Abstract: Nuclear factor erythroid 2-related factor 2 (Nrf2) is an intracellular transcription factor that helps protect against oxidative stress in different types of cells under pathological conditions. Mitochondria are vital organelles that function in diverse metabolic processes in the body, including redox reactions, lipid metabolism, and cell death. Mitophagy, a specific form of autophagy for damaged mitochondria, plays a critical role in the pathophysiology of liver diseases. In this review, we explain in detail the roles of the Nrf2 signaling pathway and mitophagy, and the relationship between them, in various hepatic diseases (nonalcoholic fatty liver disease, viral hepatitis, alcoholic liver disease, drug-induced liver injury, autoimmune hepatitis, hepatic ischemia‒reperfusion injury, and liver cancer). We also offer some potential insights and treatments relevant to clinical applications.

Keap1/Nrf2通路和线粒体自噬在肝脏疾病中的作用

[1]AbdallaMY, BritiganBE, WenF, et al., 2004. Down-regulation of heme oxygenase-1 by hepatitis C virus infection in vivo and by the in vitro expression of hepatitis C core protein. J Infect Dis, 190(6):1109-1118.

[2]AbdelazizAI, MantawyEM, GadAM, et al., 2019. Activation of pCREB/Nrf-2 signaling mediates re-positioning of liraglutide as hepato-protective for methotrexate-induced liver injury (MILI). Food Chem Toxicol, 132:110719.

[3]AbdelhamidAM, ElsheakhAR, SuddekGM, et al., 2021. Telmisartan alleviates alcohol-induced liver injury by activation of PPAR-γ/Nrf-2 crosstalk in mice. Int Immunopharmacol, 99:107963.

[4]AbulikemuA, ZhaoXY, XuHL, et al., 2023. Silica nanoparticles aggravated the metabolic associated fatty liver disease through disturbed amino acid and lipid metabolisms-mediated oxidative stress. Redox Biol, 59:102569.

[5]AhnSB, WuWH, LeeJH, et al., 2018. Fermented soymilk alleviates lipid accumulation by inhibition of SREBP-1 and activation of NRF-2 in the hepatocellular steatosis model. J Microbiol Biotechnol, 28(2):236-245.

[6]AitaVM, LiangXH, MurtyVVVS, et al., 1999. Cloning and genomic organization of Beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics, 59(1):59-65.

[7]AjiboyeTO, Ajala-LawalRA, AdeyigaAB, 2019. Caffeic acid abrogates 1,3-dichloro-2-propanol-induced hepatotoxicity by upregulating nuclear erythroid-related factor 2 and downregulating nuclear factor-kappa B. Hum Exp Toxicol, 38(9):1092-1101.

[8]AliFEM, Saad EldienHM, MostafaNAM, et al., 2021. The impact of royal jelly against hepatic ischemia/reperfusion-induced hepatocyte damage in rats: the role of cytoglobin, Nrf-2/HO-1/COX-4, and P₃₈-MAPK/NF-κB-p65/TNF-α signaling pathways. Curr Mol Pharmacol, 14(1):88-100.

[9]AliyuNO, Ajala-LawalRA, AjiboyeTO, 2018. Lophirones B and C halt acetaminophen hepatotoxicity by upregulating redox transcription factor Nrf-2 through Akt, PI3K, and PKC pathways. J Biochem Mol Toxicol, 32(6):e22055.

[10]AmpawongS, IsarangkulD, AramwitP, 2017. Sericin improves heart and liver mitochondrial architecture in hypercholesterolaemic rats and maintains pancreatic and adrenal cell biosynthesis. Exp Cell Res, 358(2):301-314.

[11]AriffiantoA, DengL, AbeT, et al., 2023. Oxidative stress sensor Keap1 recognizes HBx protein to activate the Nrf2/ARE signaling pathway, thereby inhibiting hepatitis B virus replication. J Virol, 97(10):e0128723.

[12]AslaminabadR, RahimianshahrezaN, HosseiniSA, et al., 2022. Regulation of Nrf2 and Nrf2-related proteins by ganoderma lucidum ın hepatocellular carcinoma. Mol Biol Rep, 49(10):9605-9612.

[13]AslanA, GokO, ErmanO, et al., 2018. Ellagic acid impedes carbontetrachloride-induced liver damage in rats through suppression of NF-κB, Bcl-2 and regulating Nrf-2 and caspase pathway. Biomed Pharmacother, 105:662-669.

[14]AxleyPD, RichardsonCT, SingalAK, 2019. Epidemiology of alcohol consumption and societal burden of alcoholism and alcoholic liver disease. Clin Liver Dis, 23(1):39-50.

[15]BaeSH, SungSH, OhSY, et al., 2013. Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage. Cell Metab, 17(1):73-84.

[16]BairdL, YamamotoM, 2023. Immunoediting of KEAP1-NRF2 mutant tumours is required to circumvent NRF2-mediated immune surveillance. Redox Biol, 67:102904.

[17]BairdL, TaguchiK, ZhangAQ, et al., 2023. A NRF2-induced secretory phenotype activates immune surveillance to remove irreparably damaged cells. Redox Biol, 66:102845.

[18]BauliesA, RibasV, NúñezS, et al., 2015. Lysosomal cholesterol accumulation sensitizes to acetaminophen hepatotoxicity by impairing mitophagy. Sci Rep, 5:18017.

[19]BhogalRH, WestonCJ, VelduisS, et al., 2018. The reactive oxygen species-mitophagy signaling pathway regulates liver endothelial cell survival during ischemia/reperfusion injury. Liver Transpl, 24(10):1437-1452.

[20]BiYG, LiuSL, QinX, et al., 2024. FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner. J Adv Res, 55:45-60.

[21]CaiCZ, MaHL, PengJ, et al., 2023. USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice. Nat Commun, 14:3648.

[22]CaiXP, HuaSY, DengJW, et al., 2022. Astaxanthin activated the Nrf2/HO-1 pathway to enhance autophagy and inhibit ferroptosis, ameliorating acetaminophen-induced liver injury. ACS Appl Mater Interfaces, 14(38):42887-42903.

[23]ChaoTN, ShihHT, HsuSC, et al., 2021. Autophagy restricts mitochondrial DNA damage-induced release of ENDOG (endonuclease G) to regulate genome stability. Autophagy, 17(11):3444-3460.

[24]ChaoXJ, WangH, JaeschkeH, et al., 2018. Role and mechanisms of autophagy in acetaminophen-induced liver injury. Liver Int, 38(8):1363-1374.

[25]ChaoXJ, WangSG, FulteS, et al., 2022. Hepatocytic p62 suppresses ductular reaction and tumorigenesis in mouse livers with mTORC1 activation and defective autophagy. J Hepatol, 76(3):639-651.

[26]CheJY, YangS, QiaoZJ, et al., 2019. Schisandra chinensis acidic polysaccharide partialy reverses acetaminophen-induced liver injury in mice. J Pharmacol Sci, 140(3):248-254.

[27]ChenL, ZhangWL, XieDQ, et al., 2021. Sulforaphane alleviates hepatic ischemia-reperfusion injury through promoting the activation of Nrf-2/HO-1 signaling. Transpl Immunol, 68:101439.

[28]ChenLY, YangBS, ZhouL, et al., 2015. Promotion of mitochondrial energy metabolism during hepatocyte apoptosis in a rat model of acute liver failure. Mol Med Rep, 12(4):5035-5041.

[29]ChenSY, HuangYS, SuHM, et al., 2022. The integrated analysis of transcriptomics and metabolomics unveils the therapeutical effect of asiatic acid on alcoholic hepatitis in rats. Inflammation, 45(4):1780-1799.

[30]ChenWC, WangSY, ChiuCC, et al., 2013. Lucidone suppresses hepatitis C virus replication by Nrf2-mediated heme oxygenase-1 induction. Antimicrob Agents Chemother, 57(3):1180-1191.

[31]ChenWC, WeiCK, LeeJC, 2019. MicroRNA-let-7c suppresses hepatitis C virus replication by targeting Bach1 for induction of haem oxygenase-1 expression. J Viral Hepat, 26(6):655-665.

[32]ChenY, ChenHN, WangK, et al., 2019. Ketoconazole exacerbates mitophagy to induce apoptosis by downregulating cyclooxygenase-2 in hepatocellular carcinoma. J Hepatol, 70(1):66-77.

[33]ChenYQ, ParkHJ, ParkJ, et al., 2019. Carbon monoxide ameliorates acetaminophen-induced liver injury by increasing hepatic HO-1 and Parkin expression. FASEB J, 33(12):13905-13919.

[34]ChenYT, LinYC, LinJS, et al., 2018. Sugary kefir strain Lactobacillus mali APS1 ameliorated hepatic steatosis by regulation of SIRT-1/Nrf-2 and gut microbiota in rats. Mol Nutr Food Res, 62(8):1700903.

[35]ChenYY, WangWH, CheL, et al., 2020. BNIP3L-dependent mitophagy promotes HBx-induced cancer stemness of hepatocellular carcinoma cells via glycolysis metabolism reprogramming. Cancers (Basel), 12(3):655.

[36]ChiHC, ChenSL, LinSL, et al., 2017. Thyroid hormone protects hepatocytes from HBx-induced carcinogenesis by enhancing mitochondrial turnover. Oncogene, 36(37):5274-5284.

[37]ChidaT, WatanabeS, OhtaK, et al., 2024. Impact of amino acid substitutions in hepatitis C virus core region on the severe oxidative stress. Free Radic Biol Med, 212:199-206.

[38]ChoiBK, KimTW, LeeDR, et al., 2015. A polymethoxy flavonoids-rich Citrus aurantium extract ameliorates ethanol-induced liver injury through modulation of AMPK and Nrf2-related signals in a binge drinking mouse model. Phytother Res, 29(10):1577-1584.

[39]ChowdhryS, NazmyMH, MeakinPJ, et al., 2010. Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free Radic Biol Med, 48(2):357-371.

[40]ChuJYK, OuJHJ, 2021. Autophagy in HCV replication and protein trafficking. Int J Mol Sci, 22(3):1089.

[41]DingWX, LiM, YinXM, 2011. Selective taste of ethanol-induced autophagy for mitochondria and lipid droplets. Autophagy, 7(2):248-249.

[42]di PaolaR, ModafferiS, SiracusaR, et al., 2022. S-Acetyl-glutathione attenuates carbon tetrachloride-induced liver injury by modulating oxidative imbalance and inflammation. Int J Mol Sci, 23(8):4429.

[43]DodsonM, Castro-PortuguezR, ZhangDD, 2019. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol, 23:101107.

[44]DuP, ZhangXJ, LuoKF, et al., 2022. Curculigoside mitigates hepatic ischemia/reperfusion-induced oxidative stress, inflammation, and apoptosis via activation of the Nrf-2/HO-1 pathway. Hum Exp Toxicol, 41:9603271221087146.

[45]EzhilarasanD, LakshmiT, 2022. A molecular insight into the role of antioxidants in nonalcoholic fatty liver diseases. Oxid Med Cell Longev, 2022:9233650.

[46]FaghihzadehF, AdibiP, RafieiR, et al., 2014. Resveratrol supplementation improves inflammatory biomarkers in patients with nonalcoholic fatty liver disease. Nutr Res, 34(10):837-843.

[47]GaoY, ChuSF, ZhangZ, et al., 2017. Early stage functions of mitochondrial autophagy and oxidative stress in acetaminophen-induced liver injury. J Cell Biochem, 118(10):3130-3141.

[48]GaoZM, YiW, TangJY, et al., 2022. Urolithin A protects against acetaminophen-induced liver injury in mice via sustained activation of Nrf2. Int J Biol Sci, 18(5):2146-2162.

[49]GeCX, XuMX, QinYT, et al., 2019. Loss of RIP3 initiates annihilation of high-fat diet initialized nonalcoholic hepatosteatosis: a mechanism involving Toll-like receptor 4 and oxidative stress. Free Radic Biol Med, 134:23-41.

[50]GeJ, LiGM, ChenZW, et al., 2024. Kaempferol and nicotiflorin ameliorated alcohol-induced liver injury in mice by miR-138-5p/SIRT1/FXR and gut microbiota. Heliyon, 10(1):e23336.

[51]GuoJ, LiC, YangCX, et al., 2018. Liraglutide reduces hepatic glucolipotoxicity-induced liver cell apoptosis through NRF2 signaling in Zucker diabetic fatty rats. Mol Med Rep, 17(6):8316-8324.

[52]GuoJY, ChenHY, MathewR, et al., 2011. Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev, 25(5):460-470.

[53]GuoM, GuLW, HuiHP, et al., 2022. Extracts of Dracocephalum tanguticum maxim ameliorate acute alcoholic liver disease via regulating transcription factors in mice. Front Pharmacol, 13:830532.

[54]HagaS, OzawaT, YamadaY, et al., 2014. p62/SQSTM1 plays a protective role in oxidative injury of steatotic liver in a mouse hepatectomy model. Antioxid Redox Signal, 21(18):2515-2530.

[55]HallisSP, KimJM, KwakMK, 2023. Emerging role of NRF2 signaling in cancer stem cell phenotype. Mol Cells, 46(3):153-164.

[56]HammouteneA, LaouiremS, AlbuquerqueM, et al., 2023. A new NRF2 activator for the treatment of human metabolic dysfunction-associated fatty liver disease. JHEP Rep, 5(10):100845.

[57]HanX, LiWF, HuangD, et al., 2016. Polyphenols from hawthorn peels and fleshes differently mitigate dyslipidemia, inflammation and oxidative stress in association with modulation of liver injury in high fructose diet-fed mice. Chem Biol Interact, 257:132-140.

[58]HassaneinEHM, KhaderHF, ElmansyRA, et al., 2021. Umbelliferone alleviates hepatic ischemia/reperfusion-induced oxidative stress injury via targeting Keap-1/Nrf-2/ARE and TLR4/NF-κB-p65 signaling pathway. Environ Sci Pollut Res Int, 28(47):67863-67879.

[59]HeF, HuangYR, SongZ, et al., 2021. Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance. J Exp Med, 218(3):e20201416.

[60]HeF, ZhangP, LiuJL, et al., 2023. ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to block stress-related ferroptosis. J Hepatol, 79(2):362-377.

[61]HolmströmKM, BairdL, ZhangY, et al., 2013. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biol Open, 2(8):761-770.

[62]HongJM, KimSJ, LeeSM, 2016. Role of necroptosis in autophagy signaling during hepatic ischemia and reperfusion. Toxicol Appl Pharmacol, 308:1-10.

[63]HuangQH, XuLQ, LiuYH, et al., 2017. Polydatin protects rat liver against ethanol-induced injury: involvement of CYP2E1/ROS/Nrf2 and TLR4/NF-κB p65 pathway. Evid Based Complement Alternat Med, 2017:7953850.

[64]HuiB, ShuYT, YangDD, et al., 2022. Sinomenine pretreatment alleviates hepatic ischemia/reperfusion injury through activating Nrf-2/HO-1 pathway. Immun Inflamm Dis, 10(10):e700.

[65]HwangKA, HwangY, HwangHJ, et al., 2022. Hepatoprotective effects of radish (Raphanus sativus L.) on acetaminophen-induced liver damage via inhibiting oxidative stress and apoptosis. Nutrients, 14(23):5082.

[66]IbitoyeOB, AjiboyeTO, 2020. Protocatechuic acid protects against menadione-induced liver damage by up-regulating nuclear erythroid-related factor 2. Drug Chem Toxicol, 43(6):567-573.

[67]InamiY, WaguriS, SakamotoA, et al., 2011. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J Cell Biol, 193(2):275-284.

[68]InnokentevA, KankiT, 2021. Mitophagy in yeast: molecular mechanism and regulation. Cells, 10(12):3569.

[69]JiangT, HarderB, Rojo de la Vega M, et al., 2015. p62 links autophagy and Nrf2 signaling. Free Radic Biol Med, 88:199-204.

[70]JiangZT, YangX, HanY, et al., 2022. Sarmentosin promotes USP17 and regulates Nrf2-mediated mitophagy and cellular oxidative stress to alleviate APAP-induced acute liver failure. Phytomedicine, 104:154337.

[71]JoeY, ZhengM, KimHJ, et al., 2015. Cilostazol attenuates murine hepatic ischemia and reperfusion injury via heme oxygenase-dependent activation of mitochondrial biogenesis. Am J Physiol Gastrointest Liver Physiol, 309(1):G21-G29.

[72]KalantariL, GhotbabadiZR, GholipourA, et al., 2023. A state-of-the-art review on the NRF2 in hepatitis virus-associated liver cancer. Cell Commun Signal, 21:318.

[73]Kathiswar RajR, EzhilarasanD, RajeshkumarS, 2020. β-Sitosterol-assisted silver nanoparticles activates Nrf2 and triggers mitochondrial apoptosis via oxidative stress in human hepatocellular cancer cell line. J Biomed Mater Res A, 108(9):1899-1908.

[74]KhambuB, HudaN, ChenXY, et al., 2018. HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers. J Clin Invest, 128(6):2419-2435.

[75]KhanMI, KarimaG, KhanMZ, et al., 2022. Therapeutic effects of saponins for the prevention and treatment of cancer by ameliorating inflammation and angiogenesis and inducing antioxidant and apoptotic effects in human cells. Int J Mol Sci, 23(18):10665.

[76]KimJY, OuJHJ, 2018. Regulation of apolipoprotein E trafficking by hepatitis C virus-induced autophagy. J Virol, 92(14):e00211-18.

[77]KojimaH, KadonoK, HiraoH, et al., 2023. CD4⁺ T cell NRF2 signaling improves liver transplantation outcomes by modulating T cell activation and differentiation. Antioxid Redox Signal, 38(7-9):670-683.

[78]KomatsuM, KurokawaH, WaguriS, et al., 2010. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol, 12(3):213-223.

[79]KudohK, UchinamiH, YoshiokaM, et al., 2014. Nrf2 activation protects the liver from ischemia/reperfusion injury in mice. Ann Surg, 260(1):118-127.

[80]KumarD, DwivediDK, LahkarM, et al., 2019. Hepatoprotective potential of 7,8-dihydroxyflavone against alcohol and high-fat diet induced liver toxicity via attenuation of oxido-nitrosative stress and NF-κB activation. Pharmacol Rep, 71(6):1235-1243.

[81]LauA, WangXJ, ZhaoF, et al., 2010. A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol Cell Biol, 30(13):3275-3285.

[82]LeboeufSE, WuWL, KarakousiTR, et al., 2020. Activation of oxidative stress response in cancer generates a druggable dependency on exogenous non-essential amino acids. Cell Metab, 31(2):339-350.e4.

[83]LeeJC, LinCK, TsengCK, et al., 2018. Discovery of 3-amino-2-hydroxypropoxyisoflavone derivatives as potential anti-HCV agents. Molecules, 23(11):2863.

[84]LeeLY, HarbergC, MatkowskyjKA, et al., 2016. Overactivation of the nuclear factor (erythroid-derived 2)-like 2-antioxidant response element pathway in hepatocytes decreases hepatic ischemia/reperfusion injury in mice. Liver Transpl, 22(1):91-102.

[85]LeeYA, NoonLA, AkatKM, et al., 2018. Autophagy is a gatekeeper of hepatic differentiation and carcinogenesis by controlling the degradation of Yap. Nat Commun, 9:4962.

[86]LeiYM, XuX, LiuHL, et al., 2021. HBx induces hepatocellular carcinogenesis through ARRB1-mediated autophagy to drive the G₁/S cycle. Autophagy, 17(12):4423-4441.

[87]LiD, SunFF, WangD, et al., 2020. Programmed death ligand-1 (PD-L1) regulated by NRF-2/microRNA-1 regulatory axis enhances drug resistance and promotes tumorigenic properties in sorafenib-resistant hepatoma cells. Oncol Res, 28(5):467-481.

[88]LiH, ChenYB, DingMJ, et al., 2023. Pectolinarigenin attenuates hepatic ischemia/reperfusion injury via activation of the PI3K/AKT/Nrf2 signaling pathway. Chem Biol Interact, 386:110763.

[89]LiL, GuoCC, YuY, et al., 2023. Differential effects of PGAM5 knockout on high fat high fructose diet and methionine choline-deficient diet induced non-alcoholic steatohepatitis (NASH) in mice. Cell Biosci, 13:154.

[90]LiQ, ZhangW, ChengN, et al., 2023. Pectolinarigenin ameliorates acetaminophen-induced acute liver injury via attenuating oxidative stress and inflammatory response in Nrf2 and PPARa dependent manners. Phytomedicine, 113:154726.

[91]LiRB, XinT, LiDD, et al., 2018. Therapeutic effect of Sirtuin 3 on ameliorating nonalcoholic fatty liver disease: the role of the ERK-CREB pathway and Bnip3-mediated mitophagy. Redox Biol, 18:229-243.

[92]LiXW, ShiZ, ZhuYW, et al., 2020. Cyanidin-3-O-glucoside improves non-alcoholic fatty liver disease by promoting PINK1-mediated mitophagy in mice. Br J Pharmacol, 177(15):3591-3607.

[93]LinY, WuCC, WangXY, et al., 2020. Glucosamine promotes hepatitis B virus replication through its dual effects in suppressing autophagic degradation and inhibiting MTORC1 signaling. Autophagy, 16(3):548-561.

[94]LinZF, WuF, LinSQ, et al., 2014. Adiponectin protects against acetaminophen-induced mitochondrial dysfunction and acute liver injury by promoting autophagy in mice. J Hepatol, 61(4):825-831.

[95]LiuC, WuZ, WangLP, et al., 2022. A mitophagy-related gene signature for subtype identification and prognosis prediction of hepatocellular carcinoma. Int J Mol Sci, 23(20):12123.

[96]LiuK, LeeJ, KimJY, et al., 2017. Mitophagy controls the activities of tumor suppressor p53 to regulate hepatic cancer stem cells. Mol Cell, 68(2):281-292.e5.

[97]LiuPF, AnandhanA, ChenJJ, et al., 2023. Decreased autophagosome biogenesis, reduced NRF2, and enhanced ferroptotic cell death are underlying molecular mechanisms of non-alcoholic fatty liver disease. Redox Biol, 59:102570.

[98]LiuWJ, ChenWW, ChenJY, et al., 2025. Baicalin attenuated metabolic dysfunction-associated fatty liver disease by suppressing oxidative stress and inflammation via the p62-Keap1-Nrf2 signalling pathway in db/db mice. Phytother Res, 39(4):1663-1678.

[99]LiuYQ, WuQL, ZhangFY, et al., 2023. Antioxidants-related nuclear factor erythroid 2-related factor 2 gene variants associated with HBV-related liver disease. Cancer Cell Int, 23:72.

[100]LiuZG, RenB, WangYH, et al., 2017. Sesamol induces human hepatocellular carcinoma cells apoptosis by impairing mitochondrial function and suppressing autophagy. Sci Rep, 7:45728.

[101]LuCF, XuWX, ZhangF, et al., 2016. Nrf2 knockdown disrupts the protective effect of curcumin on alcohol-induced hepatocyte necroptosis. Mol Pharm, 13(12):4043-4053.

[102]LuXY, XuanWT, LiJJ, et al., 2021. AMPK protects against alcohol-induced liver injury through UQCRC2 to up-regulate mitophagy. Autophagy, 17(11):3622-3643.

[103]MaXW, McKeenT, ZhangJH, et al., 2020. Role and mechanisms of mitophagy in liver diseases. Cells, 9(4):837.

[104]MahmoudAR, AliFEM, Abd-ElhamidTH, et al., 2019. Coenzyme Q₁₀ protects hepatocytes from ischemia reperfusion-induced apoptosis and oxidative stress via regulation of Bax/Bcl-2/PUMA and Nrf-2/FOXO-3/Sirt-1 signaling pathways. Tissue Cell, 60:1-13.

[105]MaoH, ChenW, ChenLX, et al., 2022. Potential role of mitochondria-associated endoplasmic reticulum membrane proteins in diseases. Biochem Pharmacol, 199:115011.

[106]MedvedevR, PloenD, SpenglerC, et al., 2017. HCV-induced oxidative stress by inhibition of Nrf2 triggers autophagy and favors release of viral particles. Free Radic Biol Med, 110:300-315.

[107]MengB, ZhangYZ, WangZQ, et al., 2019. Hepatoprotective effects of Morchella esculenta against alcohol-induced acute liver injury in the C57BL/6 mouse related to Nrf-2 and NF-κB signaling. Oxid Med Cell Longev, 2019:6029876.

[108]MiyakawaK, JeremiahSS, OgawaM, et al., 2022a. Crosstalk between the innate immune system and selective autophagy in hepatitis B virus infection. Autophagy, 18(8):2006-2007.

[109]MiyakawaK, NishiM, OgawaM, et al., 2022b. Galectin-9 restricts hepatitis B virus replication via p62/SQSTM1-mediated selective autophagy of viral core proteins. Nat Commun, 13:531.

[110]MizushimaN, KomatsuM, 2011. Autophagy: renovation of cells and tissues. Cell, 147(4):728-741.

[111]MohsA, OttoT, SchneiderKM, et al., 2021. Hepatocyte-specific NRF2 activation controls fibrogenesis and carcinogenesis in steatohepatitis. J Hepatol, 74(3):638-648.

[112]MorsyMA, IbrahimYF, Abdel HafezSMN, et al., 2022. Paeonol attenuates hepatic ischemia/reperfusion injury by modulating the Nrf2/HO-1 and TLR4/MYD88/NF-κB signaling pathways. Antioxidants (Basel), 11(9):1687.

[113]MunakarmiS, GurauY, ShresthaJ, et al., 2023. Synergistic effects of Vitis vinifera L. and Centella asiatica against CCl₄-induced liver injury in mice. Int J Mol Sci, 24(14):11255.

[114]NamachivayamA, Valsala GopalakrishnanA, 2021. A review on molecular mechanism of alcoholic liver disease. Life Sci, 274:119328.

[115]NiHM, BoggessN, McGillMR, et al., 2012. Liver-specific loss of Atg5 causes persistent activation of Nrf2 and protects against acetaminophen-induced liver injury. Toxicol Sci, 127(2):438-450.

[116]NiHM, DuK, YouM, et al., 2013. Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity. Am J Pathol, 183(6):1815-1825.

[117]NiHM, WoolbrightBL, WilliamsJ, et al., 2014. Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy. J Hepatol, 61(3):617-625.

[118]NiHM, McGillMR, ChaoXJ, et al., 2016. Removal of acetaminophen protein adducts by autophagy protects against acetaminophen-induced liver injury in mice. J Hepatol, 65(2):354-362.

[119]NingXJ, YanX, WangYF, et al., 2018. Parkin deficiency elevates hepatic ischemia/reperfusion injury accompanying decreased mitochondrial autophagy, increased apoptosis, impaired DNA damage repair and altered cell cycle distribution. Mol Med Rep, 18(6):5663-5668.

[120]NioY, SasaiM, AkahoriY, et al., 2019. Bardoxolone methyl as a novel potent antiviral agent against hepatitis B and C viruses in human hepatocyte cell culture systems. Antiviral Res, 169:104537.

[121]OuQ, WengYY, WangSW, et al., 2018. Silybin alleviates hepatic steatosis and fibrosis in NASH mice by inhibiting oxidative stress and involvement with the NF-κB pathway. Dig Dis Sci, 63(12):3398-3408.

[122]PanZS, GuoJY, TangKJ, et al., 2022. Ginsenoside Rc modulates SIRT6-NRF2 interaction to alleviate alcoholic liver disease. J Agric Food Chem, 70(44):14220-14234.

[123]PatelF, ParwaniK, PatelD, et al., 2021. Metformin and probiotics interplay in amelioration of ethanol-induced oxidative stress and inflammatory response in an in vitro and in vivo model of hepatic injury. Mediators Inflamm, 2021:6636152.

[124]PetersenDR, SabaLM, SayinVI, et al., 2018. Elevated Nrf-2 responses are insufficient to mitigate protein carbonylation in hepatospecific PTEN deletion mice. PLoS ONE, 13(5):e0198139.

[125]ProtzerU, SeyfriedS, QuasdorffM, et al., 2007. Antiviral activity and hepatoprotection by heme oxygenase-1 in hepatitis B virus infection. Gastroenterology, 133(4):1156-1165.

[126]QiDB, ChenP, BaoHL, et al., 2023. Dimethyl fumarate protects against hepatic ischemia-reperfusion injury by alleviating ferroptosis via the NRF2/SLC7A11/HO-1 axis. Cell Cycle, 22(7):818-828.

[127]QianQW, ZhangZY, OrwigA, et al., 2018. S-Nitrosoglutathione reductase dysfunction contributes to obesity-associated hepatic insulin resistance via regulating autophagy. Diabetes, 67(2):193-207.

[128]QuXP, YuJ, BhagatG, et al., 2003. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest, 112(12):1809-1820.

[129]RabieMA, ZakiHF, SayedHM, 2019. Telluric acid ameliorates hepatic ischemia reperfusion-induced injury in rats: involvement of TLR4, Nrf2, and PI3K/Akt signaling pathways. Biochem Pharmacol, 168:404-411.

[130]RinellaME, LazarusJV, RatziuV, et al., 2023. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol, 79(6):1542-1556.

[131]RockwellCE, ZhangMC, FieldsPE, et al., 2012. Th2 skewing by activation of Nrf2 in CD4⁺ T cells. J Immunol, 188(4):1630-1637.

[132]RussomannoG, Sison-YoungR, LivotiLA, et al., 2023. A systems approach reveals species differences in hepatic stress response capacity. Toxicol Sci, 196(1):112-125.

[133]SchneiderJL, CuervoAM, 2014. Liver autophagy: much more than just taking out the trash. Nat Rev Gastroenterol Hepatol, 11(3):187-200.

[134]SettembreC, de CegliR, MansuetoG, et al., 2013. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat Cell Biol, 15(6):647-658.

[135]ShanSL, ShenZY, ZhangCQ, et al., 2019. Mitophagy protects against acetaminophen-induced acute liver injury in mice through inhibiting NLRP3 inflammasome activation. Biochem Pharmacol, 169:113643.

[136]ShaoN, YuXY, MaXF, et al., 2018. Exenatide delays the progression of nonalcoholic fatty liver disease in C57BL/6 mice, which may involve inhibition of the NLRP3 inflammasome through the mitophagy pathway. Gastroenterol Res Pract, 2018:1864307.

[137]ShenJ, WangGF, ZuoJP, 2018. Caffeic acid inhibits HCV replication via induction of IFNα antiviral response through p62-mediated Keap1/Nrf2 signaling pathway. Antiviral Res, 154:166-173.

[138]ShenYM, ZhangHL, WuYH, et al., 2015. Dynamic correlation between induction of the expression of heme oxygenase-1 and hepatitis B viral replication. Mol Med Rep, 11(6):4706-4712.

[139]SirD, ChenWL, ChoiJ, et al., 2008a. Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. Hepatology, 48(4):1054-1061.

[140]SirD, LiangCY, ChenWL, et al., 2008b. Perturbation of autophagic pathway by hepatitis C virus. Autophagy, 4(6):830-831.

[141]SirD, TianYJ, ChenWL, et al., 2010. The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication. Proc Natl Acad Sci USA, 107(9):4383-4388.

[142]SirD, KuoCF, TianYJ, et al., 2012. Replication of hepatitis C virus RNA on autophagosomal membranes. J Biol Chem, 287(22):18036-18043.

[143]SmirnovaOA, IvanovaON, MukhtarovF, et al., 2023. Hepatitis delta virus antigens trigger oxidative stress, activate antioxidant Nrf2/ARE pathway, and induce unfolded protein response. Antioxidants (Basel), 12(4):974.

[144]Solano-UrrusquietaA, Morales-GonzálezJA, Castro-NarroGE, et al., 2020. NRF-2 and nonalcoholic fatty liver disease. Ann Hepatol, 19(5):458-465.

[145]SongJZ, ZhaoX, BoJQ, et al., 2024. A polysaccharide from Alhagi honey protects the intestinal barrier and regulates the Nrf2/HO-1-TLR4/MAPK signaling pathway to treat alcoholic liver disease in mice. J Ethnopharmacol, 321:117552.

[146]SotoG, RodríguezMJ, FuentealbaR, et al., 2020. Maresin 1, a proresolving lipid mediator, ameliorates liver ischemia-reperfusion injury and stimulates hepatocyte proliferation in Sprague-Dawley rats. Int J Mol Sci, 21(2):540.

[147]SunC, WangZH, LiuXX, et al., 2015. Disturbance of redox status enhances radiosensitivity of hepatocellular carcinoma. Am J Cancer Res, 5(4):1368-1381.

[148]SuzukiT, MurakamiS, BiswalSS, et al., 2017. Systemic activation of NRF2 alleviates lethal autoimmune inflammation in scurfy mice. Mol Cell Biol, 37(15):e00063-17.

[149]TaguchiK, FujikawaN, KomatsuM, et al., 2012. Keap1 degradation by autophagy for the maintenance of redox homeostasis. Proc Natl Acad Sci USA, 109(34):13561-13566.

[150]TakamuraA, KomatsuM, HaraT, et al., 2011. Autophagy-deficient mice develop multiple liver tumors. Genes Dev, 25(8):795-800.

[151]TamilmaniP, Sathibabu UddandraoVV, ChandrasekaranP, et al., 2023. Linalool attenuates lipid accumulation and oxidative stress in metabolic dysfunction-associated steatotic liver disease via Sirt1/Akt/PPRA-α/AMPK and Nrf-2/HO-1 signaling pathways. Clin Res Hepatol Gastroenterol, 47(10):102231.

[152]TangKZ, ChenQ, LiuYM, et al., 2022. Combination of metformin and sorafenib induces ferroptosis of hepatocellular carcinoma through p62-Keap1-Nrf2 pathway. J Cancer, 13(11):3234-3243.

[153]TargherG, ByrneCD, TilgH, 2024. MASLD: a systemic metabolic disorder with cardiovascular and malignant complications. Gut, 73(4):691-702.

[154]ThimmulappaRK, LeeH, RangasamyT, et al., 2006. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest, 116(4):984-995.

[155]ThomesPG, TramblyCS, FoxHS, et al., 2015. Acute and chronic ethanol administration differentially modulate hepatic autophagy and transcription factor EB. Alcohol Clin Exp Res, 39(12):2354-2363.

[156]TianC, MinXW, ZhaoYX, et al., 2022. MRG15 aggravates non-alcoholic steatohepatitis progression by regulating the mitochondrial proteolytic degradation of TUFM. J Hepatol, 77(6):1491-1503.

[157]Tomulic BrusichK, ŠkrtićA, SobočanN, et al., 2023. Role of NRF2 and reactive aldehydes in acute cellular rejection in liver transplant recipients. Pathol Res Pract, 250:154826.

[158]TongGZ, ChenYM, ChenXX, et al., 2023. FGF18 alleviates hepatic ischemia-reperfusion injury via the USP16-mediated KEAP1/Nrf2 signaling pathway in male mice. Nat Commun, 14:6107.

[159]TwuWI, LeeJY, KimH, et al., 2021. Contribution of autophagy machinery factors to HCV and SARS-CoV-2 replication organelle formation. Cell Rep, 37(8):110049.

[160]UrrunagaNH, JadejaRN, RachakondaV, et al., 2015. M1 muscarinic receptors modify oxidative stress response to acetaminophen-induced acute liver injury. Free Radic Biol Med, 78:66-81.

[161]WangCL, WangYJ, 2023. The role and mechanism of action of mitophagy in various liver diseases. Antioxid Redox Signal, 38(7-9):529-549.

[162]WangCR, GongJH, ZhaoZB, et al., 2024. m⁶A demethylation of FOSL1 mRNA protects hepatoma cells against necrosis under glucose deprivation. Cell Death Differ, 31:1029-1043.

[163]WangH, NiHM, ChaoXJ, et al., 2019. Double deletion of PINK1 and Parkin impairs hepatic mitophagy and exacerbates acetaminophen-induced liver injury in mice. Redox Biol, 22:101148.

[164]WangL, LiuXL, NieJ, et al., 2015. ALCAT1 controls mitochondrial etiology of fatty liver diseases, linking defective mitophagy to steatosis. Hepatology, 61(2):486-496.

[165]WangSY, TaoJ, ChenHG, et al., 2021. Ablation of Akt2 and AMPKα2 rescues high fat diet-induced obesity and hepatic steatosis through Parkin-mediated mitophagy. Acta Pharm Sin B, 11(11):3508-3526.

[166]WangX, LiuJR, ZhangXH, et al., 2018. Seabuckthorn berry polysaccharide extracts protect against acetaminophen induced hepatotoxicity in mice via activating the Nrf-2/HO-1-SOD-2 signaling pathway. Phytomedicine, 38:90-97.

[167]WangXY, WeiZQ, LanTY, et al., 2022a. CCDC88A/GIV promotes HBV replication and progeny secretion via enhancing endosomal trafficking and blocking autophagic degradation. Autophagy, 18(2):357-374.

[168]WangXY, WeiZQ, ChengB, et al., 2022b. Endoplasmic reticulum stress promotes HBV production by enhancing use of the autophagosome/multivesicular body axis. Hepatology, 75(2):438-454.

[169]WangY, WangZ, SunJJ, et al., 2021. Identification of HCC subtypes with different prognosis and metabolic patterns based on mitophagy. Front Cell Dev Biol, 9:799507.

[170]WayalV, HsiehCC, 2023. Bioactive dipeptides mitigate high-fat and high-fructose corn syrup diet-induced metabolic-associated fatty liver disease via upregulation of Nrf2/HO-1 expressions in C57BL/6J mice. Biomed Pharmacother, 168:115724.

[171]WhiteE, MehnertJM, ChanCS, 2015. Autophagy, metabolism, and cancer. Clin Cancer Res, 21(22):5037-5046.

[172]WilliamsJA, NiHM, HaynesA, et al., 2015a. Chronic deletion and acute knockdown of Parkin have differential responses to acetaminophen-induced mitophagy and liver injury in mice. J Biol Chem, 290(17):10934-10946.

[173]WilliamsJA, NiHM, DingYF, et al., 2015b. Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice. Am J Physiol Gastrointest Liver Physiol, 309(5):G324-G340.

[174]WuH, WangT, LiuYQ, et al., 2020a. Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis. J Exp Clin Cancer Res, 39:274.

[175]WuH, ChenGY, WangJY, et al., 2020b. TIM-4 interference in Kupffer cells against CCl₄-induced liver fibrosis by mediating Akt1/Mitophagy signalling pathway. Cell Prolif, 53(1):e12731.

[176]WuKC, LiuJ, KlaassenCD, 2012. Role of Nrf2 in preventing ethanol-induced oxidative stress and lipid accumulation. Toxicol Appl Pharmacol, 262(3):321-329.

[177]XiangXH, FuYN, ZhaoK, et al., 2021. Cellular senescence in hepatocellular carcinoma induced by a long non-coding RNA-encoded peptide PINT87aa by blocking FOXM1-mediated PHB2. Theranostics, 11(10):4929-4944.

[178]XieL, HuangWG, LiJL, et al., 2022. The protective effects and mechanisms of modified Lvdou Gancao decoction on acute alcohol intoxication in mice. J Ethnopharmacol, 282:114593.

[179]XieWY, JiangZH, WangJ, et al., 2016. Protective effect of hyperoside against acetaminophen (APAP) induced liver injury through enhancement of APAP clearance. Chem Biol Interact, 246:11-19.

[180]XieZY, XiaoZH, WangFF, 2018. Inhibition of autophagy reverses alcohol-induced hepatic stellate cells activation through activation of Nrf2-Keap1-ARE signaling pathway. Biochimie, 147:55-62.

[181]XuM, HangHL, HuangM, et al., 2021. DJ-1 deficiency in hepatocytes improves liver ischemia-reperfusion injury by enhancing mitophagy. Cell Mol Gastroenterol Hepatol, 12(2):567-584.

[182]XuPF, XiY, WangPC, et al., 2022. Inhibition of p53 sulfoconjugation prevents oxidative hepatotoxicity and acute liver failure. Gastroenterology, 162(4):1226-1241.

[183]YamadaT, MurataD, AdachiY, et al., 2018. Mitochondrial stasis reveals p62-mediated ubiquitination in Parkin-independent mitophagy and mitigates nonalcoholic fatty liver disease. Cell Metab, 28(4):588-604.e5.

[184]YangL, LiP, FuSN, et al., 2010. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab, 11(6):467-478.

[185]YangMM, XiaLQ, SongJ, et al., 2023. Puerarin ameliorates metabolic dysfunction-associated fatty liver disease by inhibiting ferroptosis and inflammation. Lipids Health Dis, 22:202.

[186]YangQ, ZhaoZZ, XieJ, et al., 2021. Senkyunolide I attenuates hepatic ischemia/reperfusion injury in mice via anti-oxidative, anti-inflammatory and anti-apoptotic pathways. Int Immunopharmacol, 97:107717.

[187]YangRQ, ZhangM, GustafsonAR, et al., 2015. Loss of protein targeting to glycogen sensitizes human hepatocellular carcinoma cells towards glucose deprivation mediated oxidative stress and cell death. Biosci Rep, 35(3):e00207.

[188]YangT, QuXY, ZhaoJY, et al., 2023. Macrophage PTEN controls STING-induced inflammation and necroptosis through NICD/NRF2 signaling in APAP-induced liver injury. Cell Commun Signal, 21:160.

[189]YaoJY, WangJB, XuY, et al., 2022. CDK9 inhibition blocks the initiation of PINK1-PRKN-mediated mitophagy by regulating the SIRT1-FOXO3-BNIP3 axis and enhances the therapeutic effects involving mitochondrial dysfunction in hepatocellular carcinoma. Autophagy, 18(8):1879-1897.

[190]YaoPY, LiuYJ, 2022. Terpenoids: natural compounds for non-alcoholic fatty liver disease (NAFLD) therapy. Molecules, 28(1):272.

[191]YatesMS, TranQT, DolanPM, et al., 2009. Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice. Carcinogenesis, 30(6):1024-1031.

[192]YeligarSM, MachidaK, KalraVK, 2010. Ethanol-induced HO-1 and NQO1 are differentially regulated by HIF-1α and Nrf2 to attenuate inflammatory cytokine expression. J Biol Chem, 285(46):35359-35373.

[193]YiZW, XiaYJ, LiuXF, et al., 2020. Antrodin A from mycelium of Antrodia camphorata alleviates acute alcoholic liver injury and modulates intestinal flora dysbiosis in mice. J Ethnopharmacol, 254:112681.

[194]YuLC, LiuYY, JinYC, et al., 2021. Zinc supplementation prevented type 2 diabetes-induced liver injury mediated by the Nrf2-MT antioxidative pathway. J Diabetes Res, 2021:6662418.

[195]YuZ, GuoJF, HuMY, et al., 2020. Icaritin exacerbates mitophagy and synergizes with doxorubicin to induce immunogenic cell death in hepatocellular carcinoma. ACS Nano, 14(4):4816-4828.

[196]YunNR, ChoHI, LeeSM, 2014. Impaired autophagy contributes to hepatocellular damage during ischemia/reperfusion: heme oxygenase-1 as a possible regulator. Free Radic Biol Med, 68:168-177.

[197]ZengYN, WuR, WangFZ, et al., 2023. Liberation of daidzein by gut microbial β-galactosidase suppresses acetaminophen-induced hepatotoxicity in mice. Cell Host Microbe, 31(5):766-780.e7.

[198]ZhanYQ, XuDW, TianYZ, et al., 2022. Novel role of macrophage TXNIP-mediated CYLD-NRF2-OASL1 axis in stress-induced liver inflammation and cell death. JHEP Rep, 4(9):100532.

[199]ZhangH, ZhangYQ, ZhuXY, et al., 2019. DEAD box protein 5 inhibits liver tumorigenesis by stimulating autophagy via interaction with p62/SQSTM1. Hepatology, 69(3):1046-1063.

[200]ZhangWP, ChenLH, FengH, et al., 2017. Rifampicin-induced injury in HepG2 cells is alleviated by TUDCA via increasing bile acid transporters expression and enhancing the Nrf2-mediated adaptive response. Free Radic Biol Med, 112:24-35.

[201]ZhangXR, WangMY, TengSS, et al., 2018. Indolyl-chalcone derivatives induce hepatocellular carcinoma cells apoptosis through oxidative stress related mitochondrial pathway in vitro and in vivo. Chem Biol Interact, 293:61-69.

[202]ZhangYJ, WeiH, WangMM, et al., 2023. Dexmedetomidine alleviates ferroptosis following hepatic ischemia-reperfusion injury by upregulating Nrf2/GPx4-dependent antioxidant responses. Biomed Pharmacother, 169:115915.

[203]ZhangYKJ, YeagerRL, TanakaY, et al., 2010. Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet. Toxicol Appl Pharmacol, 245(3):326-334.

[204]ZhaoN, GuoFF, XieKQ, et al., 2018. Targeting Nrf-2 is a promising intervention approach for the prevention of ethanol-induced liver disease. Cell Mol Life Sci, 75(17):3143-3157.

[205]ZhaoZ, WeiQY, HuaWW, et al., 2018. Hepatoprotective effects of berberine on acetaminophen-induced hepatotoxicity in mice. Biomed Pharmacother, 103:1319-1326.

[206]ZhengJ, ChenL, LuTY, et al., 2020. MSCs ameliorate hepatocellular apoptosis mediated by PINK1-dependent mitophagy in liver ischemia/reperfusion injury through AMPKα activation. Cell Death Dis, 11(4):256.

[207]ZhengYH, HuangC, LuL, et al., 2021. STOML2 potentiates metastasis of hepatocellular carcinoma by promoting PINK1-mediated mitophagy and regulates sensitivity to lenvatinib. J Hematol Oncol, 14:16.

[208]ZhongWZ, RaoZQ, XuJ, et al., 2022. Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation. Aging Cell, 21(6):e13622.

[209]ZhouH, ZhuPJ, WangJ, et al., 2019. DNA-PKcs promotes alcohol-related liver disease by activating Drp1-related mitochondrial fission and repressing FUNDC1-required mitophagy. Signal Transduct Target Ther, 4:56.

[210]ZhouQH, ShiY, ChenC, et al., 2021. A narrative review of the roles of indoleamine 2,3-dioxygenase and tryptophan-2,3-dioxygenase in liver diseases. Ann Transl Med, 9(2):174.

[211]ZhuH, JiaZQ, MisraH, et al., 2012. Oxidative stress and redox signaling mechanisms of alcoholic liver disease: updated experimental and clinical evidence. J Dig Dis, 13(3):133-142.

[212]ZhuQL, ZhuoHL, YangLM, et al., 2022. A peptide HEPFYGNEGALR from Apostichopus japonicus alleviates acute alcoholic liver injury by enhancing antioxidant response in male C57BL/6J mice. Molecules, 27(18):5839.

[213]ZhuZW, WilsonAT, MathahsMM, et al., 2008. Heme oxygenase-1 suppresses hepatitis C virus replication and increases resistance of hepatocytes to oxidant injury. Hepatology, 48(5):1430-1439.

[214]ZhuZW, WilsonAT, LuxonBA, et al., 2010. Biliverdin inhibits hepatitis C virus nonstructural 3/4A protease activity: mechanism for the antiviral effects of heme oxygenase? Hepatology, 52(6):1897-1905.