spring), 2013, 21(8): 1669-1675.
49. Tallino S, Duffy M, Ralle M, et al. Nutrigenomics analysis reveals that copper deficiency and dietary sucrose up-regulate inflammation, fibrosis and lipogenic pathways in a mature rat model of nonalcoholic fatty liver disease. J Nutr Biochem, 2015, 26(10): 996-1006.
50. Stättermayer AF, Traussnigg S, Aigner E, et al. Low hepatic copper content and PNPLA3 polymorphism in non-alcoholic fatty liver disease in patients without metabolic syndrome. J Trace Elem Med Biol, 2017, 39: 100-107.
51. Gatiatulina ER, Popova EV, Polyakova VS, et al. Evaluation of tissue metal and trace element content in a rat model of non-alcoholic fatty liver disease using ICP-DRC-MS. J Trace Elem Med Biol, 2017, 39: 91-99.
52. Song M, Schuschke DA, Zhou Z, et al. High fructose feeding induces copper deficiency in Sprague-Dawley rats: a novel mechanism for obesity related fatty liver. J Hepatol, 2012, 56(2): 433-440.
53. Blades B, Ayton S, Hung YH, et al. Copper and lipid metabolism: a reciprocal relationship. Biochim Biophys Acta Gen Subj, 2021, 1865(11): 129979. doi: 10.1016/j.bbagen.2021.129979.
54. Lan Y, Wu S, Wang Y, et al. Association between blood copper and nonalcoholic fatty liver disease according to sex. Clin Nutr, 2021, 40(4): 2045-2052.
55. Arefhosseini S, Pouretedal Z, Tutunchi H, et al. Serum copper, ceruloplasmin, and their relations to metabolic factors in nonalcoholic fatty liver disease: a cross-sectional study. Eur J Gastroenterol Hepatol, 2022, 34(4): 443-448.
56. Xue Q, Yan D, Chen X, et al. Copper-dependent autophagic degradation of GPX4 drives ferroptosis. Autophagy, 2023, 19(7): 1982-1996.
57. Vargas JNS, Hamasaki M, Kawabata T, et al. The mechanisms and roles of selective autophagy in mammals. Nat Rev Mol Cell Biol, 2023, 24(3): 167-185.
58. Corradini E, Buzzetti E, Dongiovanni P, et al. Ceruloplasmin gene variants are associated with hyperferritinemia and increased liver iron in patients with NAFLD. J Hepatol, 2021, 75(3): 506-513.
59. Cheli VT, Sekhar M, Santiago González DA, et al. The expression of ceruloplasmin in astrocytes is essential for postnatal myelination and myelin maintenance in the adult brain. Glia, 2023, 71(10): 2323-2342.
60. Kolarova H, Tan J, Strom TM, et al. Lifetime risk of autosomal recessive neurodegeneration with brain iron accumulation (NBIA) disorders calculated from genetic databases. EBioMedicine, 2022, 77: 103869. doi: 10.1016/j.ebiom.2022.103869.
61. Pelucchi S, Ravasi G, Piperno A. Ceruloplasmin variants might have different effects in different iron overload disorders. J Hepatol, 2021, 75(4): 1003-1004.
62. Mitrofanova A, Merscher S, Fornoni A. Kidney lipid dysmetabolism and lipid droplet accumulation in chronic kidney disease. Nat Rev Nephrol, 2023, 19(10): 629-645.
63. Dai W, Shu R, Yang F, et al. Engineered bio-heterojunction confers extra- and intracellular bacterial ferroptosis and hunger-triggered cell protection for diabetic wound repair. Adv Mater, 2024, 36(9): e2305277. doi: 10.1002/adma.202305277.
64. Pope LE, Dixon SJ. Regulation of ferroptosis by lipid metabolism. Trends Cell Biol, 2023, 33(12): 1077-1087.

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