Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Reviews in Clinical and Experimental Pharmacology
  4. Fast Track Articles
  5. Fast Track Article
image of The Role of Metformin in Modifying Ferroptosis to Treat Metabolic Dysfunction-Associated Fatty Liver Disease: A Narrative Review

Abstract

Fatty liver disease (FLD) is a well-known metabolic disorder associated with hepatic steatosis and tissue lipid accumulation. Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent and challenging condition that is linked to obesity, diabetes, and other metabolic disorders. MAFLD, previously called NAFLD or nonalcoholic fatty liver disease, is associated with pathological changes in liver tissue. In recent decades, there has been a growing interest in the potential of metformin, a commonly used medication for type-2 diabetes, to help treat MAFLD. Metformin has shown promising potential in treating MAFLD through its ability to modify ferroptosis, a novel form of programmed cell death. In this critical review, we explain the current knowledge about MAFLD, the potential role of ferroptosis in its pathogenesis, and the mechanisms by which metformin may modulate ferroptosis in the context of MAFLD. Additionally, evidence supporting the usage of metformin in treating MAFLD is explained. Overall, this review explains the potential of metformin as a novel therapeutic approach for MAFLD by targeting ferroptosis and provides valuable insights for future research in this area.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/crcep/10.2174/0127724328328193241029103831
2024-12-11
2025-01-19

  • From This Site

    /content/journals/crcep/10.2174/0127724328328193241029103831
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Rojas L.B.A. Gomes M.B. Metformin: An old but still the best treatment for type 2 diabetes. Diabetol. Metab. Syndr. 2013 5 1 6 10.1186/1758‑5996‑5‑6 23415113
    [Google Scholar]
  2. Green C.J. Marjot T. Walsby-Tickle J. Charlton C. Cornfield T. Westcott F. Pinnick K.E. Moolla A. Hazlehurst J.M. McCullagh J. Tomlinson J.W. Hodson L. Metformin maintains intrahepatic triglyceride content through increased hepatic de novo lipogenesis. Eur. J. Endocrinol. 2022 186 3 367 377 10.1530/EJE‑21‑0850 35038311
    [Google Scholar]
  3. Eslam M Sanyal AJ George J Sanyal A Neuschwander-Tetri B Tiribelli C MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology 2020 158 7 1999 2014 10.1053/j.gastro.2019.11.312
    [Google Scholar]
  4. Xian Y.X. Weng J.P. Xu F. MAFLD vs. NAFLD: shared features and potential changes in epidemiology, pathophysiology, diagnosis, and pharmacotherapy. Chin. Med. J. (Engl.) 2021 134 1 8 19 10.1097/CM9.0000000000001263 33323806
    [Google Scholar]
  5. Mokhtare M. Abdi A. Sadeghian A.M. Sotoudeheian M. Namazi A. Khalighi Sikaroudi M. Investigation about the correlation between the severity of metabolic-associated fatty liver disease and adherence to the Mediterranean diet. Clin. Nutr. ESPEN 2023 58 221 227 10.1016/j.clnesp.2023.10.001 38057010
    [Google Scholar]
  6. Mokhtare M. Sadeghian A.M. Sotoudeheian M. S1390 The Accuracy and Reliability of AST to Platelet Ratio Index, FIB-4, FIB-5, and NAFLD Fibrosis Scores in Detecting Advanced Fibrosis in Patients With Metabolic-Associated Fatty Liver Disease. ACG 2023 118 S1064-S5
    [Google Scholar]
  7. Scorletti E. Byrne C.D. Omega-3 fatty acids, hepatic lipid metabolism, and nonalcoholic fatty liver disease. Annu. Rev. Nutr. 2013 33 1 231 248 10.1146/annurev‑nutr‑071812‑161230 23862644
    [Google Scholar]
  8. Chan K.E. Koh T.J.L. Tang A.S.P. Quek J. Yong J.N. Tay P. Tan D.J.H. Lim W.H. Lin S.Y. Huang D. Chan M. Khoo C.M. Chew N.W.S. Kaewdech A. Chamroonkul N. Dan Y.Y. Noureddin M. Muthiah M. Eslam M. Ng C.H. Global prevalence and clinical characteristics of metabolic-associated fatty liver disease: a meta-analysis and systematic review of 10 739 607 individuals. J. Clin. Endocrinol. Metab. 2022 107 9 2691 2700 10.1210/clinem/dgac321 35587339
    [Google Scholar]
  9. Kurylowicz A. The role of diet in the management of MAFLD—why does a new disease require a novel, individualized approach? Hepatobiliary Surg. Nutr. 2022 11 3 419 421 10.21037/hbsn‑21‑562 35693417
    [Google Scholar]
  10. Ciardullo S. Perseghin G. Prevalence of NAFLD, MAFLD and associated advanced fibrosis in the contemporary United States population. Liver Int. 2021 41 6 1290 1293 10.1111/liv.14828 33590934
    [Google Scholar]
  11. Wu J. Tian S. Li H. Xu Z. Li S. Chen Y. Liang X. Xiao J. Song J. She R. Ma C. Feng J. Li Z. Jiang Z. Zhang Z. Wu K. Kong L. Population-specific cut-off points of fatty liver index: a study based on the National Health and Nutrition Examination Survey data. BMC Gastroenterol. 2022 22 1 265 10.1186/s12876‑022‑02303‑z 35624410
    [Google Scholar]
  12. Yuan Q. Wang H. Gao P. Chen W. Lv M. Bai S. Wu J. Prevalence and risk factors of metabolic-associated fatty liver disease among 73,566 individuals in Beijing, China. Int. J. Environ. Res. Public Health 2022 19 4 2096 10.3390/ijerph19042096 35206282
    [Google Scholar]
  13. Taheri E. Moslem A. Mousavi-Jarrahi A. Hatami B. Pourhoseingholi M.A. Asadzadeh Aghdaei H. Zali M.R. Predictors of metabolic-associated fatty liver disease (MAFLD) in adults: a population-based study in Northeastern Iran. Gastroenterol. Hepatol. Bed Bench 2021 14 Suppl. 1 S102 S111 35154609
    [Google Scholar]
  14. Liu J. Ayada I. Zhang X. Wang L. Li Y. Wen T. Ma Z. Bruno M.J. de Knegt R.J. Cao W. Peppelenbosch M.P. Ghanbari M. Li Z. Pan Q. Estimating global prevalence of metabolic dysfunction-associated fatty liver disease in overweight or obese adults. Clin. Gastroenterol. Hepatol. 2022 20 3 e573 e582 10.1016/j.cgh.2021.02.030 33618024
    [Google Scholar]
  15. Angulo P. Nonalcoholic fatty liver disease. N. Engl. J. Med. 2002 346 16 1221 1231 10.1056/NEJMra011775 11961152
    [Google Scholar]
  16. Chen J. Li X. Ge C. Min J. Wang F. The multifaceted role of ferroptosis in liver disease. Cell Death Differ. 2022 29 3 467 480 10.1038/s41418‑022‑00941‑0 35075250
    [Google Scholar]
  17. Macías-Rodríguez R.U. Inzaugarat M.E. Ruiz-Margáin A. Nelson L.J. Trautwein C. Cubero F.J. Reclassifying hepatic cell death during liver damage: ferroptosis—a novel form of non-apoptotic cell death? Int. J. Mol. Sci. 2020 21 5 1651 10.3390/ijms21051651 32121273
    [Google Scholar]
  18. Arroyave-Ospina J.C. Wu Z. Geng Y. Moshage H. Role of oxidative stress in the pathogenesis of non-alcoholic fatty liver disease: Implications for prevention and therapy. Antioxidants 2021 10 2 174 10.3390/antiox10020174 33530432
    [Google Scholar]
  19. Wu J. Wang Y. Jiang R. Xue R. Yin X. Wu M. Meng Q. Ferroptosis in liver disease: new insights into disease mechanisms. Cell Death Discov. 2021 7 1 276 10.1038/s41420‑021‑00660‑4 34611144
    [Google Scholar]
  20. Woo S.L. Beneficial effects of metformin in diet-induced obesity associated non-alcoholic fatty liver disease. 2016
    [Google Scholar]
  21. Ma W.Q. Sun X.J. Zhu Y. Liu N.F. Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects. Free Radic. Biol. Med. 2021 165 229 242 10.1016/j.freeradbiomed.2021.01.033 33513420
    [Google Scholar]
  22. Zhang T. Wang M.Y. Wang G.D. Lv Q.Y. Huang Y.Q. Zhang P. Wang W. Zhang Y. Bai Y.P. Guo L.Q. Metformin improves nonalcoholic fatty liver disease in db/db mice by inhibiting ferroptosis. Eur. J. Pharmacol. 2024 966 176341 10.1016/j.ejphar.2024.176341 38244761
    [Google Scholar]
  23. Kuchay M.S. Choudhary N.S. Mishra S.K. Pathophysiological mechanisms underlying MAFLD. Diabetes Metab. Syndr. 2020 14 6 1875 1887 10.1016/j.dsx.2020.09.026 32998095
    [Google Scholar]
  24. Sotoudeheian M. Galectin-3 and Severity of Liver Fibrosis in Metabolic Dysfunction-Associated Fatty Liver Disease. Protein Pept. Lett. 2024 31 4 290 304 10.2174/0109298665301698240404061300 38715329
    [Google Scholar]
  25. Sotoudeheian M. Value of Mac-2 Binding Protein Glycosylation Isomer (M2BPGi) in Assessing Liver Fibrosis in Metabolic Dysfunction-Associated Liver Disease: A Comprehensive Review of its Serum Biomarker Role. Curr Protein Pept Sci. 2024
    [Google Scholar]
  26. Ziolkowska S. Binienda A. Jabłkowski M. Szemraj J. Czarny P. The interplay between insulin resistance, inflammation, oxidative stress, base excision repair and metabolic syndrome in nonalcoholic fatty liver disease. Int. J. Mol. Sci. 2021 22 20 11128 10.3390/ijms222011128 34681787
    [Google Scholar]
  27. Sangro P. de la Torre Aláez M. Sangro B. D’Avola D. Metabolic dysfunction–associated fatty liver disease (MAFLD): an update of the recent advances in pharmacological treatment. J. Physiol. Biochem. 2023 79 4 869 879 10.1007/s13105‑023‑00954‑4 36976456
    [Google Scholar]
  28. Sotoudeheian M. Hoseini S. Mirahmadi S.M.S. Farahmandian N. Pazoki-Toroudi H. Oleuropein as a Therapeutic Agent for Non-alcoholic Fatty Liver Disease During Hepatitis C. Rev. Bras. Farmacogn. 2023 33 4 688 695 10.1007/s43450‑023‑00396‑5
    [Google Scholar]
  29. Mocciaro G. Allison M. Jenkins B. Azzu V. Huang-Doran I. Herrera-Marcos L.V. Hall Z. Murgia A. Susan D. Frontini M. Vidal-Puig A. Koulman A. Griffin J.L. Vacca M. Non-alcoholic fatty liver disease is characterised by a reduced polyunsaturated fatty acid transport via free fatty acids and high-density lipoproteins (HDL). Mol. Metab. 2023 73 101728 10.1016/j.molmet.2023.101728 37084865
    [Google Scholar]
  30. Zhu Z. Zhang X. Pan Q. Zhang L. Chai J. In-depth analysis of de novo lipogenesis in non-alcoholic fatty liver disease: Mechanism and pharmacological interventions. Liver Res. 2023 7 4 285 295 10.1016/j.livres.2023.11.003
    [Google Scholar]
  31. Heeren J. Scheja L. Metabolic-associated fatty liver disease and lipoprotein metabolism. Mol. Metab. 2021 50 101238 10.1016/j.molmet.2021.101238 33892169
    [Google Scholar]
  32. Qiu Y.Y. Zhang J. Zeng F.Y. Zhu Y.Z. Roles of the peroxisome proliferator-activated receptors (PPARs) in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Pharmacol. Res. 2023 192 106786 10.1016/j.phrs.2023.106786 37146924
    [Google Scholar]
  33. Ferré P. Phan F. Foufelle F. SREBP-1c and lipogenesis in the liver: an update. Biochem. J. 2021 478 20 3723 3739 10.1042/BCJ20210071 34673919
    [Google Scholar]
  34. Iannone V. Lok J. Babu A.F. Gómez-Gallego C. Willman R.M. Koistinen V.M. Klåvus A. Kettunen M.I. Kårlund A. Schwab U. Hanhineva K. Kolehmainen M. El-Nezami H. Associations of altered hepatic gene expression in American lifestyle-induced obesity syndrome diet-fed mice with metabolic changes during NAFLD development and progression. J. Nutr. Biochem. 2023 115 109307 10.1016/j.jnutbio.2023.109307 36868506
    [Google Scholar]
  35. Duan Y. Pan X. Luo J. Xiao X. Li J. Bestman P.L. Luo M. Association of inflammatory cytokines with non-alcoholic fatty liver disease. Front. Immunol. 2022 13 880298 10.3389/fimmu.2022.880298 35603224
    [Google Scholar]
  36. Thibaut R. Gage M.C. Pineda-Torra I. Chabrier G. Venteclef N. Alzaid F. Liver macrophages and inflammation in physiology and physiopathology of non‐alcoholic fatty liver disease. FEBS J. 2022 289 11 3024 3057 10.1111/febs.15877 33860630
    [Google Scholar]
  37. Alisi A Carpino G Oliveira FL Panera N Nobili V Gaudio E The role of tissue macrophage-mediated inflammation on NAFLD pathogenesis and its clinical implications. Mediators Inflamm. 2017 2017 8162421 10.1155/2017/8162421
    [Google Scholar]
  38. Patel S. Bawankule S. Acharya S. Kumar S. Cytokines and Inflammatory Markers in Nonalcoholic Fatty Liver Disease: A Narrative Review. Journal of the Scientific Society 2023 50 3 307 311 10.4103/jss.jss_237_22
    [Google Scholar]
  39. Jung U. Choi M.S. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int. J. Mol. Sci. 2014 15 4 6184 6223 10.3390/ijms15046184 24733068
    [Google Scholar]
  40. Khanmohammadi S. Kuchay M.S. Toll-like receptors and metabolic (dysfunction)-associated fatty liver disease. Pharmacol. Res. 2022 185 106507 10.1016/j.phrs.2022.106507 36252773
    [Google Scholar]
  41. Shi H. Dong L. Jiang J. Zhao J. Zhao G. Dang X. Lu X. Jia M. Chlorogenic acid reduces liver inflammation and fibrosis through inhibition of toll-like receptor 4 signaling pathway. Toxicology 2013 303 107 114 10.1016/j.tox.2012.10.025 23146752
    [Google Scholar]
  42. Pham D.V. Park P.H. Recent insights on modulation of inflammasomes by adipokines: a critical event for the pathogenesis of obesity and metabolism-associated diseases. Arch. Pharm. Res. 2020 43 10 997 1016 10.1007/s12272‑020‑01274‑7 33078304
    [Google Scholar]
  43. Chang M.L. Yang Z. Yang S.S. Roles of adipokines in digestive diseases: markers of inflammation, metabolic alteration and disease progression. Int. J. Mol. Sci. 2020 21 21 8308 10.3390/ijms21218308 33167521
    [Google Scholar]
  44. Clare K. Dillon J.F. Brennan P.N. Reactive oxygen species and oxidative stress in the pathogenesis of MAFLD. J. Clin. Transl. Hepatol. 2022 10 5 939 946 10.14218/JCTH.2022.00067 36304513
    [Google Scholar]
  45. Martín-Fernández M. Arroyo V. Carnicero C. Sigüenza R. Busta R. Mora N. Antolín B. Tamayo E. Aspichueta P. Carnicero-Frutos I. Gonzalo-Benito H. Aller R. Role of oxidative stress and lipid peroxidation in the pathophysiology of NAFLD. Antioxidants 2022 11 11 2217 10.3390/antiox11112217 36358589
    [Google Scholar]
  46. Conde de la Rosa L. Goicoechea L. Torres S. Garcia-Ruiz C. Fernandez-Checa J.C. Role of oxidative stress in liver disorders. Livers 2022 2 4 283 314 10.3390/livers2040023
    [Google Scholar]
  47. Chen Z. Tian R. She Z. Cai J. Li H. Role of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease. Free Radic. Biol. Med. 2020 152 116 141 10.1016/j.freeradbiomed.2020.02.025 32156524
    [Google Scholar]
  48. Gabbia D. Cannella L. De Martin S. The role of oxidative stress in NAFLD–NASH–HCC transition—focus on NADPH oxidases. Biomedicines 2021 9 6 687 10.3390/biomedicines9060687 34204571
    [Google Scholar]
  49. Nascè A. Gariani K. Jornayvaz F.R. Szanto I. NADPH oxidases connecting fatty liver disease, insulin resistance and type 2 diabetes: Current knowledge and therapeutic outlook. Antioxidants 2022 11 6 1131 10.3390/antiox11061131 35740032
    [Google Scholar]
  50. Ma Y. Lee G. Heo S.Y. Roh Y.S. Oxidative stress is a key modulator in the development of nonalcoholic fatty liver disease. Antioxidants 2021 11 1 91 10.3390/antiox11010091 35052595
    [Google Scholar]
  51. García-Ruiz C. Fernández-Checa J.C. Mitochondrial oxidative stress and antioxidants balance in fatty liver disease. Hepatol. Commun. 2018 2 12 1425 1439 10.1002/hep4.1271 30556032
    [Google Scholar]
  52. Lebeaupin C. Vallée D. Hazari Y. Hetz C. Chevet E. Bailly-Maitre B. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J. Hepatol. 2018 69 4 927 947 10.1016/j.jhep.2018.06.008 29940269
    [Google Scholar]
  53. Song M.J. Malhi H. The unfolded protein response and hepatic lipid metabolism in non alcoholic fatty liver disease. Pharmacol. Ther. 2019 203 107401 10.1016/j.pharmthera.2019.107401 31419516
    [Google Scholar]
  54. Fujii J. Homma T. Kobayashi S. Seo H.G. Mutual interaction between oxidative stress and endoplasmic reticulum stress in the pathogenesis of diseases specifically focusing on non-alcoholic fatty liver disease. World J. Biol. Chem. 2018 9 1 1 15 10.4331/wjbc.v9.i1.1 30364769
    [Google Scholar]
  55. Flessa C.M. Kyrou I. Nasiri-Ansari N. Kaltsas G. Kassi E. Randeva H.S. Endoplasmic reticulum stress in nonalcoholic (metabolic associated) fatty liver disease (NAFLD/MAFLD). J. Cell. Biochem. 2022 123 10 1585 1606 10.1002/jcb.30247 35490371
    [Google Scholar]
  56. Ajoolabady A. Kaplowitz N. Lebeaupin C. Kroemer G. Kaufman R.J. Malhi H. Ren J. Endoplasmic reticulum stress in liver diseases. Hepatology 2023 77 2 619 639 35524448
    [Google Scholar]
  57. Zhao J. Hu Y. Peng J. Targeting programmed cell death in metabolic dysfunction-associated fatty liver disease (MAFLD): a promising new therapy. Cell. Mol. Biol. Lett. 2021 26 1 17 10.1186/s11658‑021‑00254‑z 33962586
    [Google Scholar]
  58. Kanda T. Matsuoka S. Yamazaki M. Shibata T. Nirei K. Takahashi H. Kaneko T. Fujisawa M. Higuchi T. Nakamura H. Matsumoto N. Yamagami H. Ogawa M. Imazu H. Kuroda K. Moriyama M. Apoptosis and non-alcoholic fatty liver diseases. World J. Gastroenterol. 2018 24 25 2661 2672 10.3748/wjg.v24.i25.2661 29991872
    [Google Scholar]
  59. Alkhouri N. Carter-Kent C. Feldstein A.E. Apoptosis in nonalcoholic fatty liver disease: diagnostic and therapeutic implications. Expert Rev. Gastroenterol. Hepatol. 2011 5 2 201 212 10.1586/egh.11.6 21476915
    [Google Scholar]
  60. Xu H. Wan S. An Y. Wu Q. Xing Y. Deng C. Zhang P. Long Y. Xu B. Jiang Z. Targeting cell death in NAFLD: mechanisms and targeted therapies. Cell Death Discov. 2024 10 1 399 10.1038/s41420‑024‑02168‑z 39244571
    [Google Scholar]
  61. Sotoudeheian M Soleimani M Farahmandian N. Molecular Pathways Disturbances during COVID-19 Lead to Cardiomyocyte Necroptosis. Preprints 2023 2023 2023040882 10.20944/preprints202304.0882.v1
    [Google Scholar]
  62. Dhuriya Y.K. Sharma D. Necroptosis: a regulated inflammatory mode of cell death. J. Neuroinflammation 2018 15 1 199 10.1186/s12974‑018‑1235‑0 29980212
    [Google Scholar]
  63. Zhou Y. Wu R. Wang X. Bao X. Lu C. Roles of necroptosis in alcoholic liver disease and hepatic pathogenesis. Cell Prolif. 2022 55 3 e13193 10.1111/cpr.13193 35083817
    [Google Scholar]
  64. Hirsova P. Gores G.J. Death receptor-mediated cell death and proinflammatory signaling in nonalcoholic steatohepatitis. Cell. Mol. Gastroenterol. Hepatol. 2015 1 1 17 27 10.1016/j.jcmgh.2014.11.005 25729762
    [Google Scholar]
  65. Xiao Z. Liu M. Yang F. Liu G. Liu J. Zhao W. Ma S. Duan Z. Programmed cell death and lipid metabolism of macrophages in NAFLD. Front. Immunol. 2023 14 1118449 10.3389/fimmu.2023.1118449 36742318
    [Google Scholar]
  66. Vachliotis I.D. Polyzos S.A. The role of tumor necrosis factor-alpha in the pathogenesis and treatment of nonalcoholic fatty liver disease. Curr. Obes. Rep. 2023 12 3 191 206 10.1007/s13679‑023‑00519‑y 37407724
    [Google Scholar]
  67. Peiseler M. Schwabe R. Hampe J. Kubes P. Heikenwälder M. Tacke F. Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease – novel insights into cellular communication circuits. J. Hepatol. 2022 77 4 1136 1160 10.1016/j.jhep.2022.06.012 35750137
    [Google Scholar]
  68. Wang H. Mehal W. Nagy L.E. Rotman Y. Immunological mechanisms and therapeutic targets of fatty liver diseases. Cell. Mol. Immunol. 2021 18 1 73 91 10.1038/s41423‑020‑00579‑3 33268887
    [Google Scholar]
  69. Wandrer F. Liebig S. Marhenke S. Vogel A. John K. Manns M.P. Teufel A. Itzel T. Longerich T. Maier O. Fischer R. Kontermann R.E. Pfizenmaier K. Schulze-Osthoff K. Bantel H. TNF-Receptor-1 inhibition reduces liver steatosis, hepatocellular injury and fibrosis in NAFLD mice. Cell Death Dis. 2020 11 3 212 10.1038/s41419‑020‑2411‑6 32235829
    [Google Scholar]
  70. Ichimiya T. Yamakawa T. Hirano T. Yokoyama Y. Hayashi Y. Hirayama D. Wagatsuma K. Itoi T. Nakase H. Autophagy and autophagy-related diseases: a review. Int. J. Mol. Sci. 2020 21 23 8974 10.3390/ijms21238974 33255983
    [Google Scholar]
  71. Kouroumalis E. Voumvouraki A. Augoustaki A. Samonakis D.N. Autophagy in liver diseases. World J. Hepatol. 2021 13 1 6 65 10.4254/wjh.v13.i1.6 33584986
    [Google Scholar]
  72. Zhang S. Peng X. Yang S. Li X. Huang M. Wei S. Liu J. He G. Zheng H. Yang L. Li H. Fan Q. The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders. Cell Death Dis. 2022 13 2 132 10.1038/s41419‑022‑04593‑3 35136038
    [Google Scholar]
  73. Flessa C.M. Kyrou I. Nasiri-Ansari N. Kaltsas G. Papavassiliou A.G. Kassi E. Randeva H.S. Endoplasmic reticulum stress and autophagy in the pathogenesis of non-alcoholic fatty liver disease (NAFLD): current evidence and perspectives. Curr. Obes. Rep. 2021 10 2 134 161 10.1007/s13679‑021‑00431‑3 33751456
    [Google Scholar]
  74. Armandi A. Rosso C. Caviglia G.P. Bugianesi E. Insulin resistance across the spectrum of nonalcoholic fatty liver disease. Metabolites 2021 11 3 155 10.3390/metabo11030155 33800465
    [Google Scholar]
  75. Pal S.C. Eslam M. Mendez-Sanchez N. Detangling the interrelations between MAFLD, insulin resistance, and key hormones. Hormones (Athens) 2022 21 4 573 589 10.1007/s42000‑022‑00391‑w 35921046
    [Google Scholar]
  76. Zhang C. Zhou B. Sheng J. Chen Y. Cao Y. Chen C. Molecular mechanisms of hepatic insulin resistance in nonalcoholic fatty liver disease and potential treatment strategies. Pharmacol. Res. 2020 159 104984 10.1016/j.phrs.2020.104984 32502637
    [Google Scholar]
  77. Suren Garg S. Kushwaha K. Dubey R. Gupta J. Association between obesity, inflammation and insulin resistance: Insights into signaling pathways and therapeutic interventions. Diabetes Res. Clin. Pract. 2023 200 110691 10.1016/j.diabres.2023.110691 37150407
    [Google Scholar]
  78. Feng J. Lu S. Ou B. Liu Q. Dai J. Ji C. Zhou H. Huang H. Ma Y. The role of JNk signaling pathway in obesity-driven insulin resistance. Diabetes Metab. Syndr. Obes. 2020 13 1399 1406 10.2147/DMSO.S236127 32425571
    [Google Scholar]
  79. Hrncir T. Hrncirova L. Kverka M. Hromadka R. Machova V. Trckova E. Kostovcikova K. Kralickova P. Krejsek J. Tlaskalova-Hogenova H. Gut microbiota and NAFLD: pathogenetic mechanisms, microbiota signatures, and therapeutic interventions. Microorganisms 2021 9 5 957 10.3390/microorganisms9050957 33946843
    [Google Scholar]
  80. Di Vincenzo F. Del Gaudio A. Petito V. Lopetuso L.R. Scaldaferri F. Gut microbiota, intestinal permeability, and systemic inflammation: A narrative review. Intern. Emerg. Med. 2023 ••• 1 19 37505311
    [Google Scholar]
  81. Albillos A. de Gottardi A. Rescigno M. The gut-liver axis in liver disease: Pathophysiological basis for therapy. J. Hepatol. 2020 72 3 558 577 10.1016/j.jhep.2019.10.003 31622696
    [Google Scholar]
  82. Luukkonen P.K. Qadri S. Ahlholm N. Porthan K. Männistö V. Sammalkorpi H. Penttilä A.K. Hakkarainen A. Lehtimäki T.E. Gaggini M. Gastaldelli A. Ala-Korpela M. Orho-Melander M. Arola J. Juuti A. Pihlajamäki J. Hodson L. Yki-Järvinen H. Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease. J. Hepatol. 2022 76 3 526 535 10.1016/j.jhep.2021.10.013 34710482
    [Google Scholar]
  83. Sakurai Y. Kubota N. Yamauchi T. Kadowaki T. Role of insulin resistance in MAFLD. Int. J. Mol. Sci. 2021 22 8 4156 10.3390/ijms22084156 33923817
    [Google Scholar]
  84. Sookoian S. Pirola C.J. Valenti L. Davidson N.O. Genetic pathways in nonalcoholic fatty liver disease: insights from systems biology. Hepatology 2020 72 1 330 346 10.1002/hep.31229 32170962
    [Google Scholar]
  85. Jonas W. Schürmann A. Genetic and epigenetic factors determining NAFLD risk. Mol. Metab. 2021 50 101111 10.1016/j.molmet.2020.101111 33160101
    [Google Scholar]
  86. Sharma D. Mandal P. NAFLD: genetics and its clinical implications. Clin. Res. Hepatol. Gastroenterol. 2022 46 9 102003 10.1016/j.clinre.2022.102003 35963605
    [Google Scholar]
  87. Vachliotis I. Goulas A. Papaioannidou P. Polyzos S.A. Nonalcoholic fatty liver disease: lifestyle and quality of life. Hormones (Athens) 2022 21 1 41 49 10.1007/s42000‑021‑00339‑6 34854066
    [Google Scholar]
  88. Juanola O. Martínez-López S. Francés R. Gómez-Hurtado I. Non-alcoholic fatty liver disease: metabolic, genetic, epigenetic and environmental risk factors. Int. J. Environ. Res. Public Health 2021 18 10 5227 10.3390/ijerph18105227 34069012
    [Google Scholar]
  89. Prasoppokakorn T. Pitisuttithum P. Treeprasertsuk S. Pharmacological therapeutics: current trends for metabolic dysfunction-associated fatty liver disease (MAFLD). J. Clin. Transl. Hepatol. 2021 000 000 000 10.14218/JCTH.2021.00189 34966657
    [Google Scholar]
  90. Nguyen V. George J. Nonalcoholic fatty liver disease management: dietary and lifestyle modifications. Seminars in Liver Disease. 2015 318 337
    [Google Scholar]
  91. Ordonez R. Carbajo-Pescador S. Mauriz J.L. Gonzalez-Gallego J. Understanding nutritional interventions and physical exercise in non-alcoholic fatty liver disease. Curr. Mol. Med. 2015 15 1 3 26 10.2174/1566524015666150114110551 25601465
    [Google Scholar]
  92. Barb D. Portillo-Sanchez P. Cusi K. Pharmacological management of nonalcoholic fatty liver disease. Metabolism 2016 65 8 1183 1195 10.1016/j.metabol.2016.04.004 27301803
    [Google Scholar]
  93. Tacke F. Weiskirchen R. Non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH)-related liver fibrosis: mechanisms, treatment and prevention. Ann. Transl. Med. 2021 9 8 729 10.21037/atm‑20‑4354 33987427
    [Google Scholar]
  94. Sandhu N. Au J. Herbal medicines for the treatment of nonalcoholic steatohepatitis. Curr. Hepatol. Rep. 2021 20 1 1 11 10.1007/s11901‑020‑00558‑2
    [Google Scholar]
  95. Cespiati A. Youngson N.A. Tourna A. Valenti L. Genetics and epigenetics in the clinic: precision medicine in the management of fatty liver disease. Curr. Pharm. Des. 2020 26 10 998 1009 10.2174/1381612826666200122151251 31969087
    [Google Scholar]
  96. Wong V.W.S. Adams L.A. de Lédinghen V. Wong G.L.H. Sookoian S. Noninvasive biomarkers in NAFLD and NASH — current progress and future promise. Nat. Rev. Gastroenterol. Hepatol. 2018 15 8 461 478 10.1038/s41575‑018‑0014‑9 29844588
    [Google Scholar]
  97. Papatheodoridi M. Cholongitas E. Diagnosis of non-alcoholic fatty liver disease (NAFLD): current concepts. Curr. Pharm. Des. 2019 24 38 4574 4586 10.2174/1381612825666190117102111 30652642
    [Google Scholar]
  98. Negi C.K. Babica P. Bajard L. Bienertova-Vasku J. Tarantino G. Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease. Metabolism 2022 126 154925 10.1016/j.metabol.2021.154925 34740573
    [Google Scholar]
  99. Francque S.M. Towards precision medicine in non-alcoholic fatty liver disease. Rev. Endocr. Metab. Disord. 2023 24 5 885 899 10.1007/s11154‑023‑09820‑6 37477772
    [Google Scholar]
  100. Lazarus J.V. Anstee Q.M. Hagström H. Cusi K. Cortez-Pinto H. Mark H.E. Roden M. Tsochatzis E.A. Wong V.W.S. Younossi Z.M. Zelber-Sagi S. Romero-Gómez M. Schattenberg J.M. Defining comprehensive models of care for NAFLD. Nat. Rev. Gastroenterol. Hepatol. 2021 18 10 717 729 10.1038/s41575‑021‑00477‑7 34172937
    [Google Scholar]
  101. Lei P. Bai T. Sun Y. Mechanisms of ferroptosis and relations with regulated cell death: a review. Front. Physiol. 2019 10 139 10.3389/fphys.2019.00139 30863316
    [Google Scholar]
  102. Zhu L. Luo S. Zhu Y. Tang S. Li C. Jin X. Wu F. Jiang H. Wu L. Xu Y. The emerging role of ferroptosis in various chronic liver diseases: opportunity or challenge. J. Inflamm. Res. 2023 16 381 389 10.2147/JIR.S385977 36748023
    [Google Scholar]
  103. Rochette L. Dogon G. Rigal E. Zeller M. Cottin Y. Vergely C. Lipid peroxidation and iron metabolism: two corner stones in the homeostasis control of ferroptosis. Int. J. Mol. Sci. 2022 24 1 449 10.3390/ijms24010449 36613888
    [Google Scholar]
  104. He Y.J. Liu X.Y. Xing L. Wan X. Chang X. Jiang H.L. Fenton reaction-independent ferroptosis therapy via glutathione and iron redox couple sequentially triggered lipid peroxide generator. Biomaterials 2020 241 119911 10.1016/j.biomaterials.2020.119911 32143060
    [Google Scholar]
  105. Chen X. Yu C. Kang R. Tang D. Iron metabolism in ferroptosis. Front. Cell Dev. Biol. 2020 8 590226 10.3389/fcell.2020.590226 33117818
    [Google Scholar]
  106. Dixon S.J. Stockwell B.R. The hallmarks of ferroptosis. Annu. Rev. Cancer Biol. 2019 3 1 35 54 10.1146/annurev‑cancerbio‑030518‑055844
    [Google Scholar]
  107. Yang W.S. Kim K.J. Gaschler M.M. Patel M. Shchepinov M.S. Stockwell B.R. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc. Natl. Acad. Sci. USA 2016 113 34 E4966 E4975 10.1073/pnas.1603244113 27506793
    [Google Scholar]
  108. Su L-J Zhang J-H Gomez H Murugan R Hong X Xu D Reactive oxygen species-induced lipid peroxidation in apoptosis, autophagy, and ferroptosis. Oxid Med Cell Longev. 2019 2019 5080843 10.1155/2019/5080843
    [Google Scholar]
  109. Liu J. Kang R. Tang D. Signaling pathways and defense mechanisms of ferroptosis. FEBS J. 2022 289 22 7038 7050 10.1111/febs.16059 34092035
    [Google Scholar]
  110. Mao L. Zhao T. Song Y. Lin L. Fan X. Cui B. Feng H. Wang X. Yu Q. Zhang J. Jiang K. Wang B. Sun C. The emerging role of ferroptosis in non-cancer liver diseases: hype or increasing hope? Cell Death Dis. 2020 11 7 518 10.1038/s41419‑020‑2732‑5 32647111
    [Google Scholar]
  111. Shi J.F. Liu Y. Wang Y. Gao R. Wang Y. Liu J. Targeting ferroptosis, a novel programmed cell death, for the potential of alcohol-related liver disease therapy. Front. Pharmacol. 2023 14 1194343 10.3389/fphar.2023.1194343 37214434
    [Google Scholar]
  112. Liu J. He H. Wang J. Guo X. Lin H. Chen H. Jiang C. Chen L. Yao P. Tang Y. Oxidative stress-dependent frataxin inhibition mediated alcoholic hepatocytotoxicity through ferroptosis. Toxicology 2020 445 152584 10.1016/j.tox.2020.152584 33017621
    [Google Scholar]
  113. Feng G. Byrne C.D. Targher G. Wang F. Zheng M.H. Ferroptosis and metabolic dysfunction‐associated fatty liver disease: Is there a link? Liver Int. 2022 42 7 1496 1502 10.1111/liv.15163 35007392
    [Google Scholar]
  114. Jia M. Zhang H. Qin Q. Hou Y. Zhang X. Chen D. Zhang H. Chen Y. Ferroptosis as a new therapeutic opportunity for nonviral liver disease. Eur. J. Pharmacol. 2021 908 174319 10.1016/j.ejphar.2021.174319 34252441
    [Google Scholar]
  115. Li Y. Qin M. Zhong W. Liu C. Deng G. Yang M. Li J. Ye H. Shi H. Wu C. Lin H. Chen Y. Huang S. Zhou C. Lv Z. Gao L. RAGE promotes dysregulation of iron and lipid metabolism in alcoholic liver disease. Redox Biol. 2023 59 102559 10.1016/j.redox.2022.102559 36502724
    [Google Scholar]
  116. Shi J Liu Z Li W Wang D. Selenium Donor Inhibited Hepatitis B virus associated hepatotoxicity via the apoptosis and ferroptosis pathways. Anal Cell Pathol 2023 2023 6681065
    [Google Scholar]
  117. Yamane D Hayashi Y Matsumoto M Nakanishi H Imagawa H Kohara M FADS2-dependent fatty acid desaturation dictates cellular sensitivity to ferroptosis and permissiveness for hepatitis C virus replication. Cell Chem Biol. 2022 29 5 799 810 10.1016/j.chembiol.2021.07.022
    [Google Scholar]
  118. Wang M. Joshua B. Jin N. Du S. Li C. Ferroptosis in viral infection: the unexplored possibility. Acta Pharmacol. Sin. 2022 43 8 1905 1915 10.1038/s41401‑021‑00814‑1 34873317
    [Google Scholar]
  119. Wang Q. Bin C. Xue Q. Gao Q. Huang A. Wang K. Tang N. GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis. Cell Death Dis. 2021 12 5 426 10.1038/s41419‑021‑03718‑4 33931597
    [Google Scholar]
  120. Yao X. Li W. Fang D. Xiao C. Wu X. Li M. Luo Z. Emerging roles of energy metabolism in ferroptosis regulation of tumor cells. Adv. Sci. (Weinh.) 2021 8 22 2100997 10.1002/advs.202100997 34632727
    [Google Scholar]
  121. Mo Y. Zou Z. Chen E. Targeting ferroptosis in hepatocellular carcinoma. Hepatol. Int. 2023 ••• 1 18 37880567
    [Google Scholar]
  122. Qi J. Kim J.W. Zhou Z. Lim C.W. Kim B. Ferroptosis affects the progression of nonalcoholic steatohepatitis via the modulation of lipid peroxidation–mediated cell death in mice. Am. J. Pathol. 2020 190 1 68 81 10.1016/j.ajpath.2019.09.011 31610178
    [Google Scholar]
  123. Jiang X. Stockwell B.R. Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 2021 22 4 266 282 10.1038/s41580‑020‑00324‑8 33495651
    [Google Scholar]
  124. Mortensen M.S. Ruiz J. Watts J.L. Polyunsaturated fatty acids drive lipid peroxidation during ferroptosis. Cells 2023 12 5 804 10.3390/cells12050804 36899940
    [Google Scholar]
  125. Pope L.E. Dixon S.J. Regulation of ferroptosis by lipid metabolism. Trends Cell Biol. 2023 33 12 1077 1087 10.1016/j.tcb.2023.05.003 37407304
    [Google Scholar]
  126. Ursini F. Maiorino M. Lipid peroxidation and ferroptosis: The role of GSH and GPx4. Free Radic. Biol. Med. 2020 152 175 185 10.1016/j.freeradbiomed.2020.02.027 32165281
    [Google Scholar]
  127. Wang B. Wang Y. Zhang J. Hu C. Jiang J. Li Y. Peng Z. ROS-induced lipid peroxidation modulates cell death outcome: mechanisms behind apoptosis, autophagy, and ferroptosis. Arch. Toxicol. 2023 97 6 1439 1451 10.1007/s00204‑023‑03476‑6 37127681
    [Google Scholar]
  128. Ma C. Han L. Zhu Z. Heng Pang C. Pan G. Mineral metabolism and ferroptosis in non-alcoholic fatty liver diseases. Biochem. Pharmacol. 2022 205 115242 10.1016/j.bcp.2022.115242 36084708
    [Google Scholar]
  129. Gensluckner S. Wernly B. Datz C. Aigner E. Iron, Oxidative Stress, and Metabolic Dysfunction—Associated Steatotic Liver Disease. Antioxidants 2024 13 2 208 10.3390/antiox13020208 38397806
    [Google Scholar]
  130. Cai X. Hua S. Deng J. Du Z. Zhang D. Liu Z. Khan N.U. Zhou M. Chen Z. Astaxanthin activated the Nrf2/HO-1 pathway to enhance autophagy and inhibit ferroptosis, ameliorating acetaminophen-induced liver injury. ACS Appl. Mater. Interfaces 2022 14 38 42887 42903 10.1021/acsami.2c10506 36094079
    [Google Scholar]
  131. Dodson M. Castro-Portuguez R. Zhang D.D. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol. 2019 23 101107 10.1016/j.redox.2019.101107 30692038
    [Google Scholar]
  132. Chen G.H. Song C.C. Pantopoulos K. Wei X.L. Zheng H. Luo Z. Mitochondrial oxidative stress mediated Fe-induced ferroptosis via the NRF2-ARE pathway. Free Radic. Biol. Med. 2022 180 95 107 10.1016/j.freeradbiomed.2022.01.012 35045311
    [Google Scholar]
  133. Tong J. Li D. Meng H. Sun D. Lan X. Ni M. Ma J. Zeng F. Sun S. Fu J. Li G. Ji Q. Zhang G. Shen Q. Wang Y. Zhu J. Zhao Y. Wang X. Liu Y. Ouyang S. Sheng C. Shen F. Wang P. Targeting a novel inducible GPX4 alternative isoform to alleviate ferroptosis and treat metabolic-associated fatty liver disease. Acta Pharm. Sin. B 2022 12 9 3650 3666 10.1016/j.apsb.2022.02.003 36176906
    [Google Scholar]
  134. Xie Y. Kang R. Klionsky D.J. Tang D. GPX4 in cell death, autophagy, and disease. Autophagy 2023 19 10 2621 2638 10.1080/15548627.2023.2218764 37272058
    [Google Scholar]
  135. Zhang H. Zhang E. Hu H. Role of ferroptosis in non-alcoholic fatty liver disease and its implications for therapeutic strategies. Biomedicines 2021 9 11 1660 10.3390/biomedicines9111660 34829889
    [Google Scholar]
  136. Liu S. Gao Z. He W. Wu Y. Liu J. Zhang S. Yan L. Mao S. Shi X. Fan W. Song S. The gut microbiota metabolite glycochenodeoxycholate activates TFR-ACSL4-mediated ferroptosis to promote the development of environmental toxin–linked MAFLD. Free Radic. Biol. Med. 2022 193 Pt 1 213 226 10.1016/j.freeradbiomed.2022.10.270 36265794
    [Google Scholar]
  137. Nam Y. Cadmium-Induced Nonalcoholic Fatty Liver Disease: Implications of the Heme Oxygenase 1/Biliverdin Reductase Enzymatic Pathway. The University of Alabama 2022
    [Google Scholar]
  138. Cao J. Progress of heme oxygenase-1 mediated ferroptosis in non-alcoholic fatty liver disease. Chinese General Practice 2024
    [Google Scholar]
  139. Carotti S. Aquilano K. Valentini F. Ruggiero S. Alletto F. Morini S. Picardi A. Antonelli-Incalzi R. Lettieri-Barbato D. Vespasiani-Gentilucci U. An overview of deregulated lipid metabolism in nonalcoholic fatty liver disease with special focus on lysosomal acid lipase. Am. J. Physiol. Gastrointest. Liver Physiol. 2020 319 4 G469 G480 10.1152/ajpgi.00049.2020 32812776
    [Google Scholar]
  140. Zhao T. Yu Z. Zhou L. Wang X. Hui Y. Mao L. Fan X. Wang B. Zhao X. Sun C. Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice. Cell Death Discov. 2022 8 1 380 10.1038/s41420‑022‑01173‑4 36071041
    [Google Scholar]
  141. Cho S.S. Yang J.H. Lee J.H. Baek J.S. Ku S.K. Cho I.J. Kim K.M. Ki S.H. Ferroptosis contribute to hepatic stellate cell activation and liver fibrogenesis. Free Radic. Biol. Med. 2022 193 Pt 2 620 637 10.1016/j.freeradbiomed.2022.11.011 36370962
    [Google Scholar]
  142. Mazza A. Fruci B. Garinis G.A. Giuliano S. Malaguarnera R. Belfiore A. The role of metformin in the management of NAFLD. Exp. Diabetes Res. 2012 2012 1 13 10.1155/2012/716404 22194737
    [Google Scholar]
  143. Lin C.S. Ma H. The Therapeutic Potential of Metformin for Metabolic Associated Fatty Liver Disease: Bioinformatics Analysis. Arch. Clin. Med. Case Rep. 2024 8 1 16 22 10.26502/acmcr.96550652
    [Google Scholar]
  144. Araújo A.R. Rosso N. Bedogni G. Tiribelli C. Bellentani S. Global epidemiology of non‐alcoholic fatty liver disease/non‐alcoholic steatohepatitis: What we need in the future. Liver Int. 2018 38 S1 Suppl. 1 47 51 10.1111/liv.13643 29427488
    [Google Scholar]
  145. Zhou J. Massey S. Story D. Li L. Metformin: an old drug with new applications. Int. J. Mol. Sci. 2018 19 10 2863 10.3390/ijms19102863 30241400
    [Google Scholar]
  146. Smith B.K. Marcinko K. Desjardins E.M. Lally J.S. Ford R.J. Steinberg G.R. Treatment of nonalcoholic fatty liver disease: role of AMPK. Am. J. Physiol. Endocrinol. Metab. 2016 311 4 E730 E740 10.1152/ajpendo.00225.2016 27577854
    [Google Scholar]
  147. Bai B. Chen H. Metformin: a novel weapon against inflammation. Front. Pharmacol. 2021 12 622262 10.3389/fphar.2021.622262 33584319
    [Google Scholar]
  148. Drzewoski J. Hanefeld M. The current and potential therapeutic use of metformin—the good old drug. Pharmaceuticals (Basel) 2021 14 2 122 10.3390/ph14020122 33562458
    [Google Scholar]
  149. Bhat A. Sebastiani G. Bhat M. Systematic review: Preventive and therapeutic applications of metformin in liver disease. World J. Hepatol. 2015 7 12 1652 1659 10.4254/wjh.v7.i12.1652 26140084
    [Google Scholar]
  150. Ruan G. Wu F. Shi D. Sun H. Wang F. Xu C. Metformin: update on mechanisms of action on liver diseases. Front. Nutr. 2023 10 1327814 10.3389/fnut.2023.1327814 38192642
    [Google Scholar]
  151. Yue F. Shi Y. Wu S. Xing L. He D. Wei L. Qiu A. Russell R. Zhang D. Metformin alleviates hepatic iron overload and ferroptosis through AMPK-ferroportin pathway in HFD-induced NAFLD. iScience 2023 26 12 108560 10.1016/j.isci.2023.108560 38089577
    [Google Scholar]
  152. Bao J. Zhao Y. Xu X. Ling S. Advance of metformin in liver disease. Curr. Med. Chem. 2024 31 10.2174/0109298673274268231215110330 38299294
    [Google Scholar]
  153. Zhang D. Ma Y. Liu J. Deng Y. Zhou B. Wen Y. Li M. Wen D. Ying Y. Luo S. Shi C. Pu G. Miao Y. Zou C. Chen Y. Ma L. Metformin alleviates hepatic steatosis and insulin resistance in a mouse model of high-fat diet-induced nonalcoholic fatty liver disease by promoting transcription factor EB-dependent autophagy. Front. Pharmacol. 2021 12 689111 10.3389/fphar.2021.689111 34366846
    [Google Scholar]
  154. Niranjan S. Phillips B.E. Giannoukakis N. Uncoupling hepatic insulin resistance – hepatic inflammation to improve insulin sensitivity and to prevent impaired metabolism-associated fatty liver disease in type 2 diabetes. Front. Endocrinol. (Lausanne) 2023 14 1193373 10.3389/fendo.2023.1193373 37396181
    [Google Scholar]
  155. Sotoudeheian M Hoseini S Therapeutic Properties of Polyphenols Affect AMPK Molecular Pathway in Hyperlipidemia. Preprints 2023 2023 2023010528 10.20944/preprints202301.0528.v1
    [Google Scholar]
  156. Dehkordi A.H. Abbaszadeh A. Mir S. Hasanvand A. Metformin and its anti-inflammatory and anti-oxidative effects; new concepts. J. Renal Inj. Prev. 2018 8 1 54 61 10.15171/jrip.2019.11
    [Google Scholar]
  157. Zhang A. Qian F. Li Y. Li B. Yang F. Hu C. Sun W. Huang Y. Research progress of metformin in the treatment of liver fibrosis. Int. Immunopharmacol. 2023 116 109738 10.1016/j.intimp.2023.109738 36696857
    [Google Scholar]
  158. Buczyńska A. Sidorkiewicz I. Krętowski A.J. Adamska A. Examining the clinical relevance of metformin as an antioxidant intervention. Front. Pharmacol. 2024 15 1330797 10.3389/fphar.2024.1330797 38362157
    [Google Scholar]
  159. Haber R. Zarzour F. Ghezzawi M. Saadeh N. Bacha D.S. Al Jebbawi L. Chakhtoura M. Mantzoros C.S. The impact of metformin on weight and metabolic parameters in patients with obesity: A systematic review and meta‐analysis of randomized controlled trials. Diabetes Obes. Metab. 2024 26 5 1850 1867 10.1111/dom.15501 38468148
    [Google Scholar]
  160. Lavine J.E. Schwimmer J.B. Van Natta M.L. Molleston J.P. Murray K.F. Rosenthal P. Abrams S.H. Scheimann A.O. Sanyal A.J. Chalasani N. Tonascia J. Ünalp A. Clark J.M. Brunt E.M. Kleiner D.E. Hoofnagle J.H. Robuck P.R. Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. JAMA 2011 305 16 1659 1668 10.1001/jama.2011.520 21521847
    [Google Scholar]
  161. Homaei A Alhadad M Arad B Saffari F Effect of Metformin or Vitamin E on ultrasonographic grade and biochemical findings of children and adolescents with nonalcoholic fatty liver disease: A randomized clinical trial. J. Compr. Pediatr. 2022 13 2 10.5812/compreped‑123944
    [Google Scholar]
  162. Nadeau K.J. Ehlers L.B. Zeitler P.S. Love-Osborne K. Treatment of non-alcoholic fatty liver disease with metformin versus lifestyle intervention in insulin-resistant adolescents. Pediatr. Diabetes 2009 10 1 5 13 10.1111/j.1399‑5448.2008.00450.x 18721166
    [Google Scholar]
  163. Gkiourtzis N. Michou P. Moutafi M. Glava A. Cheirakis K. Christakopoulos A. Vouksinou E. Fotoulaki M. The benefit of metformin in the treatment of pediatric non-alcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials. Eur. J. Pediatr. 2023 182 11 4795 4806 10.1007/s00431‑023‑05169‑9 37639015
    [Google Scholar]
  164. Pinyopornpanish K. Leerapun A. Pinyopornpanish K. Chattipakorn N. Effects of metformin on hepatic steatosis in adults with nonalcoholic fatty liver disease and diabetes: insights from the cellular to patient levels. Gut Liver 2021 15 6 827 840 10.5009/gnl20367 33820884
    [Google Scholar]
  165. Zhang R. Cheng K. Xu S. Li S. Zhou Y. Zhou S. Kong R. Li L. Li J. Feng J. Wu L. Liu T. Xia Y. Lu J. Guo C. Zhou Y. Metformin and Diammonium Glycyrrhizinate Enteric-Coated Capsule versus Metformin Alone versus Diammonium Glycyrrhizinate Enteric-Coated Capsule Alone in Patients with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus. Gastroenterol. Res. Pract. 2017 2017 1 11 10.1155/2017/8491742 28133479
    [Google Scholar]
  166. Fan H. Pan Q. Xu Y. Yang X. Exenatide improves type 2 diabetes concomitant with non-alcoholic fatty liver disease. Arq. Bras. Endocrinol. Metabol 2013 57 9 702 708 10.1590/S0004‑27302013000900005 24402015
    [Google Scholar]
  167. Feng W. Gao C. Bi Y. Wu M. Li P. Shen S. Chen W. Yin T. Zhu D. Randomized trial comparing the effects of gliclazide, liraglutide, and metformin on diabetes with non‐alcoholic fatty liver disease. J. Diabetes 2017 9 8 800 809 10.1111/1753‑0407.12555 28332301
    [Google Scholar]
  168. Yabiku K. Mutoh A. Miyagi K. Takasu N. Effects of oral antidiabetic drugs on changes in the liver-to-spleen ratio on computed tomography and inflammatory biomarkers in patients with type 2 diabetes and nonalcoholic fatty liver disease. Clin. Ther. 2017 39 3 558 566 10.1016/j.clinthera.2017.01.015 28185715
    [Google Scholar]
  169. Tian F. Zheng Z. Zhang D. He S. Shen J. Efficacy of liraglutide in treating type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease. Biosci. Rep. 2018 38 6 BSR20181304 10.1042/BSR20181304 30473540
    [Google Scholar]
  170. Zsóri G. Illés D. Ivány E. Kosár K. Holzinger G. Tajti M. Pálinkás E. Szabovik G. Nagy A. Palkó A. Czakó L. In new-onset diabetes mellitus, metformin reduces fat accumulation in the liver, but not in the pancreas or pericardium. Metab. Syndr. Relat. Disord. 2019 17 5 289 295 10.1089/met.2018.0086 31013454
    [Google Scholar]
  171. Shibuya T. Fushimi N. Kawai M. Yoshida Y. Hachiya H. Ito S. Kawai H. Ohashi N. Mori A. Luseogliflozin improves liver fat deposition compared to metformin in type 2 diabetes patients with non‐alcoholic fatty liver disease: A prospective randomized controlled pilot study. Diabetes Obes. Metab. 2018 20 2 438 442 10.1111/dom.13061 28719078
    [Google Scholar]
  172. Huang Y. Wang X. Yan C. Li C. Zhang L. Zhang L. Liang E. Liu T. Mao J. Effect of metformin on nonalcoholic fatty liver based on meta-analysis and network pharmacology. Medicine (Baltimore) 2022 101 43 e31437 10.1097/MD.0000000000031437 36316840
    [Google Scholar]
  173. Caturano A. Galiero R. Loffredo G. Vetrano E. Medicamento G. Acierno C. Rinaldi L. Marrone A. Salvatore T. Monda M. Sardu C. Marfella R. Sasso F.C. Effects of a combination of empagliflozin plus metformin vs. metformin monotherapy on NAFLD progression in type 2 diabetes: the IMAGIN pilot study. Biomedicines 2023 11 2 322 10.3390/biomedicines11020322 36830859
    [Google Scholar]
  174. Lavin B. Eykyn T.R. Phinikaridou A. Xavier A. Kumar S. Buqué X. Aspichueta P. Sing-Long C. Arrese M. Botnar R.M. Andia M.E. Characterization of hepatic fatty acids using magnetic resonance spectroscopy for the assessment of treatment response to metformin in an eNOS −/− mouse model of metabolic nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. NMR Biomed. 2023 36 8 e4932 10.1002/nbm.4932 36940044
    [Google Scholar]
  175. Chiu H-y Tsai S-C Tsai F-j Lo Y-h Cheng C-c Liu T-y Liraglutide with metformin therapy ameliorates hepatic steatosis and liver injury in a mouse model of non-alcoholic steatohepatitis. In Vivo. 2023 37 3 1037 1065
    [Google Scholar]
  176. Shaaban H.H. Alzaim I. El-Mallah A. Aly R.G. El-Yazbi A.F. Wahid A. Metformin, pioglitazone, dapagliflozin and their combinations ameliorate manifestations associated with NAFLD in rats via anti-inflammatory, anti-fibrotic, anti-oxidant and anti-apoptotic mechanisms. Life Sci. 2022 308 120956 10.1016/j.lfs.2022.120956 36103959
    [Google Scholar]
  177. Muzurović E. Mikhailidis D.P. Mantzoros C. Non-alcoholic fatty liver disease, insulin resistance, metabolic syndrome and their association with vascular risk. Metabolism 2021 119 154770 10.1016/j.metabol.2021.154770 33864798
    [Google Scholar]
  178. Rajgopal R.K. Kochhar R.S. Efficacy and cardiovascular safety of metformin. Curr. Drug Saf. 2021 16 2 165 177 10.2174/1574886315666210106142244 33413067
    [Google Scholar]
  179. Caussy C. Aubin A. Loomba R. The relationship between type 2 diabetes, NAFLD, and cardiovascular risk. Curr. Diab. Rep. 2021 21 5 15 10.1007/s11892‑021‑01383‑7 33742318
    [Google Scholar]
  180. Perazza F. Leoni L. Colosimo S. Musio A. Bocedi G. D’Avino M. Agnelli G. Nicastri A. Rossetti C. Sacilotto F. Marchesini G. Petroni M.L. Ravaioli F. Metformin and the Liver: Unlocking the Full Therapeutic Potential. Metabolites 2024 14 4 186 10.3390/metabo14040186 38668314
    [Google Scholar]
  181. Smith F.C. Stocker S.L. Danta M. Carland J.E. Kumar S.S. Liu Z. Greenfield J.R. Braithwaite H.E. Cheng T.S. Graham G.G. Williams K.M. Day R.O. The safety and pharmacokinetics of metformin in patients with chronic liver disease. Aliment. Pharmacol. Ther. 2020 51 5 565 575 10.1111/apt.15635 31960986
    [Google Scholar]
  182. Sun Y. Guo L. Wang D. Xing Y. Bai Y. Zhang T. Wang W. Zhou S. Yao X. Cheng J. Chang W. Lv K. Li C. Kong X. Metformin alleviates glucolipotoxicity-induced pancreatic β cell ferroptosis through regulation of the GPX4/ACSL4 axis. Eur. J. Pharmacol. 2023 956 175967 10.1016/j.ejphar.2023.175967 37549729
    [Google Scholar]
  183. Zhao Y. Zhao Y. Tian Y. Zhou Y. Metformin suppresses foam cell formation, inflammation and ferroptosis via the AMPK/ERK signaling pathway in ox‑LDL‑induced THP‑1 monocytes. Exp. Ther. Med. 2022 24 4 636 10.3892/etm.2022.11573 36160906
    [Google Scholar]
  184. Tang K. Chen Q. Liu Y. Wang L. Lu W. Combination of metformin and sorafenib induces ferroptosis of hepatocellular carcinoma through p62-keap1-nrf2 pathway. J. Cancer 2022 13 11 3234 3243 10.7150/jca.76618 36118519
    [Google Scholar]
  185. Deng C. Xiong L. Chen Y. Wu K. Wu J. Metformin induces ferroptosis through the Nrf2/HO-1 signaling in lung cancer. BMC Pulm. Med. 2023 23 1 360 10.1186/s12890‑023‑02655‑6 37749553
    [Google Scholar]
  186. Wu X. Xu W.W. Huan X. Wu G. Li G. Zhou Y.H. Najafi M. Mechanisms of cancer cell killing by metformin: a review on different cell death pathways. Mol. Cell. Biochem. 2023 478 1 197 214 10.1007/s11010‑022‑04502‑4 35771397
    [Google Scholar]
  187. Wang Z. Wu Z. Xie Z. Zhou W. Li M. Metformin attenuates ferroptosis and promotes functional recovery of spinal cord injury. World Neurosurg. 2022 167 e929 e939 10.1016/j.wneu.2022.08.121 36058489
    [Google Scholar]
  188. Wang Z. Zhou W. Zhang Z. Zhang L. Li M. Metformin alleviates spinal cord injury by inhibiting nerve cell ferroptosis through upregulation of heme oxygenase-1 expression. Neural Regen. Res. 2024 19 9 2041 2049 10.4103/1673‑5374.390960 38227534
    [Google Scholar]
  189. Zhu J Wang P Wang X Liu T Lv J Yuan J. Metformin Prevents Dopaminergic Neuron Death in MPTP/P-Induced Mouse Model of Parkinson's Disease via Autophagy and Mitochondrial ROS Clearance. Int J Neuropsychopharmacol. 2023 19 9 pyw047
    [Google Scholar]
  190. Hu Z. Zhao Y. Li L. Jiang J. Li W. Mang Y. Gao Y. Dong Y. Zhu J. Yang C. Ran J. Li L. Zhang S. Metformin promotes ferroptosis and sensitivity to sorafenib in hepatocellular carcinoma cells via ATF4/STAT3. Mol. Biol. Rep. 2023 50 8 6399 6413 10.1007/s11033‑023‑08492‑4 37326750
    [Google Scholar]
  191. Ozbey G. Nemutlu-Samur D. Parlak H. Yildirim S. Aslan M. Tanriover G. Agar A. Metformin protects rotenone-induced dopaminergic neurodegeneration by reducing lipid peroxidation. Pharmacol. Rep. 2020 72 5 1397 1406 10.1007/s43440‑020‑00095‑1 32207092
    [Google Scholar]
  192. Chen H. Wang C. Liu Z. He X. Tang W. He L. Feng Y. Liu D. Yin Y. Li T. Ferroptosis and its multifaceted role in cancer: mechanisms and therapeutic approach. Antioxidants 2022 11 8 1504 10.3390/antiox11081504 36009223
    [Google Scholar]
  193. Hung C.H. Chan S.H. Chu P.M. Lin H.C. Tsai K.L. Metformin regulates oxLDL-facilitated endothelial dysfunction by modulation of SIRT1 through repressing LOX-1-modulated oxidative signaling. Oncotarget 2016 7 10 10773 10787 10.18632/oncotarget.7387 26885898
    [Google Scholar]
  194. Li X. Wang X. Snyder M.P. Metformin affects heme function as a possible mechanism of action. G3: Genes, Genomes. G3 (Bethesda) 2019 9 2 513 522 10.1534/g3.118.200803 30554148
    [Google Scholar]
  195. Hou Y. Cai S. Yu S. Lin H. Metformin induces ferroptosis by targeting miR-324-3p/GPX4 axis in breast cancer. Acta Biochim. Biophys. Sin. (Shanghai) 2021 53 3 333 341 10.1093/abbs/gmaa180 33522578
    [Google Scholar]
  196. Howell J.J. Hellberg K. Turner M. Talbott G. Kolar M.J. Ross D.S. Hoxhaj G. Saghatelian A. Shaw R.J. Manning B.D. Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex. Cell Metab. 2017 25 2 463 471 10.1016/j.cmet.2016.12.009 28089566
    [Google Scholar]
  197. Lei G. Zhuang L. Gan B. mTORC1 and ferroptosis: Regulatory mechanisms and therapeutic potential. BioEssays 2021 43 8 2100093 10.1002/bies.202100093 34121197
    [Google Scholar]
  198. Liu Y. Wang Y. Liu J. Kang R. Tang D. Interplay between MTOR and GPX4 signaling modulates autophagy-dependent ferroptotic cancer cell death. Cancer Gene Ther. 2021 28 1-2 55 63 10.1038/s41417‑020‑0182‑y 32457486
    [Google Scholar]
  199. Kita Y Takamura T Misu H Ota T Kurita S Takeshita Y Metformin prevents and reverses inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis. PLoS One. 2012 7 9 e43056 10.1371/journal.pone.0043056
    [Google Scholar]
  200. Tehrani S.S. Goodarzi G. Panahi G. Zamani-Garmsiri F. Meshkani R. The combination of metformin with morin alleviates hepatic steatosis via modulating hepatic lipid metabolism, hepatic inflammation, brown adipose tissue thermogenesis, and white adipose tissue browning in high-fat diet-fed mice. Life Sci. 2023 323 121706 10.1016/j.lfs.2023.121706 37075944
    [Google Scholar]
  201. Lee H.W. Lee J.S. Kim B.K. Park J.Y. Kim D.Y. Ahn S.H. Kim S.U. Evolution of liver fibrosis and steatosis markers in patients with type 2 diabetes after metformin treatment for 2 years. J. Diabetes Complications 2021 35 1 107747 10.1016/j.jdiacomp.2020.107747 33616043
    [Google Scholar]
  202. Yang T. Guan Q. Shi J.S. Xu Z.H. Geng Y. Metformin alleviates liver fibrosis in mice by enriching Lactobacillus sp. MF-1 in the gut microbiota. Biochim. Biophys. Acta Mol. Basis Dis. 2023 1869 5 166664 10.1016/j.bbadis.2023.166664 36893671
    [Google Scholar]
  203. Fan K. Wu K. Lin L. Ge P. Dai J. He X. Hu K. Zhang L. Metformin mitigates carbon tetrachloride-induced TGF-β1/Smad3 signaling and liver fibrosis in mice. Biomed. Pharmacother. 2017 90 421 426 10.1016/j.biopha.2017.03.079 28390311
    [Google Scholar]
  204. Song Y.M. Lee Y. Kim J.W. Ham D.S. Kang E.S. Cha B.S. Lee H.C. Lee B.W. Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway. Autophagy 2015 11 1 46 59 10.4161/15548627.2014.984271 25484077
    [Google Scholar]
  205. Lu J.L. Yu C.X. Song L.J. Programmed cell death in hepatic fibrosis: current and perspectives. Cell Death Discov. 2023 9 1 449 10.1038/s41420‑023‑01749‑8 38086792
    [Google Scholar]
/content/journals/crcep/10.2174/0127724328328193241029103831
Loading
The Role of Metformin in Modifying Ferroptosis to Treat Metabolic Dysfunction-Associated Fatty Liver Disease: A Narrative Review
Bentham Science Publishers ; https://doi.org/10.2174/0127724328328193241029103831
/content/journals/crcep/10.2174/0127724328328193241029103831
/content/journals/crcep/10.2174/0127724328328193241029103831
Loading

Data & Media loading...


  • Article Type:     Review Article
Keywords: GPX4 ; Biguanides ; cell death ; NAFLD ; dimethylguanylguanidine ; hepatocyte ; necroptosis ; apoptosis

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test