{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:27:59Z","timestamp":1788456479124,"version":"build-2803163510"},"reference-count":131,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,28]],"date-time":"2023-12-28T00:00:00Z","timestamp":1703721600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatic fibrosis is a complex process that develops in chronic liver diseases. Even though the initiation and progression of fibrosis rely on the underlying etiology, mutual mechanisms can be recognized and targeted for therapeutic purposes. Irrespective of the primary cause of liver disease, persistent damage to parenchymal cells triggers the overproduction of reactive species, with the consequent disruption of redox balance. Reactive species are important mediators for the homeostasis of both hepatocytes and non-parenchymal liver cells. Indeed, other than acting as cytotoxic agents, reactive species are able to modulate specific signaling pathways that may be relevant to hepatic fibrogenesis. After a brief introduction to redox biology and the mechanisms of fibrogenesis, this review aims to summarize the current evidence of the involvement of redox-dependent pathways in liver fibrosis and focuses on possible therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms25010410","type":"journal-article","created":{"date-parts":[[2023,12,28]],"date-time":"2023-12-28T03:30:34Z","timestamp":1703734234000},"page":"410","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Redox Biology and Liver Fibrosis"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8196-7373","authenticated-orcid":false,"given":"Francesco","family":"Bellanti","sequence":"first","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7350-9383","authenticated-orcid":false,"given":"Domenica","family":"Mangieri","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluigi","family":"Vendemiale","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis","volume":"115","author":"Bataller","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.1111\/j.1440-1746.2006.04584.x","article-title":"Hepatic stellate cells and the reversal of fibrosis","volume":"21","author":"Kisseleva","year":"2006","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"E3297","DOI":"10.1073\/pnas.1400062111","article-title":"Origin of myofibroblasts in the fibrotic liver in mice","volume":"111","author":"Iwaisako","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1055\/s-0035-1554915","article-title":"Origin and function of myofibroblasts in the liver","volume":"35","author":"Wells","year":"2015","journal-title":"Semin. Liver Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41575-020-00372-7","article-title":"Molecular and cellular mechanisms of liver fibrosis and its regression","volume":"18","author":"Kisseleva","year":"2021","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1172\/JCI88881","article-title":"Liver inflammation and fibrosis","volume":"127","author":"Koyama","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1089\/ars.2013.5697","article-title":"Extracellular matrix and liver disease","volume":"21","author":"Arriazu","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1080\/17474124.2021.1949289","article-title":"Chronic liver disease and oxidative stress\u2014A narrative review","volume":"15","author":"Seen","year":"2021","journal-title":"Expert. Rev. Gastroenterol. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ramos-Tovar, E., and Muriel, P. (2020). Molecular Mechanisms That Link Oxidative Stress, Inflammation, and Fibrosis in the Liver. Antioxidants, 9.","DOI":"10.3390\/antiox9121279"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"180","DOI":"10.4254\/wjh.v15.i2.180","article-title":"Antioxidant and anti-inflammatory agents in chronic liver diseases: Molecular mechanisms and therapy","volume":"15","author":"Zhang","year":"2023","journal-title":"World J. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1146\/annurev.nu.16.070196.001143","article-title":"Zonation of parenchymal and nonparenchymal metabolism in liver","volume":"16","author":"Jungermann","year":"1996","journal-title":"Annu. Rev. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/j.redox.2017.01.012","article-title":"Metabolic zonation of the liver: The oxygen gradient revisited","volume":"11","author":"Kietzmann","year":"2017","journal-title":"Redox Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.bpj.2016.11.3194","article-title":"Optimal Compartmentalization Strategies for Metabolic Microcompartments","volume":"112","author":"Hinzpeter","year":"2017","journal-title":"Biophys. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1089\/ars.2017.7216","article-title":"NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism","volume":"28","author":"Xiao","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.jhep.2010.09.014","article-title":"Regulation of hepatic metabolism by AMPK","volume":"54","author":"Foretz","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3527579","DOI":"10.1155\/2016\/3527579","article-title":"Xanthine Oxidoreductase-Derived Reactive Species: Physiological and Pathological Effects","volume":"2016","author":"Battelli","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1111\/j.1572-0241.2002.05925.x","article-title":"Xanthine oxidoreductase activity in human liver disease","volume":"97","author":"Stirpe","year":"2002","journal-title":"Am. J. Gastroenterol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1152\/physrev.00026.2013","article-title":"Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release","volume":"94","author":"Zorov","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1042\/bj1280617","article-title":"The cellular production of hydrogen peroxide","volume":"128","author":"Boveris","year":"1972","journal-title":"Biochem. J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1111\/febs.12086","article-title":"Reactive oxygen species are generated by the respiratory complex II--evidence for lack of contribution of the reverse electron flow in complex I","volume":"280","author":"Neuzil","year":"2013","journal-title":"FEBS J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.redox.2013.04.005","article-title":"Sites of reactive oxygen species generation by mitochondria oxidizing different substrates","volume":"1","author":"Quinlan","year":"2013","journal-title":"Redox Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1093\/oxfordjournals.jbchem.a121859","article-title":"Subcellular distribution of OM cytochrome b-mediated NADH-semidehydroascorbate reductase activity in rat liver","volume":"100","author":"Nishino","year":"1986","journal-title":"J. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1007\/PL00005371","article-title":"Reactive oxygen species production by monoamine oxidases in intact cells","volume":"359","author":"Pizzinat","year":"1999","journal-title":"Naunyn Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.freeradbiomed.2019.02.012","article-title":"Estimation of the hydrogen peroxide producing capacities of liver and cardiac mitochondria isolated from C57BL\/6N and C57BL\/6J mice","volume":"135","author":"Oldford","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4322","DOI":"10.1016\/S0021-9258(19)41421-X","article-title":"Superoxide production and electron transport in mitochondrial oxidation of dihydroorotic acid","volume":"250","author":"Forman","year":"1975","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.abb.2008.10.011","article-title":"High efficiency of ROS production by glycerophosphate dehydrogenase in mammalian mitochondria","volume":"481","author":"Mracek","year":"2009","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1910","DOI":"10.1016\/j.bbabio.2010.10.007","article-title":"The electron transfer flavoprotein: Ubiquinone oxidoreductases","volume":"1797","author":"Watmough","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gronemeyer, T., Wiese, S., Ofman, R., Bunse, C., Pawlas, M., Hayen, H., Eisenacher, M., Stephan, C., Meyer, H.E., and Waterham, H.R. (2013). The proteome of human liver peroxisomes: Identification of five new peroxisomal constituents by a label-free quantitative proteomics survey. PLoS ONE, 8.","DOI":"10.1371\/annotation\/3552e5c7-88d1-42c5-844d-4c2f2d722533"},{"key":"ref_29","first-page":"137","article-title":"Localization of xanthine oxidase in crystalline cores of peroxisomes. A cytochemical and biochemical study","volume":"45","author":"Angermuller","year":"1987","journal-title":"Eur. J. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/jgh.12021","article-title":"Forkhead box class O transcription factors in liver function and disease","volume":"28","author":"Tikhanovich","year":"2013","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/j.bbadis.2011.12.001","article-title":"Role of peroxisomes in ROS\/RNS-metabolism: Implications for human disease","volume":"1822","author":"Fransen","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.livres.2019.01.002","article-title":"Endoplasmic reticulum stress and liver diseases","volume":"3","author":"Liu","year":"2019","journal-title":"Liver Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Zeeshan, H.M., Lee, G.H., Kim, H.R., and Chae, H.J. (2016). Endoplasmic Reticulum Stress and Associated ROS. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17030327"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.freeradbiomed.2014.04.033","article-title":"Purified NADH-cytochrome b5 reductase is a novel superoxide anion source inhibited by apocynin: Sensitivity to nitric oxide and peroxynitrite","volume":"73","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"39872","DOI":"10.1074\/jbc.M406912200","article-title":"Glutathione is required to regulate the formation of native disulfide bonds within proteins entering the secretory pathway","volume":"279","author":"Chakravarthi","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1089\/ars.2007.1782","article-title":"Endoplasmic reticulum stress and oxidative stress: A vicious cycle or a double-edged sword?","volume":"9","author":"Malhotra","year":"2007","journal-title":"Antioxid. Redox Signal."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1053\/j.gastro.2015.09.042","article-title":"Regulation of Liver Metabolism by Autophagy","volume":"150","author":"Cuervo","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1126\/science.1193497","article-title":"Autophagy and metabolism","volume":"330","author":"Rabinowitz","year":"2010","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1126\/science.aax3769","article-title":"Cellular quality control by the ubiquitin-proteasome system and autophagy","volume":"366","author":"Pohl","year":"2019","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1023\/A:1015288220217","article-title":"The bifunctional activity of ubiquinone in lysosomal membranes","volume":"3","author":"Nohl","year":"2002","journal-title":"Biogerontology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1053\/j.gastro.2006.05.048","article-title":"NADPH oxidase in the liver: Defensive, offensive, or fibrogenic?","volume":"131","author":"Bataller","year":"2006","journal-title":"Gastroenterology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1254\/jphs.10R01CR","article-title":"NOX\/NADPH oxidase, the superoxide-generating enzyme: Its transcriptional regulation and physiological roles","volume":"114","author":"Katsuyama","year":"2010","journal-title":"J. Pharmacol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1172\/JCI18212","article-title":"NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis","volume":"112","author":"Bataller","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1002\/hep.20719","article-title":"NAD(P)H oxidase plays a crucial role in PDGF-induced proliferation of hepatic stellate cells","volume":"41","author":"Adachi","year":"2005","journal-title":"Hepatology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/hep.21093","article-title":"Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo","volume":"43","author":"Zhan","year":"2006","journal-title":"Hepatology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jss.2009.09.019","article-title":"Nitric oxide and redox regulation in the liver: Part I. General considerations and redox biology in hepatitis","volume":"162","author":"Diesen","year":"2010","journal-title":"J. Surg. Res."},{"key":"ref_47","first-page":"766","article-title":"Inducible nitric oxide synthase in the liver: Regulation and function","volume":"63","author":"Taylor","year":"1998","journal-title":"Biochemistry"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/S0940-2993(96)80054-6","article-title":"Regulation of hepatic glutathione metabolism and its role in hepatotoxicity","volume":"48","author":"Kretzschmar","year":"1996","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/0304-4165(87)90183-8","article-title":"Ubiquinone biosynthesis by the microsomal fraction from rat liver","volume":"926","author":"Kalen","year":"1987","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.tcb.2015.12.007","article-title":"Understanding Ubiquinone","volume":"26","author":"Wang","year":"2016","journal-title":"Trends Cell Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1002\/iub.102","article-title":"Thioredoxin and thioredoxin binding protein 2 in the liver","volume":"60","author":"Okuyama","year":"2008","journal-title":"IUBMB Life"},{"key":"ref_52","first-page":"19","article-title":"Distribution of CuZn superoxide dismutase and Mn superoxide dismutase in human tissues and extracellular fluids","volume":"492","author":"Marklund","year":"1980","journal-title":"Acta Physiol. Scand. Suppl."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1089\/ars.2011.3999","article-title":"Superoxide dismutases: Role in redox signaling, vascular function, and diseases","volume":"15","author":"Fukai","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"38388","DOI":"10.1074\/jbc.M105395200","article-title":"Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu,Zn-SOD in mitochondria","volume":"276","author":"Fridovich","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1007\/s13238-010-0113-z","article-title":"Human catalase: Looking for complete identity","volume":"1","author":"Goyal","year":"2010","journal-title":"Protein Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1111\/bph.14498","article-title":"Disulfide reductase systems in liver","volume":"176","author":"Miller","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1089\/ars.2008.2057","article-title":"Evolutionary and structural insights into the multifaceted glutathione peroxidase (Gpx) superfamily","volume":"10","author":"Toppo","year":"2008","journal-title":"Antioxid. Redox Signal."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1089\/ars.2017.7167","article-title":"The Role of Peroxiredoxins in the Transduction of H(2)O(2) Signals","volume":"28","author":"Rhee","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1111\/jgh.16081","article-title":"A bibliometric and visualized analysis of liver fibrosis from 2002 to 2022","volume":"38","author":"Zhao","year":"2023","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1097\/MOG.0b013e32832914b4","article-title":"Cholestasis and cholestatic syndromes","volume":"25","author":"Hirschfield","year":"2009","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"283","DOI":"10.3390\/livers2040023","article-title":"Role of oxidative stress in liver disorders","volume":"2","author":"Goicoechea","year":"2022","journal-title":"Livers"},{"key":"ref_62","first-page":"1262","article-title":"Stimulation of collagen alpha 1(I) gene expression is associated with lipid peroxidation in hepatocellular injury: A link to tissue fibrosis?","volume":"19","author":"Bedossa","year":"1994","journal-title":"Hepatology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/hep.510250218","article-title":"Neutrophil-derived superoxide anion induces lipid peroxidation and stimulates collagen synthesis in human hepatic stellate cells: Role of nitric oxide","volume":"25","author":"Casini","year":"1997","journal-title":"Hepatology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"9853","DOI":"10.1074\/jbc.M110506200","article-title":"Cytochrome P450 2E1-derived reactive oxygen species mediate paracrine stimulation of collagen I protein synthesis by hepatic stellate cells","volume":"277","author":"Nieto","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1002\/hep.21427","article-title":"Oxidative-stress and IL-6 mediate the fibrogenic effects of [corrected] Kupffer cells on stellate cells","volume":"44","author":"Nieto","year":"2006","journal-title":"Hepatology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1730","DOI":"10.1002\/hep.24281","article-title":"The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2\/gp91phox mediate hepatic fibrosis in mice","volume":"53","author":"Paik","year":"2011","journal-title":"Hepatology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jhep.2013.02.016","article-title":"Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy","volume":"59","author":"Hilscher","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/S0006-2952(98)00220-2","article-title":"Nitric oxide protection of rat liver from lipid peroxidation, collagen accumulation, and liver damage induced by carbon tetrachloride","volume":"56","author":"Muriel","year":"1998","journal-title":"Biochem. Pharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1053\/j.gastro.2008.12.065","article-title":"Reactive nitrogen species switch on early extracellular matrix remodeling via induction of MMP1 and TNFalpha","volume":"136","author":"Urtasun","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1002\/hep.22278","article-title":"Lack of inducible nitric oxide synthase leads to increased hepatic apoptosis and decreased fibrosis in mice after chronic carbon tetrachloride administration","volume":"47","author":"Aram","year":"2008","journal-title":"Hepatology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3119","DOI":"10.1016\/j.febslet.2005.04.071","article-title":"Peroxynitrite-mediated matrix metalloproteinase-2 activation in human hepatic stellate cells","volume":"579","author":"Migita","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nature02006","article-title":"Smad-dependent and Smad-independent pathways in TGF-beta family signalling","volume":"425","author":"Derynck","year":"2003","journal-title":"Nature"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1111\/febs.13665","article-title":"TGF-\u03b2 signalling and liver disease","volume":"283","author":"Fabregat","year":"2016","journal-title":"FEBS J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/cr.2008.328","article-title":"Non-Smad pathways in TGF-beta signaling","volume":"19","author":"Zhang","year":"2009","journal-title":"Cell Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"196","DOI":"10.3109\/08977194.2011.595714","article-title":"TGF-beta signaling in fibrosis","volume":"29","author":"Biernacka","year":"2011","journal-title":"Growth Factors"},{"key":"ref_76","first-page":"2142","article-title":"Regulation of transforming growth factor beta1 by nitric oxide","volume":"59","author":"Vodovotz","year":"1999","journal-title":"Cancer Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1080\/15476910802085822","article-title":"The latent form of TGFbeta(1) is induced by TNFalpha through an ERK specific pathway and is activated by asbestos-derived reactive oxygen species in vitro and in vivo","volume":"5","author":"Sullivan","year":"2008","journal-title":"J. Immunotoxicol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1053\/j.gastro.2010.03.008","article-title":"Hepatitis C virus regulates transforming growth factor beta1 production through the generation of reactive oxygen species in a nuclear factor kappaB-dependent manner","volume":"138","author":"Lin","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Sancho, P., Mainez, J., Crosas-Molist, E., Roncero, C., Fernandez-Rodriguez, C.M., Pinedo, F., Huber, H., Eferl, R., Mikulits, W., and Fabregat, I. (2012). NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0045285"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1074\/jbc.M112.431973","article-title":"Mitochondrial reactive oxygen species regulate transforming growth factor-beta signaling","volume":"288","author":"Jain","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3153240","DOI":"10.1155\/2019\/3153240","article-title":"TGF-beta3 Induces Autophagic Activity by Increasing ROS Generation in a NOX4-Dependent Pathway","volume":"2019","author":"Zhang","year":"2019","journal-title":"Mediat. Inflamm."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/path.5678","article-title":"Understanding the implication of autophagy in the activation of hepatic stellate cells in liver fibrosis: Are we there yet?","volume":"254","author":"Lucantoni","year":"2021","journal-title":"J. Pathol."},{"key":"ref_83","first-page":"960","article-title":"Targeting the Wnt Signaling Pathway in Liver Fibrosis for Drug Options: An Update","volume":"9","author":"Duspara","year":"2021","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41392-021-00762-6","article-title":"Wnt\/beta-catenin signalling: Function, biological mechanisms, and therapeutic opportunities","volume":"7","author":"Liu","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.gene.2018.06.053","article-title":"Emerging role and therapeutic implication of Wnt signaling pathways in liver fibrosis","volume":"674","author":"Wang","year":"2018","journal-title":"Gene"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1016\/j.cub.2010.09.065","article-title":"Nucleoredoxin sustains Wnt\/beta-catenin signaling by retaining a pool of inactive dishevelled protein","volume":"20","author":"Funato","year":"2010","journal-title":"Curr. Biol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.taap.2014.03.008","article-title":"Morin ameliorates chemically induced liver fibrosis in vivo and inhibits stellate cell proliferation in vitro by suppressing Wnt\/beta-catenin signaling","volume":"277","author":"Madankumar","year":"2014","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1038\/nrm3598","article-title":"The mechanisms of Hedgehog signalling and its roles in development and disease","volume":"14","author":"Briscoe","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1038\/labinvest.3700689","article-title":"Hepatic accumulation of Hedgehog-reactive progenitors increases with severity of fatty liver damage in mice","volume":"87","author":"Fleig","year":"2007","journal-title":"Lab. Investig."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1136\/gut.2008.148619","article-title":"The hedgehog pathway regulates remodelling responses to biliary obstruction in rats","volume":"57","author":"Omenetti","year":"2008","journal-title":"Gut"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.toxlet.2019.11.017","article-title":"Hedgehog signaling pathway regulates hexavalent chromium-induced liver fibrosis by activation of hepatic stellate cells","volume":"320","author":"Yan","year":"2020","journal-title":"Toxicol. Lett."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/s10522-023-10034-1","article-title":"The role of Smo-Shh\/Gli signaling activation in the prevention of neurological and ageing disorders","volume":"24","author":"Prajapati","year":"2023","journal-title":"Biogerontology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1016\/j.celrep.2020.01.024","article-title":"Phenformin Inhibits Hedgehog-Dependent Tumor Growth through a Complex I-Independent Redox\/Corepressor Module","volume":"30","author":"Manni","year":"2020","journal-title":"Cell Rep."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Thauvin, M., Amblard, I., Rampon, C., Mourton, A., Queguiner, I., Li, C., Gautier, A., Joliot, A., Volovitch, M., and Vriz, S. (2022). Reciprocal Regulation of Shh Trafficking and H2O2 Levels via a Noncanonical BOC-Rac1 Pathway. Antioxidants, 11.","DOI":"10.3390\/antiox11040718"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"259664","DOI":"10.1242\/jcs.259664","article-title":"An early Shh-H2O2 reciprocal regulatory interaction controls the regenerative program during zebrafish fin regeneration","volume":"135","author":"Thauvin","year":"2022","journal-title":"J. Cell Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.cmet.2020.10.011","article-title":"The Metabolic Underpinnings of Ferroptosis","volume":"32","author":"Zheng","year":"2020","journal-title":"Cell Metab."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Shojaie, L., Iorga, A., and Dara, L. (2020). Cell Death in Liver Diseases: A Review. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249682"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nchembio.1416","article-title":"The role of iron and reactive oxygen species in cell death","volume":"10","author":"Dixon","year":"2014","journal-title":"Nat. Chem. Biol."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Feng, H., and Stockwell, B.R. (2018). Unsolved mysteries: How does lipid peroxidation cause ferroptosis?. PLoS Biol., 16.","DOI":"10.1371\/journal.pbio.2006203"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/j.bbrc.2017.07.136","article-title":"Haloperidol, a sigma receptor 1 antagonist, promotes ferroptosis in hepatocellular carcinoma cells","volume":"491","author":"Bai","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1002\/hep.29117","article-title":"Characterization of ferroptosis in murine models of hemochromatosis","volume":"66","author":"Wang","year":"2017","journal-title":"Hepatology"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1182\/blood.2019002907","article-title":"Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis","volume":"136","author":"Yu","year":"2020","journal-title":"Blood"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.biopha.2018.06.060","article-title":"Magnesium isoglycyrrhizinate ameliorates liver fibrosis and hepatic stellate cell activation by regulating ferroptosis signaling pathway","volume":"106","author":"Sui","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1016\/j.biopha.2018.11.030","article-title":"Artesunate alleviates liver fibrosis by regulating ferroptosis signaling pathway","volume":"109","author":"Kong","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.1016\/j.jhep.2015.02.039","article-title":"Hepatic fibrosis: Concept to treatment","volume":"62","author":"Trautwein","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Jangra, A., Kothari, A., Sarma, P., Medhi, B., Omar, B.J., and Kaushal, K. (2022). Recent Advancements in Antifibrotic Therapies for Regression of Liver Fibrosis. Cells, 11.","DOI":"10.3390\/cells11091500"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.addr.2017.05.017","article-title":"Therapeutic pro-fibrogenic signaling pathways in fibroblasts","volume":"121","author":"Cannito","year":"2017","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"e1800519","DOI":"10.1002\/mnfr.201800519","article-title":"Gamma-Tocotrienol Attenuates the Hepatic Inflammation and Fibrosis by Suppressing Endoplasmic Reticulum Stress in Mice","volume":"62","author":"Kim","year":"2018","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"G298","DOI":"10.1152\/ajpgi.00135.2019","article-title":"Mitochondria-targeted antioxidant mitoquinone attenuates liver inflammation and fibrosis in cirrhotic rats","volume":"318","author":"Turkseven","year":"2020","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1056\/NEJMoa0907929","article-title":"Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis","volume":"362","author":"Sanyal","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.2337\/dc19-0167","article-title":"Role of Vitamin E for Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes: A Randomized Controlled Trial","volume":"42","author":"Bril","year":"2019","journal-title":"Diabetes Care"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1002\/hep.32285","article-title":"Hepatic fibrosis 2022: Unmet needs and a blueprint for the future","volume":"75","author":"Friedman","year":"2022","journal-title":"Hepatology"},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Chen, Z., Tian, R., She, Z., Cai, J., and Li, H. (2021). Corrigendum to \u201cRole of oxidative stress in the pathogenesis of nonalcoholic fatty liver disease\u201d [Free Radic. Biol. Med. 152 (2020) 116\u2013141]. Free Radic. Biol. Med., 162.","DOI":"10.1016\/j.freeradbiomed.2020.06.011"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Roehlen, N., Crouchet, E., and Baumert, T.F. (2020). Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells, 9.","DOI":"10.3390\/cells9040875"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.taap.2009.07.030","article-title":"Inhibition of liver fibrosis by solubilized coenzyme Q10: Role of Nrf2 activation in inhibiting transforming growth factor-beta1 expression","volume":"240","author":"Choi","year":"2009","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"579","DOI":"10.3945\/ajcn.115.119834","article-title":"Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in a male rat model of poor maternal nutrition and accelerated postnatal growth","volume":"103","author":"Hargreaves","year":"2016","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1093\/toxres\/tfac062","article-title":"MitoQ alleviates carbon tetrachloride-induced liver fibrosis in mice through regulating JNK\/YAP pathway","volume":"11","author":"Shan","year":"2022","journal-title":"Toxicol. Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1515\/med-2021-0394","article-title":"MitoQ inhibits hepatic stellate cell activation and liver fibrosis by enhancing PINK1\/parkin-mediated mitophagy","volume":"16","author":"Dou","year":"2021","journal-title":"Open Med."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1111\/jpi.12319","article-title":"Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride-induced liver fibrosis","volume":"60","author":"Kang","year":"2016","journal-title":"J. Pineal Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1111\/jcmm.17649","article-title":"Pre-clinical evidence of a dual NADPH oxidase 1\/4 inhibitor (setanaxib) in liver, kidney and lung fibrosis","volume":"27","author":"Thannickal","year":"2023","journal-title":"J. Cell Mol. Med."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.freeradbiomed.2012.05.007","article-title":"Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4\/NOX1 inhibitor in vivo","volume":"53","author":"Jiang","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1053\/j.gastro.2015.04.009","article-title":"Hepatocyte Nicotinamide Adenine Dinucleotide Phosphate Reduced Oxidase 4 Regulates Stress Signaling, Fibrosis, and Insulin Sensitivity during Development of Steatohepatitis in Mice","volume":"149","author":"Bettaieb","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Lan, T., Kisseleva, T., and Brenner, D.A. (2015). Deficiency of NOX1 or NOX4 Prevents Liver Inflammation and Fibrosis in Mice through Inhibition of Hepatic Stellate Cell Activation. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129743"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.jhep.2020.09.037","article-title":"Hepatocyte-specific NRF2 activation controls fibrogenesis and carcinogenesis in steatohepatitis","volume":"74","author":"Mohs","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.jcmgh.2017.11.016","article-title":"Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2)","volume":"5","author":"Sharma","year":"2018","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"100651","DOI":"10.1016\/j.jhepr.2022.100651","article-title":"Selective disruption of NRF2-KEAP1 interaction leads to NASH resolution and reduction of liver fibrosis in mice","volume":"5","author":"Seedorf","year":"2023","journal-title":"JHEP Rep."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"11686","DOI":"10.1039\/D1FO02657G","article-title":"Piperine inhibits AML-12 hepatocyte EMT and LX-2 HSC activation and alleviates mouse liver fibrosis provoked by CCl(4): Roles in the activation of the Nrf2 cascade and subsequent suppression of the TGF-beta1\/Smad axis","volume":"12","author":"Shu","year":"2021","journal-title":"Food Funct."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s00018-012-1046-x","article-title":"Peroxisome proliferator-activated receptor-gamma as a therapeutic target for hepatic fibrosis: From bench to bedside","volume":"70","author":"Zhang","year":"2013","journal-title":"Cell Mol. Life Sci."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"44612","DOI":"10.1038\/srep44612","article-title":"Effect of modulation of PPAR-gamma activity on Kupffer cells M1\/M2 polarization in the development of non-alcoholic fatty liver disease","volume":"7","author":"Luo","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"108391","DOI":"10.1016\/j.pharmthera.2023.108391","article-title":"PPAR-gamma signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets","volume":"245","author":"Chen","year":"2023","journal-title":"Pharmacol. Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/1\/410\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:43:13Z","timestamp":1760132593000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/1\/410"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,28]]},"references-count":131,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["ijms25010410"],"URL":"https:\/\/doi.org\/10.3390\/ijms25010410","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,28]]}}}