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Iron overload in alcoholic liver disease: underlying mechanisms, detrimental effects, and potential therapeutic targets

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Abstract

Alcoholic liver disease (ALD) is a global public health challenge due to the high incidence and lack of effective therapeutics. Evidence from animal studies and ALD patients has demonstrated that iron overload is a hallmark of ALD. Ethanol exposure can promote iron absorption by downregulating the hepcidin expression, which is probably mediated by inducing oxidative stress and promoting erythropoietin (EPO) production. In addition, ethanol may enhance iron uptake in hepatocytes by upregulating the expression of transferrin receptor (TfR). Iron overload in the liver can aggravate ethanol-elicited liver damage by potentiating oxidative stress via Fenton reaction, promoting activation of Kupffer cells (KCs) and hepatic stellate cells (HSCs), and inducing a recently discovered programmed iron-dependent cell death, ferroptosis. This article reviews the current knowledge of iron metabolism, regulators of iron homeostasis, the mechanism of ethanol-induced iron overload, detrimental effects of iron overload in the liver, and potential therapeutic targets.

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All data relevant to this review are included in the text, references, and figures.

Abbreviations

ALD:

Alcoholic liver disease

BMDM:

Bone marrow-derived macrophage

BMP:

Bone morphogenetic protein

CDT:

Carbohydrate-deficient transferrin

C/EBPα:

CCAAT/enhancer-binding protein α

CP:

Ceruloplasmin

DAMPs:

Damage-associated molecular patterns

DcytB:

Duodenal cytochrome b

DMT1:

Divalent metal transporter-1

EGF:

Epidermal growth factor

EPO:

Erythropoietin

ERFE:

Erythroferrone

FPN:

Ferroportin

GLUT4:

Glucose transporter 4

GPX4:

Glutathione peroxidase 4

GSH:

Glutathione

HCP1:

Heme carrier protein-1

HIFs:

Hypoxia-inducible factors

HJV:

Hemojuvelin

HO1:

Heme oxygenase 1

HSCs:

Hepatic stellate cells

HGF:

Hepatocyte growth factor

4-HNE:

4-Hydroxy-2-nonenal

IL6:

Interleukin 6

IL1β:

Interleukin 1β

IL22:

Interleukin 22

IRE:

Iron-responsive element

IRPs:

Iron regulatory proteins

IRS1:

Insulin receptor substrate 1

JAK2:

Janus kinase 2

KCs:

Kupffer cells

LCN2:

Lipocalin-2

LPS:

Lipopolysaccharide

NAC:

N-Acetylcysteine

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

NF-κB:

Nuclear factor-κB

NLRP3:

NOD-like receptor family pyrin domain containing 3

NRF2:

Nuclear factor erythroid 2-related factor 2

PDGFRβ:

Platelet-derived growth factor receptor β

ROS:

Reactive oxygen species

SIRT1:

Sirtuin1

αSMA:

Smooth muscle α-actin

STAT3:

Signal transducers and activators of transcription 3

TS:

Transferrin saturation

TfR:

Transferrin receptor

TNFα:

Tumor necrosis factor α

References

  1. Manthey J, Shield KD, Rylett M, Hasan OSM, Probst C, Rehm J (2019) Global alcohol exposure between 1990 and 2017 and forecasts until 2030: a modelling study. Lancet 393:2493–2502

    Article  PubMed  Google Scholar 

  2. WHO (2014) Global status report on noncommunicable diseases 2014. WHO

    Google Scholar 

  3. Dang K, Hirode G, Singal AK, Sundaram V, Wong RJ (2020) Alcoholic liver disease epidemiology in the United States: a retrospective analysis of 3 US Databases. Am J Gastroenterol 115:96–104

    Article  PubMed  Google Scholar 

  4. Liu Z, Mao X, Jiang Y, Cai N, Jin L, Zhang T, Chen X (2019) Changing trends in the disease burden of primary liver cancer caused by specific etiologies in China. Cancer Med 8:5787–5799

    Article  PubMed  PubMed Central  Google Scholar 

  5. Jang JY, Kim DJ (2018) Epidemiology of alcoholic liver disease in Korea. Clin Mol Hepatol 24:93–99

    Article  PubMed  PubMed Central  Google Scholar 

  6. Singal AK, Bataller R, Ahn J, Kamath PS, Shah VH (2018) ACG clinical guideline: alcoholic liver disease. Am J Gastroenterol 113:175–194

    Article  PubMed  PubMed Central  Google Scholar 

  7. Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, Mathurin P, Mueller S, Szabo G, Tsukamoto H (2018) Alcoholic liver disease. Nat Rev Dis Primers 4:16

    Article  PubMed  Google Scholar 

  8. Ganz T (2013) Systemic iron homeostasis. Physiol Rev 93:1721–1741

    Article  CAS  PubMed  Google Scholar 

  9. Geissler C, Singh M (2011) Iron, meat and health. Nutrients 3:283–316

    Article  PubMed  PubMed Central  Google Scholar 

  10. Stal P, Broome U, Scheynius A, Befrits R, Hultcrantz R (1995) Kupffer cell iron overload induces intercellular adhesion molecule-1 expression on hepatocytes in genetic hemochromatosis. Hepatology 21:1308–1316

    Article  CAS  PubMed  Google Scholar 

  11. Wang H, An P, Xie E, Wu Q, Fang X, Gao H, Zhang Z, Li Y, Wang X, Zhang J, Li G, Yang L, Liu W, Min J, Wang F (2017) Transcription. Hepatology (Baltimore, MD) 66:449–465

    Article  CAS  Google Scholar 

  12. Chen X, Yu C, Kang R, Tang D (2020) Iron metabolism in ferroptosis. Front Cell Dev Biol 8:590226

    Article  PubMed  PubMed Central  Google Scholar 

  13. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascon S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD (2017) Ferroptosis: a regulated cell death nexus linking metabolism. Redox Biol Dis Cell 171:273–285

    CAS  Google Scholar 

  14. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149:1060–1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Koh EH, Yoon JE, Ko MS, Leem J, Yun JY, Hong CH, Cho YK, Lee SE, Jang JE, Baek JY, Yoo HJ, Kim SJ, Sung CO, Lim JS, Jeong WI, Back SH, Baek IJ, Torres S, Solsona-Vilarrasa E, Conde De La Rosa L, Garcia-Ruiz C, Feldstein AE, Fernandez-Checa JC, Lee KU (2021) Sphingomyelin synthase 1 mediates hepatocyte pyroptosis to trigger non-alcoholic steatohepatitis. Gut 70:1954–1964

    Article  CAS  PubMed  Google Scholar 

  16. Huang H, Tohme S, Al-Khafaji AB, Tai S, Loughran P, Chen L, Wang S, Kim J, Billiar T, Wang Y, Tsung A (2015) Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology 62:600–614

    Article  CAS  PubMed  Google Scholar 

  17. Harrison-Findik DD (2007) Role of alcohol in the regulation of iron metabolism. World J Gastroenterol 13:4925–4930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ioannou GN, Dominitz JA, Weiss NS, Heagerty PJ, Kowdley KV (2004) The effect of alcohol consumption on the prevalence of iron overload, iron deficiency, and iron deficiency anemia. Gastroenterology 126:1293–1301

    Article  CAS  PubMed  Google Scholar 

  19. Liu YS, Xu GY, Cheng DQ, Li YM (2005) Determination of serum carbohydrate-deficient transferrin in the diagnosis of alcoholic liver disease. Hepatobiliary Pancreat Dis Int 4:265–268

    CAS  PubMed  Google Scholar 

  20. Nomura F, Kanda T, Seimiya M, Satoh M, Kageyama Y, Yamashita T, Yokosuka O, Kato N, Maruyama K (2018) Determination of serum carbohydrate-deficient transferrin by a nephelometric immunoassay for differential diagnosis of alcoholic and non-alcoholic liver diseases. Clin Chim Acta 485:181–186

    Article  CAS  PubMed  Google Scholar 

  21. Anderson ER, Shah YM (2013) Iron homeostasis in the liver. Compr Physiol 3:315–330

    Article  PubMed  PubMed Central  Google Scholar 

  22. Steinbicker AU, Muckenthaler MU (2013) Out of balance–systemic iron homeostasis in iron-related disorders. Nutrients 5:3034–3061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Delaby C, Pilard N, Puy H, Canonne-Hergaux F (2008) Sequential regulation of ferroportin expression after erythrophagocytosis in murine macrophages: early mRNA induction by haem, followed by iron-dependent protein expression. Biochem J 411:123–131

    Article  CAS  PubMed  Google Scholar 

  24. Delaby C, Pilard N, Hetet G, Driss F, Grandchamp B, Beaumont C, Canonne-Hergaux F (2005) A physiological model to study iron recycling in macrophages. Exp Cell Res 310:43–53

    Article  CAS  PubMed  Google Scholar 

  25. Siah CW, Ombiga J, Adams LA, Trinder D, Olynyk JK (2006) Normal iron metabolism and the pathophysiology of iron overload disorders. Clin Biochem Rev 27:5–16

    PubMed  PubMed Central  Google Scholar 

  26. Mackenzie B, Garrick MD (2005) Iron imports. II. Iron uptake at the apical membrane in the intestine. Am J Physiol Gastrointest Liver Physiol 289:G981–G986

    Article  CAS  PubMed  Google Scholar 

  27. Donovan A, Lima CA, Pinkus JL, Pinkus GS, Zon LI, Robine S, Andrews NC (2005) The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 1:191–200

    Article  CAS  PubMed  Google Scholar 

  28. Winter WE, Bazydlo LA, Harris NS (2014) The molecular biology of human iron metabolism. Lab Med 45:92–102

    Article  PubMed  Google Scholar 

  29. West AR, Oates PS (2008) Mechanisms of heme iron absorption: current questions and controversies. World J Gastroenterol 14:4101–4110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Anderson GJ, Frazer DM, Mckie AT, Vulpe CD, Smith A (2005) Mechanisms of haem and non-haem iron absorption: lessons from inherited disorders of iron metabolism. Biometals 18:339–348

    Article  CAS  PubMed  Google Scholar 

  31. Hahn P, Qian Y, Dentchev T, Chen L, Beard J, Harris ZL, Dunaief JL (2004) Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration. Proc Natl Acad Sci USA 101:13850–13855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cherukuri S, Potla R, Sarkar J, Nurko S, Harris ZL, Fox PL (2005) Unexpected role of ceruloplasmin in intestinal iron absorption. Cell Metab 2:309–319

    Article  CAS  PubMed  Google Scholar 

  33. Ward DM, Kaplan J (2012) Ferroportin-mediated iron transport: expression and regulation. Biochim Biophys Acta 1823:1426–1433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kawabata H (2019) Transferrin and transferrin receptors update. Free Radic Biol Med 133:46–54

    Article  CAS  PubMed  Google Scholar 

  35. Arosio P, Ingrassia R, Cavadini P (2009) Ferritins: a family of molecules for iron storage, antioxidation and more. Biochim Biophys Acta 1790:589–599

    Article  CAS  PubMed  Google Scholar 

  36. Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, Paw BH, Drejer A, Barut B, Zapata A, Law TC, Brugnara C, Lux SE, Pinkus GS, Pinkus JL, Kingsley PD, Palis J, Fleming MD, Andrews NC, Zon LI (2000) Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403:776–781

    Article  CAS  PubMed  Google Scholar 

  37. Li Y, Huang X, Wang J, Huang R, Wan D (2020) Regulation of iron homeostasis and related diseases. Mediat Inflamm 2020:6062094

    Google Scholar 

  38. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093

    Article  CAS  PubMed  Google Scholar 

  39. Sangkhae V, Nemeth E (2017) Regulation of the iron homeostatic hormone hepcidin. Adv Nutr 8:126–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang RH, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, Cooperman S, Eckhaus M, Rouault T, Mishra L, Deng CX (2005) A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2:399–409

    Article  CAS  PubMed  Google Scholar 

  41. Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang RH, Deng C, Vaulont S, Mosser J, Coppin H, Roth MP (2008) Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad 7, Id1, and Atoh8 in the mouse liver. Blood 112:1503–1509

    Article  CAS  PubMed  Google Scholar 

  42. Wessling-Resnick M (2010) Iron homeostasis and the inflammatory response. Annu Rev Nutr 30:105–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Inamura J, Ikuta K, Jimbo J, Shindo M, Sato K, Torimoto Y, Kohgo Y (2005) Upregulation of hepcidin by interleukin-1beta in human hepatoma cell lines. Hepatol Res 33:198–205

    Article  CAS  PubMed  Google Scholar 

  44. Wallace DF, Subramaniam VN (2015) Analysis of IL-22 contribution to hepcidin induction and hypoferremia during the response to LPS in vivo. Int Immunol 27:281–287

    Article  CAS  PubMed  Google Scholar 

  45. Chung B, Verdier F, Matak P, Deschemin JC, Mayeux P, Vaulont S (2010) Oncostatin M is a potent inducer of hepcidin, the iron regulatory hormone. Faseb J 24:2093–2103

    Article  CAS  PubMed  Google Scholar 

  46. Falzacappa MVV, Spasic MV, Kessler R, Stolte J, Hentze MW, Muckenthaler MU (2007) STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 109:353–358

    Article  CAS  Google Scholar 

  47. Pellegrini S, Dusanter-Fourt I (1997) The structure, regulation and function of the Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs). Eur J Biochem 248:615–633

    Article  CAS  PubMed  Google Scholar 

  48. Sakamori R, Takehara T, Tatsumi T, Shigekawa M, Hikita H, Hiramatsu N, Kanto T, Hayashi N (2010) STAT3 signaling within hepatocytes is required for anemia of inflammation in vivo. J Gastroenterol 45:244–248

    Article  PubMed  Google Scholar 

  49. Long J, Wang G, Matsuura I, He D, Liu F (2004) Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3). Proc Natl Acad Sci USA 101:99–104

    Article  CAS  PubMed  Google Scholar 

  50. Mastrogiannaki M, Matak P, Mathieu JR, Delga S, Mayeux P, Vaulont S, Peyssonnaux C (2012) Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis. Haematologica 97:827–834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, Nizet V, Johnson RS (2007) Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest 117:1926–1932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Origa R, Galanello R, Ganz T, Giagu N, Maccioni L, Faa G, Nemeth E (2007) Liver iron concentrations and urinary hepcidin in beta-thalassemia. Haematologica 92:583–588

    Article  CAS  PubMed  Google Scholar 

  53. Pinto JP, Ribeiro S, Pontes H, Thowfeequ S, Tosh D, Carvalho F, Porto G (2008) Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBPalpha. Blood 111:5727–5733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T (2014) Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet 46:678–684

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang CY, Core AB, Canali S, Zumbrennen-Bullough KB, Ozer S, Umans L, Zwijsen A, Babitt JL (2017) Smad1/5 is required for erythropoietin-mediated suppression of hepcidin in mice. Blood 130:73–83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Arezes J, Foy N, Mchugh K, Sawant A, Quinkert D, Terraube V, Brinth A, Tam M, Lavallie ER, Taylor S, Armitage AE, Pasricha SR, Cunningham O, Lambert M, Draper SJ, Jasuja R, Drakesmithm H (2018) Erythroferrone inhibits the induction of hepcidin by BMP6. Blood 132:1473–1477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Goodnough JB, Ramos E, Nemeth E, Ganz T (2012) Inhibition of hepcidin transcription by growth factors. Hepatology (Baltimore, MD) 56:291–299

    Article  CAS  Google Scholar 

  58. Guo W, Bachman E, Li M, Roy CN, Blusztajn J, Wong S, Chan SY, Serra C, Jasuja R, Travison TG, Muckenthaler MU, Nemeth E, Bhasin S (2013) Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells. Aging Cell 12:280–291

    Article  CAS  PubMed  Google Scholar 

  59. Lehtihet M, Bonde Y, Beckman L, Berinder K, Hoybye C, Rudling M, Sloan JH, Konrad RJ, Angelin B (2016) Circulating Hepcidin-25 is reduced by endogenous estrogen in humans. PLoS ONE 11:e0148802

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Yang Q, Jian J, Katz S, Abramson SB, Huang X (2012) 17beta-Estradiol inhibits iron hormone hepcidin through an estrogen responsive element half-site. Endocrinology 153:3170–3178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang J, Pantopoulos K (2011) Regulation of cellular iron metabolism. Biochem J 434:365–381

    Article  CAS  PubMed  Google Scholar 

  62. Muckenthaler MU, Galy B, Hentze MW (2008) Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr 28:197–213

    Article  CAS  PubMed  Google Scholar 

  63. Wilkinson N, Pantopoulos K (2014) The IRP/IRE system in vivo: insights from mouse models. Front Pharmacol 5:176

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Sanchez M, Galy B, Muckenthaler MU, Hentze MW (2007) Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency. Nat Struct Mol Biol 14:420–426

    Article  CAS  PubMed  Google Scholar 

  65. Salahudeen AA, Thompson JW, Ruiz JC, Ma HW, Kinch LN, Li Q, Grishin NV, Bruick RK (2009) An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis. Science 326:722–726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Vashisht AA, Zumbrennen KB, Huang X, Powers DN, Durazo A, Sun D, Bhaskaran N, Persson A, Uhlen M, Sangfelt O, Spruck C, Leibold EA, Wohlschlegel JA (2009) Control of iron homeostasis by an iron-regulated ubiquitin ligase. Science 326:718–721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhou ZD, Tan EK (2017) Iron regulatory protein (IRP)-iron responsive element (IRE) signaling pathway in human neurodegenerative diseases. Mol Neurodegener 12:75

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Pantopoulos K (2004) Iron metabolism and the IRE/IRP regulatory system: an update. Ann N Y Acad Sci 1012:1–13

    Article  CAS  PubMed  Google Scholar 

  69. Hentze MW, Muckenthaler MU, Galy B, Camaschella C (2010) Two to tango: regulation of Mammalian iron metabolism. Cell 142:24–38

    Article  CAS  PubMed  Google Scholar 

  70. Ford C, Wells FE, Rogers JN (1995) Assessment of iron status in association with excess alcohol consumption. Ann Clin Biochem 32(Pt 6):527–531

    Article  CAS  PubMed  Google Scholar 

  71. Bell H, Skinningsrud A, Raknerud N, Try K (1994) Serum ferritin and transferrin saturation in patients with chronic alcoholic and non-alcoholic liver diseases. J Intern Med 236:315–322

    Article  CAS  PubMed  Google Scholar 

  72. Whitfield JB, Zhu G, Heath AC, Powell LW, Martin NG (2001) Effects of alcohol consumption on indices of iron stores and of iron stores on alcohol intake markers. Alcohol Clin Exp Res 25:1037–1045

    Article  CAS  PubMed  Google Scholar 

  73. Friedman IM, Kraemer HC, Mendoza FS, Hammer LD (1988) Elevated serum iron concentration in adolescent alcohol users. Am J Dis Child 142:156–159

    CAS  PubMed  Google Scholar 

  74. Ganne-Carrie N, Christidis C, Chastang C, Ziol M, Chapel F, Imbert-Bismut F, Trinchet JC, Guettier C, Beaugrand M (2000) Liver iron is predictive of death in alcoholic cirrhosis: a multivariate study of 229 consecutive patients with alcoholic and/or hepatitis C virus cirrhosis: a prospective follow up study. Gut 46:277–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Atkinson SR, Hamesch K, Spivak I, Guldiken N, Cabezas J, Argemi J, Theurl I, Zoller H, Cao S, Mathurin P, Shah VH, Trautwein C, Bataller R, Thursz MR, Strnad P (2020) Serum transferrin is an independent predictor of mortality in severe alcoholic hepatitis. Am J Gastroenterol 115:398–405

    Article  PubMed  Google Scholar 

  76. Stal P, Hultcrantz R (1993) Iron increases ethanol toxicity in rat liver. J Hepatol 17:108–115

    Article  CAS  PubMed  Google Scholar 

  77. Tsukamoto H, Horne W, Kamimura S, Niemela O, Parkkila S, Yla-Herttuala S, Brittenham GM (1995) Experimental liver cirrhosis induced by alcohol and iron. J Clin Invest 96:620–630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Harrison-Findik DD, Schafer D, Klein E, Timchenko NA, Kulaksiz H, Clemens D, Fein E, Andriopoulos B, Pantopoulos K, Gollan J (2006) Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J Biol Chem 281:22974–22982

    Article  CAS  PubMed  Google Scholar 

  79. Harrison-Findik DD, Lu S, Zmijewski EM, Jones J, Zimmerman MC (2013) Effect of alcohol exposure on hepatic superoxide generation and hepcidin expression World. J Biol Chem 4:119–130

    Google Scholar 

  80. Bridle K, Cheung TK, Murphy T, Walters M, Anderson G, Crawford DG, Fletcher LM (2006) Hepcidin is down-regulated in alcoholic liver injury: implications for the pathogenesis of alcoholic liver disease. Alcohol Clin Exp Res 30:106–112

    Article  CAS  PubMed  Google Scholar 

  81. Harrison-Findik DD, Klein E, Crist C, Evans J, Timchenko N, Gollan J (2007) Iron-mediated regulation of liver hepcidin expression in rats and mice is abolished by alcohol. Hepatology (Baltimore, MD) 46:1979–1985

    Article  CAS  Google Scholar 

  82. Dostalikova-Cimburova M, Balusikova K, Kratka K, Chmelikova J, Hejda V, Hnanicek J, Neubauerova J, Vranova J, Kovar J, Horak J (2014) Role of duodenal iron transporters and hepcidin in patients with alcoholic liver disease. J Cell Mol Med 18:1840–1850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Nishimura K, Katuyama H, Nakagawa H, Matuo S (2014) Stimulating effect of ethanol on erythropoietin production in the liver cells. J Metab Syndr 3:164

    Google Scholar 

  84. Giglio MJ, Santoro RC, Bozzini CE (1984) Effect of chronic ethanol administration on production of and response to erythropoietin in the mouse. Alcohol Clin Exp Res 8:323–325

    Article  CAS  PubMed  Google Scholar 

  85. Suzuki Y, Saito H, Suzuki M, Hosoki Y, Sakurai S, Fujimoto Y, Kohgo Y (2002) Up-regulation of transferrin receptor expression in hepatocytes by habitual alcohol drinking is implicated in hepatic iron overload in alcoholic liver disease. Alcohol Clin Exp Res 26:26S-31S

    Article  CAS  PubMed  Google Scholar 

  86. Suzuki M, Fujimoto Y, Suzuki Y, Hosoki Y, Saito H, Nakayama K, Ohtake T, Kohgo Y (2004) Induction of transferrin receptor by ethanol in rat primary hepatocyte culture. Alcohol Clin Exp Res 28:98S-105S

    Article  CAS  PubMed  Google Scholar 

  87. Zhou Z, Ye TJ, Decaro E, Buehler B, Stahl Z, Bonavita G, Daniels M, You M (2020) Intestinal SIRT1 deficiency protects mice from ethanol-induced liver injury by mitigating ferroptosis. Am J Pathol 190:82–92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Song E, Ramos SV, Huang X, Liu Y, Botta A, Sung HK, Turnbull PC, Wheeler MB, Berger T, Wilson DJ, Perry CGR, Mak TW, Sweeney G (2018) Holo-lipocalin-2-derived siderophores increase mitochondrial ROS and impair oxidative phosphorylation in rat cardiomyocytes. Proc Natl Acad Sci USA 115:1576–1581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Harrison-Findik DD, Klein E, Evans J, Gollan J (2009) Regulation of liver hepcidin expression by alcohol in vivo does not involve Kupffer cell activation or TNF-alpha signaling. Am J Physiol Gastrointest Liver Physiol 296:G112–G118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Casanovas G, Mleczko-Sanecka K, Altamura S, Hentze MW, Muckenthaler MU (2009) Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV/BMP/SMAD. J Mol Med (Berl) 87:471–480

    Article  CAS  Google Scholar 

  91. Falzacappa MVV, Casanovas G, Hentze MW, Muckenthaler MU (2008) A bone morphogenetic protein (BMP)-responsive element in the hepcidin promoter controls HFE2-mediated hepatic hepcidin expression and its response to IL-6 in cultured cells. J Mol Med (Berl) 86:531–540

    Article  CAS  Google Scholar 

  92. Bacon BR, Britton RS (1990) The pathology of hepatic iron overload: a free radical–mediated process? Hepatology 11:127–137

    Article  CAS  PubMed  Google Scholar 

  93. Latunde-Dada GO (2017) Ferroptosis: Role of lipid peroxidation, iron and ferritinophagy. Biochimica et Biophysica Acta Gen Subj 1861:1893–1900

    Article  CAS  Google Scholar 

  94. Liu CY, Wang M, Yu HM, Han FX, Wu QS, Cai XJ, Kurihara H, Chen YX, Li YF, He RR (2020) Ferroptosis is involved in alcohol-induced cell death in vivo and in vitro. Biosci Biotechnol Biochem 84:1621–1628

    Article  CAS  PubMed  Google Scholar 

  95. Dodson M, Castro-Portuguez R, Zhang DD (2019) NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol 23:101107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhang Y, Zhao S, Fu Y, Yan L, Feng YL, Chen YQ, Wu YJ, Deng YL, Zhang GY, Chen ZC, Chen YH, Liu T (2020) Computational repositioning of dimethyl fumarate for treating alcoholic liver disease. Cell Death Dis 11:641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Liu JJ, He H, Wang J, Guo XP, Lin HK, Chen HM, Jiang CJ, Chen L, Yao P, Tang YH (2020) Oxidative stress-dependent frataxin inhibition mediated alcoholic hepatocytotoxicity through ferroptosis. Toxicology 445:152584

    Article  CAS  PubMed  Google Scholar 

  98. Ivanov AV, Bartosch B, Smirnova OA, Isaguliants MG, Kochetkov SN (2013) HCV and oxidative stress in the liver. Viruses 5:439–469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Pietrangelo A (2003) Iron-induced oxidant stress in alcoholic liver fibrogenesis. Alcohol (Fayetteville, NY) 30:121–129

    Article  CAS  Google Scholar 

  100. Handa P, Thomas S, Morgan-Stevenson V, Maliken BD, Gochanour E, Boukhar S, Yeh MM, Kowdley KV (2019) Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis. J Leukoc Biol 105:1015–1026

    Article  CAS  PubMed  Google Scholar 

  101. Tsukamoto H, Lin M, Ohata M, Giulivi C, French SW, Brittenham G (1999) Iron primes hepatic macrophages for NF-kappaB activation in alcoholic liver injury. Am J Physiol 277:G1240–G1250

    CAS  PubMed  Google Scholar 

  102. Xiong S, She H, Sung CK, Tsukamoto H (2003) Iron-dependent activation of NF-kappaB in Kupffer cells: a priming mechanism for alcoholic liver disease. Alcohol 30:107–113

    Article  CAS  PubMed  Google Scholar 

  103. Xiong S, She H, Zhang AS, Wang J, Mkrtchyan H, Dynnyk A, Gordeuk VR, French SW, Enns CA, Tsukamoto H (2008) Hepatic macrophage iron aggravates experimental alcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 295:G512–G521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zeng T, Zhang C-L, Xiao M, Yang R, Xie K-Q (2016) Critical roles of Kupffer cells in the pathogenesis of alcoholic liver disease: from basic science to clinical trials. Front Immunol 7:538

    PubMed  PubMed Central  Google Scholar 

  105. Hoeft K, Bloch DB, Graw JA, Malhotra R, Ichinose F, Bagchi A (2017) Iron loading exaggerates the inflammatory response to the toll-like receptor 4 ligand lipopolysaccharide by altering mitochondrial homeostasis. Anesthesiology 127:121–135

    Article  CAS  PubMed  Google Scholar 

  106. Houglum K, Bedossa P, Chojkier M (1994) TGF-beta and collagen-alpha 1 (I) gene expression are increased in hepatic acinar zone 1 of rats with iron overload. Am J Physiol 267:G908–G913

    CAS  PubMed  Google Scholar 

  107. Carthew P, Edwards RE, Smith AG, Dorman B, Francis JE (1991) Rapid induction of hepatic fibrosis in the gerbil after the parenteral administration of iron-dextran complex. Hepatology 13:534–539

    Article  CAS  PubMed  Google Scholar 

  108. Arezzini B, Lunghi B, Lungarella G, Gardi C (2003) Iron overload enhances the development of experimental liver cirrhosis in mice. Int J Biochem Cell Biol 35:486–495

    Article  CAS  PubMed  Google Scholar 

  109. Gardi C, Arezzini B, Fortino V, Comporti M (2002) Effect of free iron on collagen synthesis, cell proliferation and MMP-2 expression in rat hepatic stellate cells. Biochem Pharmacol 64:1139–1145

    Article  CAS  PubMed  Google Scholar 

  110. Otogawa K, Ogawa T, Shiga R, Nakatani K, Ikeda K, Nakajima Y, Kawada N (2008) Attenuation of acute and chronic liver injury in rats by iron-deficient diet. Am J Physiol Regul Integr Comp Physiol 294:R311–R320

    Article  CAS  PubMed  Google Scholar 

  111. Datz C, Muller E, Aigner E (2017) Iron overload and non-alcoholic fatty liver disease. Minerva Endocrinol 42:173–183

    Article  PubMed  Google Scholar 

  112. Aigner E, Theurl I, Theurl M, Lederer D, Haufe H, Dietze O, Strasser M, Datz C, Weiss G (2008) Pathways underlying iron accumulation in human nonalcoholic fatty liver disease. Am J Clin Nutr 87:1374–1383

    Article  CAS  PubMed  Google Scholar 

  113. Fujita N, Miyachi H, Tanaka H, Takeo M, Nakagawa N, Kobayashi Y, Iwasa M, Watanabe S, Takei Y (2009) Iron overload is associated with hepatic oxidative damage to DNA in nonalcoholic steatohepatitis. Cancer Epidemiol Biomarkers Prev 18:424–432

    Article  CAS  PubMed  Google Scholar 

  114. Fargion S, Mattioli M, Fracanzani AL, Sampietro M, Tavazzi D, Fociani P, Taioli E, Valenti L, Fiorelli G (2001) Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis. Am J Gastroenterol 96:2448–2455

    Article  CAS  PubMed  Google Scholar 

  115. Turlin B, Mendler MH, Moirand R, Guyader D, Guillygomarc’h A, Deugnier Y (2001) Histologic features of the liver in insulin resistance-associated iron overload. A study of 139 patients. Am J Clin Pathol 116:263–270

    Article  CAS  PubMed  Google Scholar 

  116. Buzzetti E, Petta S, Manuguerra R, Luong TV, Cabibi D, Corradini E, Craxi A, Pinzani M, Tsochatzis E, Pietrangelo A (2019) Evaluating the association of serum ferritin and hepatic iron with disease severity in non-alcoholic fatty liver disease. Liver Int 39:1325–1334

    Article  CAS  PubMed  Google Scholar 

  117. Kowdley KV, Belt P, Wilson LA, Yeh MM, Neuschwander-Tetri BA, Chalasani N, Sanyal AJ, Nelson JE, Network NCR (2012) Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 55:77–85

    Article  CAS  PubMed  Google Scholar 

  118. Valenti L, Dongiovanni P, Fargion S (2012) Diagnostic and therapeutic implications of the association between ferritin level and severity of nonalcoholic fatty liver disease. World J Gastroenterol 18:3782–3786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Barisani D, Pelucchi S, Mariani R, Galimberti S, Trombini P, Fumagalli D, Meneveri R, Nemeth E, Ganz T, Piperno A (2008) Hepcidin and iron-related gene expression in subjects with dysmetabolic hepatic iron overload. J Hepatol 49:123–133

    Article  CAS  PubMed  Google Scholar 

  120. Boga S, Alkim H, Alkim C, Koksal AR, Bayram M, Yilmaz Ozguven MB, Tekin NS (2015) The relationship of serum hemojuvelin and hepcidin levels with iron overload in nonalcoholic fatty liver disease. J Gastrointest Liver Dis 24:293–300

    Article  Google Scholar 

  121. Wang C, Wang X, Song G, Xing H, Yang L, Han K, Chang YZ (2021) A high-fructose diet in rats induces systemic iron deficiency and hepatic iron overload by an inflammation mechanism. J Food Biochem 45:e13578

    CAS  PubMed  Google Scholar 

  122. Hoki T, Miyanishi K, Tanaka S, Takada K, Kawano Y, Sakurada A, Sato M, Kubo T, Sato T, Sato Y, Takimoto R, Kobune M, Kato J (2015) Increased duodenal iron absorption through up-regulation of divalent metal transporter 1 from enhancement of iron regulatory protein 1 activity in patients with nonalcoholic steatohepatitis. Hepatology 62:751–761

    Article  CAS  PubMed  Google Scholar 

  123. Otogawa K, Kinoshita K, Fujii H, Sakabe M, Shiga R, Nakatani K, Ikeda K, Nakajima Y, Ikura Y, Ueda M, Arakawa T, Hato F, Kawada N (2007) Erythrophagocytosis by liver macrophages (Kupffer cells) promotes oxidative stress, inflammation, and fibrosis in a rabbit model of steatohepatitis: implications for the pathogenesis of human nonalcoholic steatohepatitis. Am J Pathol 170:967–980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Tan TC, Crawford DH, Jaskowski LA, Subramaniam VN, Clouston AD, Crane DI, Bridle KR, Anderson GJ, Fletcher LM (2013) Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury. Lab Invest 93:1295–1312

    Article  CAS  PubMed  Google Scholar 

  125. Nelson JE, Klintworth H, Kowdley KV (2012) Iron metabolism in nonalcoholic fatty liver disease. Curr Gastroenterol Rep 14:8–16

    Article  PubMed  Google Scholar 

  126. Handa P, Morgan-Stevenson V, Maliken BD, Nelson JE, Washington S, Westerman M, Yeh MM, Kowdley KV (2016) Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice. Am J Physiol Gastrointest Liver Physiol 310:G117–G127

    Article  PubMed  Google Scholar 

  127. Jia M, Zhang H, Qin Q, Hou Y, Zhang X, Chen D, Zhang H, Chen Y (2021) Ferroptosis as a new therapeutic opportunity for nonviral liver disease. Eur J Pharmacol 908:174319

    Article  CAS  PubMed  Google Scholar 

  128. Rumberger JM, Peters T Jr, Burrington C, Green A (2004) Transferrin and iron contribute to the lipolytic effect of serum in isolated adipocytes. Diabetes 53:2535–2541

    Article  CAS  PubMed  Google Scholar 

  129. Green A, Basile R, Rumberger JM (2006) Transferrin and iron induce insulin resistance of glucose transport in adipocytes. Metabolism 55:1042–1045

    Article  CAS  PubMed  Google Scholar 

  130. Krawczyk M, Bonfrate L, Portincasa P (2010) Nonalcoholic fatty liver disease. Best Pract Res Clin Gastroenterol 24:695–708

    Article  CAS  PubMed  Google Scholar 

  131. Dongiovanni P, Valenti L, Ludovica Fracanzani A, Gatti S, Cairo G, Fargion S (2008) Iron depletion by deferoxamine up-regulates glucose uptake and insulin signaling in hepatoma cells and in rat liver. Am J Pathol 172:738–747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Silva M, Silva ME, De Paula H, Carneiro CM, Pedrosa ML (2008) Iron overload alters glucose homeostasis, causes liver steatosis, and increases serum triacylglycerols in rats. Nutr Res 28:391–398

    Article  CAS  PubMed  Google Scholar 

  133. Kirsch R, Sijtsema HP, Tlali M, Marais AD, Hall PL (2006) Effects of iron overload in a rat nutritional model of non-alcoholic fatty liver disease. Liver Int 26:1258–1267

    Article  CAS  PubMed  Google Scholar 

  134. Farooq MO, Bataller R (2016) Pathogenesis and management of alcoholic liver disease. Dig Dis 34:347–355

    Article  PubMed  Google Scholar 

  135. Golka K, Wiese A (2004) Carbohydrate-deficient transferrin (CDT)–a biomarker for long-term alcohol consumption. J Toxicol Environ Health Part B Crit Rev 7:319–337

    Article  CAS  Google Scholar 

  136. Lakso HA, Wuolikainen A, Sundkvist A, Johansson I, Marklund SL (2019) Long-term stability of the alcohol consumption biomarker phosphatidylethanol in erythrocytes at − 80 degrees C. Clin Mass Spectrom 11:37–41

    Article  PubMed  Google Scholar 

  137. Stadheim LM, O’brien JF, Lindor KD, Gores GJ, Mcgill DB (2003) Value of determining carbohydrate-deficient transferrin isoforms in the diagnosis of alcoholic liver disease. Mayo Clin Proc 78:703–707

    Article  CAS  PubMed  Google Scholar 

  138. Ribot-Hernandez I, Martin-Gonzalez C, Vera-Delgado V, Gonzalez-Navarrete L, De Armas-Gonzalez JF, Vina-Rodriguez J, Sanchez-Perez MJ, Rodriguez-Gaspar M, Gonzalez-Reimers E (2020) Prognostic value of serum iron, ferritin, and transferrin in chronic alcoholic liver disease. Biol Trace Elem Res 195:427–435

    Article  CAS  PubMed  Google Scholar 

  139. Nahon P, Nuraldeen R, Rufat P, Sutton A, Trautwein C, Strnad P (2016) In alcoholic cirrhosis, low-serum hepcidin levels associate with poor long-term survival. Liver Int 36:185–188

    Article  CAS  PubMed  Google Scholar 

  140. Maggio A, Kattamis A, Felisi M, Reggiardo G, El-Beshlawy A, Bejaoui M, Sherief L, Christou S, Cosmi C, Della Pasqua O, Del Vecchio GC, Filosa A, Cuccia L, Hassab H, Kreka M, Origa R, Putti MC, Spino M, Telfer P, Tempesta B, Vitrano A, Tsang YC, Zaka A, Tricta F, Bonifazi D, Ceci A (2020) Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial. Lancet Haematol 7:e469–e478

    Article  PubMed  Google Scholar 

  141. Bollig C, Schell LK, Rucker G, Allert R, Motschall E, Niemeyer CM, Bassler D, Meerpohl JJ (2017) Deferasirox for managing iron overload in people with thalassaemia. Cochrane Database Syst Rev 8:CD007476

    PubMed  Google Scholar 

  142. Sadrzadeh SM, Nanji AA, Price PL (1994) The oral iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one reduces hepatic-free iron, lipid peroxidation and fat accumulation in chronically ethanol-fed rats. J Pharmacol Exp Ther 269:632–636

    CAS  PubMed  Google Scholar 

  143. Xiao J, Lv Y, Lin B, Tipoe GL, Youdim MB, Xing F, Liu Y (2015) A novel antioxidant multitarget iron chelator M30 protects hepatocytes against ethanol-induced injury. Oxid Med Cell Longev 2015:607271

    PubMed  PubMed Central  Google Scholar 

  144. Sadrzadeh SM, Hallaway PE, Nanji AA (1997) The long-acting parenteral iron chelator, hydroxyethyl starch-deferoxamine, fails to protect against alcohol-induced liver injury in rats. J Pharmacol Exp Ther 280:1038–1042

    CAS  PubMed  Google Scholar 

  145. Scindia Y, Wlazlo E, Leeds J, Loi V, Ledesma J, Cechova S, Ghias E, Swaminathan S (2019) Protective role of hepcidin in polymicrobial sepsis and acute kidney injury. Front Pharmacol 10:615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Huang YH, Yang YL, Tiao MM, Kuo HC, Huang LT, Chuang JH (2012) Hepcidin protects against lipopolysaccharide-induced liver injury in a mouse model of obstructive jaundice. Peptides 35:212–217

    Article  CAS  PubMed  Google Scholar 

  147. Preza GC, Ruchala P, Pinon R, Ramos E, Qiao B, Peralta MA, Sharma S, Waring A, Ganz T, Nemeth E (2011) Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Investig 121:4880–4888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Ramos E, Ruchala P, Goodnough JB, Kautz L, Preza GC, Nemeth E, Ganz T (2012) Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood 120:3829–3836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Stewart S, Prince M, Bassendine M, Hudson M, James O, Jones D, Record C, Day CP (2007) A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis. J Hepatol 47:277–283

    Article  CAS  PubMed  Google Scholar 

  150. Mezey E, Potter JJ, Rennie-Tankersley L, Caballeria J, Pares A (2004) A randomized placebo controlled trial of vitamin E for alcoholic hepatitis. J Hepatol 40:40–46

    Article  CAS  PubMed  Google Scholar 

  151. Medici V, Virata MC, Peerson JM, Stabler SP, French SW, Gregory JF 3rd, Albanese A, Bowlus CL, Devaraj S, Panacek EA, Richards JR, Halsted CH (2011) S-adenosyl-l-methionine treatment for alcoholic liver disease: a double-blinded, randomized, placebo-controlled trial. Alcohol Clin Exp Res 35:1960–1965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Li Y, Chen M, Xu Y, Yu X, Xiong T, Du M, Sun J, Liu L, Tang Y, Yao P (2016) Iron-mediated lysosomal membrane permeabilization in ethanol-induced hepatic oxidative damage and apoptosis: protective effects of quercetin. Oxid Med Cell Longev 2016:4147610

    PubMed  Google Scholar 

  153. Tang Y, Li Y, Yu H, Gao C, Liu L, Xing M, Liu L, Yao P (2014) Quercetin attenuates chronic ethanol hepatotoxicity: implication of “free” iron uptake and release. Food Chem Toxicol 67:131–138

    Article  CAS  PubMed  Google Scholar 

  154. Zhao Y, Li H, Gao Z, Xu H (2005) Effects of dietary baicalin supplementation on iron overload-induced mouse liver oxidative injury. Eur J Pharmacol 509:195–200

    Article  CAS  PubMed  Google Scholar 

  155. Zhang Y, Li H, Zhao Y, Gao Z (2006) Dietary supplementation of baicalin and quercetin attenuates iron overload induced mouse liver injury. Eur J Pharmacol 535:263–269

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81872653 and No. 82073585).

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  1. Institute of Toxicology, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China

    Long-Xia Li, Hong Liu & Tao Zeng

  2. Department of Pharmacy, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China

    Fang-Fang Guo

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  1. Long-Xia Li
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  4. Tao Zeng
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TZ conceived the concept of the manuscript. L-XL, F-FG, and HL reviewed the literature and wrote the manuscript.

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Li, LX., Guo, FF., Liu, H. et al. Iron overload in alcoholic liver disease: underlying mechanisms, detrimental effects, and potential therapeutic targets. Cell. Mol. Life Sci. 79, 201 (2022). https://doi.org/10.1007/s00018-022-04239-9

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