{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T09:10:42Z","timestamp":1791882642692,"version":"4.3.4"},"reference-count":188,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T00:00:00Z","timestamp":1682553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"U.S. National Institutes of Health (NIH)\/National Institute on Drug Abuse (NIDA)","award":["R01DA042632"],"award-info":[{"award-number":["R01DA042632"]}]},{"name":"U.S. National Institutes of Health (NIH)\/National Institute on Drug Abuse (NIDA)","award":["R01DA058458"],"award-info":[{"award-number":["R01DA058458"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Antiviral protease inhibitors are peptidomimetic molecules that block the active catalytic center of viral proteases and, thereby, prevent the cleavage of viral polyprotein precursors into maturation. They continue to be a key class of antiviral drugs that can be used either as boosters for other classes of antivirals or as major components of current regimens in therapies for the treatment of infections with human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, sustained\/lifelong treatment with the drugs or drugs combined with other substance(s) often leads to severe hepatic side effects such as lipid abnormalities, insulin resistance, and hepatotoxicity. The underlying pathogenic mechanisms are not fully known and are under continuous investigation. This review focuses on the general as well as specific molecular mechanisms of the protease inhibitor-induced hepatotoxicity involving transporter proteins, apolipoprotein B, cytochrome P450 isozymes, insulin-receptor substrate 1, Akt\/PKB signaling, lipogenic factors, UDP-glucuronosyltransferase, pregnane X receptor, hepatocyte nuclear factor 4\u03b1, reactive oxygen species, inflammatory cytokines, off-target proteases, and small GTPase Rab proteins related to ER-Golgi trafficking, organelle stress, and liver injury. Potential pharmaceutical\/therapeutic solutions to antiviral drug-induced hepatic side effects are also discussed.<\/jats:p>","DOI":"10.3390\/ijms24097938","type":"journal-article","created":{"date-parts":[[2023,4,28]],"date-time":"2023-04-28T02:27:56Z","timestamp":1682648876000},"page":"7938","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Molecular Factors and Pathways of Hepatotoxicity Associated with HIV\/SARS-CoV-2 Protease Inhibitors"],"prefix":"10.3390","volume":"24","author":[{"given":"Cheng","family":"Ji","sequence":"first","affiliation":[{"name":"Research Center for Liver Disease, GI\/Liver Division, Department of Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA 90089, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,27]]},"reference":[{"key":"ref_1","unstructured":"(2023, January 15). HIV.gov. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV, Available online: https:\/\/clinicalinfo.hiv.gov\/en\/guidelines\/adult-and-adolescent-arv\/initiation-antiretroviral-therapy."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1001\/jama.2022.22246","article-title":"Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2022 Recommendations of the International Antiviral Society-USA Panel","volume":"329","author":"Gandhi","year":"2023","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Otto, A.O., Rivera, C.G., Zeuli, J.D., and Temesgen, Z. (2021). Hepatotoxicity of Contemporary Antiretroviral Drugs: A Review and Evaluation of Published Clinical Data. Cells, 10.","DOI":"10.3390\/cells10051263"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1056\/NEJM199804303381808","article-title":"HIV-protease inhibitors","volume":"338","author":"Flexner","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7341493","DOI":"10.1155\/2022\/7341493","article-title":"Paxlovid: Mechanism of Action, Synthesis, and In Silico Study","volume":"2022","author":"Marzi","year":"2022","journal-title":"Biomed. Res. Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1080\/14740338.2022.2160446","article-title":"Liver tests abnormalities with licensed antiviral drugs for COVID-19: A narrative review","volume":"21","author":"Casalini","year":"2022","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lory, P., Combret, S., Michot, J., Veyrac, G., Chouchana, L., and Grandvuillemin, A. (Therapie, 2022). Safety profile of the lopinavir\/ritonavir combination before and during the SARS-CoV-2 pandemic, Therapie, in press.","DOI":"10.1016\/j.therap.2022.10.066"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Grandvuillemin, A., Rocher, F., Valnet-Rabier, M.B., Drici, M.D., and Dautriche, A. (Therapie, 2023). French Pharmacovigilance Network. Pharmacovigilance follow-up of patients in the context of the COVID-19 pandemic, Therapie, in press.","DOI":"10.1016\/j.therap.2023.01.004"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1056\/NEJMra1816149","article-title":"Drug-Induced Liver Injury\u2014Types and Phenotypes","volume":"381","author":"Hoofnagle","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_10","first-page":"95","article-title":"HIV protease inhibitors: A review of molecular selectivity and toxicity","volume":"7","author":"Lv","year":"2015","journal-title":"HIV AIDS Auckl."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.2174\/1568026619666190619115243","article-title":"Protease Inhibitors for the Treatment of HIV\/AIDS: Recent Advances and Future Challenges","volume":"19","author":"Voshavar","year":"2019","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1097\/COH.0000000000000706","article-title":"Hepatotoxicity of contemporary antiretroviral drugs","volume":"16","author":"Rivera","year":"2021","journal-title":"Curr. Opin. HIV AIDS"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"104267","DOI":"10.1016\/j.phrs.2019.104267","article-title":"\u201cGruppo Italiano Studio-NASH in malattie infettive\u201d. Drug-induced liver steatosis in patients with HIV infection","volume":"145","author":"Gervasoni","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1517\/17425255.2015.996546","article-title":"Drug-drug interactions between anti-retroviral therapies and drugs of abuse in HIV systems","volume":"11","author":"Kumar","year":"2015","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"851","DOI":"10.3390\/biom9120851","article-title":"Alcohol Metabolism Potentiates HIV-Induced Hepatotoxicity: Contribution to End-Stage Liver Disease","volume":"9","author":"Makarov","year":"2019","journal-title":"Biomolecules"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4728","DOI":"10.3748\/wjg.v24.i42.4728","article-title":"Liver as a target of human immunodeficiency virus infection","volume":"24","author":"Ganesan","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1097\/00002030-200111090-00004","article-title":"Lipodystrophy in HIV-1-positive patients is associated with insulin resistance in multiple metabolic pathways","volume":"15","author":"Bisschop","year":"2001","journal-title":"Aids"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1053\/meta.2002.34704","article-title":"Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antiretroviral therapy","volume":"51","author":"Hadigan","year":"2002","journal-title":"Metabolism"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1080\/14740338.2019.1644317","article-title":"Metabolic complications affecting adipose tissue, lipid and glucose metabolism associated with HIV antiretroviral treatment","volume":"18","author":"Lagathu","year":"2019","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/414799a","article-title":"Insulin signalling and the regulation of glucose and lipid metabolism","volume":"414","author":"Saltiel","year":"2001","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/1476-511X-4-4","article-title":"Changes in lipids over twelve months after initiating protease inhibitor therapy among persons treated for HIV\/AIDS","volume":"4","author":"Levy","year":"2005","journal-title":"Lipids Health Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1002\/cphy.c160028","article-title":"Adipose Tissue in HIV Infection","volume":"7","author":"Koethe","year":"2017","journal-title":"Compr. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1093\/jac\/dkl214","article-title":"Grupo Andaluz Para el Estudio de las Enfermedades Infecciosas (GAEI). Incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among HIV-infected patients with chronic hepatitis C","volume":"58","author":"Mira","year":"2006","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"237","DOI":"10.2174\/187153007782794362","article-title":"HIV-therapy associated lipodystrophy: Experimental and clinical evidence for the pathogenesis and treatment","volume":"7","author":"Stankov","year":"2007","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/377151a0","article-title":"Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4","volume":"377","author":"Katz","year":"1995","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"20251","DOI":"10.1074\/jbc.C000228200","article-title":"The mechanism of insulin resistance caused by HIV protease inhibitor therapy","volume":"275","author":"Murata","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1097\/00002030-200204120-00005","article-title":"Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations","volume":"16","author":"Murata","year":"2002","journal-title":"Aids"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0163-7827(02)00046-2","article-title":"Effects of HIV protease inhibitor therapy on lipid metabolism","volume":"42","author":"Hui","year":"2003","journal-title":"Prog. Lipid Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"937","DOI":"10.2337\/diabetes.51.4.937","article-title":"Indinavir induces acute and reversible peripheral insulin resistance in rats","volume":"51","author":"Hruz","year":"2002","journal-title":"Diabetes"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"F11","DOI":"10.1097\/00002030-200105040-00001","article-title":"Metabolic effects of indinavir in healthy HIV-seronegative men","volume":"15","author":"Noor","year":"2001","journal-title":"Aids"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1172\/JCI200421341","article-title":"GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization","volume":"114","author":"Kotani","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"36395","DOI":"10.1074\/jbc.M110.176321","article-title":"Effects of the HIV protease inhibitor ritonavir on GLUT4 knock-out mice","volume":"285","author":"Vyas","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.ecl.2008.09.001","article-title":"Hypothalamic control of hepatic glucose production and its potential role in insulin resistance","volume":"37","author":"Buettner","year":"2008","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1677\/joe.1.05620","article-title":"Long-term effects of HIV-1 protease inhibitors on insulin secretion and insulin signaling in INS-1 beta cells","volume":"183","author":"Zhou","year":"2004","journal-title":"J. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1007\/s001250051505","article-title":"The HIV-1 protease inhibitor indinavir impairs insulin signalling in HepG2 hepatoma cells","volume":"43","author":"Meier","year":"2000","journal-title":"Diabetologia"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Hresko, R.C., and Hruz, P.W. (2011). HIV protease inhibitors act as competitive inhibitors of the cytoplasmic glucose binding site of GLUTs with differing affinities for GLUT1 and GLUT4. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025237"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.2337\/diabetes.49.10.1643","article-title":"Glucose sensing by the hepatoportal sensor is GLUT2-dependent: In vivo analysis in GLUT2-null mice","volume":"49","author":"Burcelin","year":"2000","journal-title":"Diabetes"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"32345","DOI":"10.1074\/jbc.M313478200","article-title":"Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease","volume":"279","author":"Samuel","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1055\/s-2003-37495","article-title":"The HIV protease inhibitor indinavir impairs glycogen synthesis in HepG2 hepatoma cells","volume":"111","author":"Meier","year":"2003","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1038\/nm1201-1327","article-title":"HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: A potential mechanism for protease inhibitor-induced hyperlipidemia","volume":"7","author":"Liang","year":"2001","journal-title":"Nat. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"37514","DOI":"10.1074\/jbc.M104557200","article-title":"HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus","volume":"276","author":"Riddle","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/S0140-6736(02)08094-7","article-title":"Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance","volume":"359","author":"Bastard","year":"2002","journal-title":"Lancet"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.biocel.2011.03.002","article-title":"Molecular mechanisms of human lipodystrophies: From adipocyte lipid droplet to oxidative stress and lipotoxicity","volume":"43","author":"Vigouroux","year":"2011","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1742-6405-3-19","article-title":"The effect of different combination therapies on oxidative stress markers in HIV infected patients in Cameroon","volume":"22","author":"Ngondi","year":"2006","journal-title":"AIDS Res. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"442","DOI":"10.3181\/0811-RM-317","article-title":"HIV-1 protease inhibitor induced oxidative stress suppresses glucose stimulated insulin release: Protection with thymoquinone","volume":"234","author":"Chandra","year":"2009","journal-title":"Exp. Biol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"291","DOI":"10.3109\/10715762.2013.770149","article-title":"Effects of oxidative stress on the pharmacokinetics and hepatic metabolism of atazanavir in rats","volume":"47","author":"Kobuchi","year":"2013","journal-title":"Free Radic. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s10565-018-09451-7","article-title":"Endoplasmic reticulum stress leads to mitochondria-mediated apoptosis in cells treated with anti-HIV protease inhibitor ritonavir","volume":"35","author":"Ganta","year":"2019","journal-title":"Cell Biol. Toxicol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"ElZohary, L., Weglicki, W.B., Chmielinska, J.J., Kramer, J.H., and Mak, I.T. (2019). Mg-supplementation attenuated lipogenic and oxidative\/nitrosative gene expression caused by Combination Antiretroviral Therapy (cART) in HIV-1-transgenic rats. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0210107"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1002\/hep.27985","article-title":"Plasma cholesteryl ester transfer protein is predominantly derived from Kupffer cells","volume":"62","author":"Wang","year":"2015","journal-title":"Hepatology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"304","DOI":"10.2353\/ajpath.2007.060965","article-title":"Human immunodeficiency virus protease inhibitor ritonavir inhibits cholesterol efflux from human macrophage-derived foam cells","volume":"171","author":"Wang","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_51","first-page":"4076","article-title":"Oxidative Stress and Mitochondrial Impairment After Treatment with Anti-HIV Drugs: Clinical Implications","volume":"17","author":"Apostolova","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_52","first-page":"329","article-title":"Interactions of HIV protease inhibitors with a human organic cation transporter in a mammalian expression system","volume":"28","author":"Zhang","year":"2000","journal-title":"Drug Metab. Dispos."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1002\/bdd.701","article-title":"Interaction of eight HIV protease inhibitors with the canalicular efflux transporter ABCC2 (MRP2) in sandwich-cultured rat and human hepatocytes","volume":"31","author":"Ye","year":"2010","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1124\/dmd.117.079467","article-title":"MRP2 Inhibition by HIV Protease Inhibitors in Rat and Human Hepatocytes: A Quantitative Confocal Microscopy Study","volume":"46","author":"Holmstock","year":"2018","journal-title":"Drug Metab. Dispos."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1124\/jpet.106.102657","article-title":"Ritonavir, saquinavir, and efavirenz, but not nevirapine, inhibit bile acid transport in human and rat hepatocytes","volume":"318","author":"McRae","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1002\/jps.24564","article-title":"Clearance Prediction of HIV Protease Inhibitors in Man: Role of Hepatic Uptake","volume":"105","author":"Stieger","year":"2016","journal-title":"J. Pharm. Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"163","DOI":"10.3109\/00498250903509375","article-title":"Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1","volume":"40","author":"Annaert","year":"2010","journal-title":"Xenobiotica"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"220","DOI":"10.2133\/dmpk.DMPK-10-RV-094","article-title":"Clinical importance of OATP1B1 and OATP1B3 in drug-drug interactions","volume":"26","author":"Shitara","year":"2011","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"T\u00e1trai, P., and Krajcsi, P. (2020). Prediction of Drug-Induced Hyperbilirubinemia by In Vitro Testing. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12080755"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"12671","DOI":"10.1073\/pnas.231140698","article-title":"Mechanism of indinavir-induced hyperbilirubinemia","volume":"98","author":"Zucker","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1007\/s15010-008-8010-6","article-title":"Hyperbilirubinemia during atazanavir treatment in 2404 patients in the Italian atazanavir expanded access program and MASTER Cohorts","volume":"37","author":"Torti","year":"2009","journal-title":"Infection"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1345\/aph.1R550","article-title":"Effect of the UGT1A1*28 allele on unconjugated hyperbilirubinemia in HIV-positive patients receiving Atazanavir: A systematic review","volume":"47","author":"Culley","year":"2013","journal-title":"Ann. Pharmacother."},{"key":"ref_63","first-page":"205","article-title":"Hyperbilirubinemia in atazanavir treated HIV-infected patients: The impact of the UGT1A1*28 allele","volume":"10","author":"Panagopoulos","year":"2017","journal-title":"Pharmgenomics Pers. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"BSR20182105","DOI":"10.1042\/BSR20182105","article-title":"Association between the UGT1A1*28 allele and hyperbilirubinemia in HIV-positive patients receiving atazanavir: A meta-analysis","volume":"39","author":"Du","year":"2019","journal-title":"Biosci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e016310","DOI":"10.1161\/JAHA.120.016310","article-title":"Association Between Atazanavir-Induced Hyperbilirubinemia and Cardiovascular Disease in Patients Infected with HIV","volume":"9","author":"Li","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1016\/j.jhep.2008.12.030","article-title":"Gilbert\u2019s syndrome and hyperbilirubinemia in protease inhibitor therapy\u2014An extended haplotype of genetic variants increases risk in indinavir treatment","volume":"50","author":"Lankisch","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Mencarelli, A., Cipriani, S., Renga, B., Francisci, D., Palladino, G., Distrutti, E., Baldelli, F., and Fiorucci, S. (2010). The bile acid sensor FXR protects against dyslipidemia and aortic plaques development induced by the HIV protease inhibitor ritonavir in mice. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013238"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2898","DOI":"10.1172\/JCI128274","article-title":"Pregnane X receptor activation potentiates ritonavir hepatotoxicity","volume":"129","author":"Shehu","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1016\/j.apsb.2021.09.031","article-title":"PXR activation impairs hepatic glucose metabolism partly via inhibiting the HNF4\u03b1-GLUT2 pathway","volume":"12","author":"Liu","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1124\/dmd.121.000693","article-title":"Long Noncoding RNAs Hepatocyte Nuclear Factor 4A Antisense RNA 1 and Hepatocyte Nuclear Factor 1A Antisense RNA 1 Are Involved in Ritonavir-Induced Cytotoxicity in Hepatoma Cells","volume":"50","author":"Wang","year":"2022","journal-title":"Drug Metab. Dispos."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"329","DOI":"10.3109\/01913123.2014.914114","article-title":"Ritonavir-induced hepatotoxicity and ultrastructural changes of hepatocytes","volume":"38","author":"Kuang","year":"2014","journal-title":"Ultrastruct. Pathol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1179\/1973947812Y.0000000011","article-title":"Antitumour effects of a protease inhibitor, nelfinavir, in hepatocellular carcinoma cancer cells","volume":"24","author":"Sun","year":"2012","journal-title":"J. Chemother."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.lfs.2018.10.023","article-title":"Formononetin and biochanin A protects against ritonavir induced hepatotoxicity via modulation of Nf\u03baB\/pAkt signaling molecules","volume":"213","author":"Chaturvedi","year":"2018","journal-title":"Life Sci."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Gruevska, A., Moragrega, \u00c1.B., Cossarizza, A., Esplugues, J.V., Blas-Garc\u00eda, A., and Apostolova, N. (2021). Apoptosis of Hepatocytes: Relevance for HIV-Infected Patients under Treatment. Cells, 10.","DOI":"10.3390\/cells10020410"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.bcp.2009.03.022","article-title":"HIV protease inhibitor lopinavir-induced TNF-alpha and IL-6 expression is coupled to the unfolded protein response and ERK signaling pathways in macrophages","volume":"78","author":"Chen","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"545","DOI":"10.2174\/157016210793499222","article-title":"Differential effects of efavirenz and lopinavir\/ritonavir on human adipocyte differentiation, gene expression and release of adipokines and pro-inflammatory cytokines","volume":"8","author":"Gutierrez","year":"2010","journal-title":"Curr. HIV Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"S90","DOI":"10.1086\/381444","article-title":"Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors","volume":"38","author":"Sulkowski","year":"2004","journal-title":"Clin. Infect. Dis."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1002\/hep.27920","article-title":"A clinician\u2019s guide to drug-drug interactions with direct-acting antiviral agents for the treatment of hepatitis C viral infection","volume":"63","author":"Dick","year":"2016","journal-title":"Hepatology"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1097\/00002030-200203080-00005","article-title":"The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir","volume":"16","author":"Kosel","year":"2002","journal-title":"Aids"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"27","DOI":"10.2147\/HMER.S282662","article-title":"Special Considerations in the Management of HIV and Viral Hepatitis Coinfections in Liver Transplantation","volume":"14","author":"McCain","year":"2022","journal-title":"Hepatic Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1097\/QAI.0000000000003122","article-title":"Prevalence of Potentially Clinically Significant Drug-Drug Interactions With Antiretrovirals Against HIV Over Three Decades: A Systematic Review of the Literature","volume":"92","author":"Hodge","year":"2023","journal-title":"JAIDS J. Acquir. Immune Defic. Syndr."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Basoulis, D., Mastrogianni, E., Voutsinas, P.M., and Psichogiou, M. (2023). HIV and COVID-19 Co-Infection: Epidemiology, Clinical Characteristics, and Treatment. Viruses, 15.","DOI":"10.3390\/v15020577"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1097\/01.aids.0000237377.61809.87","article-title":"Severe hepatotoxicity associated with the combination of enfuvirtide and tipranavir\/ritonavir: Case report","volume":"20","author":"Bogner","year":"2006","journal-title":"Aids"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1089\/apc.2008.0043","article-title":"Intracranial hemorrhage and liver-associated deaths associated with tipranavir\/ritonavir: Review of cases from the FDA\u2019s Adverse Event Reporting System","volume":"22","author":"Struble","year":"2008","journal-title":"AIDS Patient Care STDS"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1124\/dmd.109.030817","article-title":"Metabolism-mediated drug interactions associated with ritonavir-boosted tipranavir in mice","volume":"38","author":"Li","year":"2010","journal-title":"Drug Metab. Dispos."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1093\/cid\/cis968","article-title":"Pharmacokinetic interactions between the hepatitis C virus protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, darunavir, and lopinavir","volume":"56","author":"Hulskotte","year":"2013","journal-title":"Clin. Infect. Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1517\/17425255.2014.883379","article-title":"Clinically relevant drug-drug interactions between antiretrovirals and antifungals","volume":"10","author":"Vadlapatla","year":"2014","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"111","DOI":"10.2165\/00002018-200225020-00005","article-title":"Clinically significant interactions with drugs used in the treatment of tuberculosis","volume":"25","author":"Yew","year":"2002","journal-title":"Drug Saf."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"819","DOI":"10.2165\/00003088-200342090-00003","article-title":"Pharmacokinetic interactions with rifampicin: Clinical relevance","volume":"42","author":"Niemi","year":"2003","journal-title":"Clin. Pharmacokinet."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/j.1753-5174.2009.00017.x","article-title":"Unexpected Hepatotoxicity of Rifampin and Saquinavir\/Ritonavir in Healthy Male Volunteers","volume":"2","author":"Schmitt","year":"2009","journal-title":"Arch. Drug Inf."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1111\/cts.13281","article-title":"A literature review of liver function test elevations in rifampin drug-drug interaction studies","volume":"15","author":"Ibrahim","year":"2022","journal-title":"Clin. Transl. Sci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"965","DOI":"10.3851\/IMP1399","article-title":"P-glycoprotein, multidrug resistance-associated proteins and human organic anion transporting polypeptide influence the intracellular accumulation of atazanavir","volume":"14","author":"Janneh","year":"2009","journal-title":"Antivir Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e01060","DOI":"10.1002\/prp2.1060","article-title":"Mechanistic in vitro studies indicate that the clinical drug-drug interactions between protease inhibitors and rosuvastatin are driven by inhibition of intestinal BCRP and hepatic OATP1B1 with minimal contribution from OATP1B3, NTCP and OAT3","volume":"11","author":"Elsby","year":"2023","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1007\/s11095-005-5271-y","article-title":"Quantitative assessment of HIV-1 protease inhibitor interactions with drug efflux transporters in the blood-brain barrier","volume":"22","author":"Bachmeier","year":"2005","journal-title":"Pharm. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1007\/s40262-013-0075-4","article-title":"Drug-drug interactions between HMG-CoA reductase inhibitors (statins) and antiviral protease inhibitors","volume":"52","author":"Chauvin","year":"2013","journal-title":"Clin. Pharmacokinet."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"86","DOI":"10.5501\/wjv.v10.i3.86","article-title":"Angiotensin-converting enzyme 2 receptors, chronic liver diseases, common medications, and clinical outcomes in coronavirus disease 2019 patients","volume":"10","author":"Leowattana","year":"2021","journal-title":"World J. Virol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"443","DOI":"10.5501\/wjv.v11.i6.443","article-title":"COVID-19-induced liver injury in adult patients: A brief overview","volume":"11","author":"Grando","year":"2022","journal-title":"World J. Virol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"619","DOI":"10.21037\/atm-22-2791","article-title":"The feasibility, safety, and efficacy of Paxlovid treatment in SARS-CoV-2-infected children aged 6-14 years: A cohort study","volume":"10","author":"Yan","year":"2022","journal-title":"Ann. Transl. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1002\/cpt.2646","article-title":"Recommendations for the Management of Drug-Drug Interactions Between the COVID-19 Antiviral Nirmatrelvir\/Ritonavir (Paxlovid) and Comedications","volume":"112","author":"Marzolini","year":"2022","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"258","DOI":"10.7326\/0003-4819-139-4-200308190-00008","article-title":"Short-term effects of cannabinoids in patients with HIV-1 infection: A randomized, placebo-controlled clinical trial","volume":"139","author":"Abrams","year":"2003","journal-title":"Ann. Intern. Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/clpt.2008.102","article-title":"Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: II. Ritonavir effects on CYP3A and P-glycoprotein activities","volume":"84","author":"Kharasch","year":"2008","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1021\/tx300418w","article-title":"Bioactivation of the cannabinoid receptor antagonist rimonabant to a cytotoxic iminium ion metabolite","volume":"26","author":"Foster","year":"2013","journal-title":"Chem. Res. Toxicol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.bcp.2015.03.007","article-title":"Influence of HIV antiretrovirals on methadone N-demethylation and transport","volume":"95","author":"Campbell","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1111\/pan.14529","article-title":"Interactions of the protease inhibitor, ritonavir, with common anesthesia drugs","volume":"32","author":"Svedmyr","year":"2022","journal-title":"Paediatr. Anaesth."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1002\/hep.32562","article-title":"Endoplasmic reticulum stress in liver diseases","volume":"77","author":"Ajoolabady","year":"2023","journal-title":"Hepatology"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1016\/S0016-5085(03)00276-2","article-title":"Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice","volume":"124","author":"Ji","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/hep.24368","article-title":"Liver-specific loss of glucose-regulated protein 78 perturbs the unfolded protein response and exacerbates a spectrum of liver diseases in mice","volume":"54","author":"Ji","year":"2011","journal-title":"Hepatology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.3390\/biom5021099","article-title":"Advances and New Concepts in Alcohol-Induced Organelle Stress, Unfolded Protein Responses and Organ Damage","volume":"5","author":"Ji","year":"2015","journal-title":"Biomolecules"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: From stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/s41580-020-0250-z","article-title":"Mechanisms, regulation and functions of the unfolded protein response","volume":"21","author":"Hetz","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1055\/s-0033-1358522","article-title":"The unfolded protein response in fatty liver disease","volume":"33","author":"Henkel","year":"2013","journal-title":"Semin. Liver Dis."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1194\/jlr.R067595","article-title":"The role of ER stress in lipid metabolism and lipotoxicity","volume":"57","author":"Han","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2330","DOI":"10.1002\/1873-3468.13554","article-title":"Golgi stress response and organelle zones","volume":"593","author":"Sasaki","year":"2019","journal-title":"FEBS Lett."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1177\/0192623308327119","article-title":"The role of protease inhibitors in the pathogenesis of HIV-associated lipodystrophy: Cellular mechanisms and clinical implications","volume":"37","author":"Flint","year":"2009","journal-title":"Toxicol. Pathol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1002\/hep.25702","article-title":"Human immunodeficiency virus protease inhibitors modulate Ca2+ homeostasis and potentiate alcoholic stress and injury in mice and primary mouse and human hepatocytes","volume":"56","author":"Kao","year":"2012","journal-title":"Hepatology"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1002\/hep.26107","article-title":"The role of CCAAT enhancer-binding protein homologous protein in human immunodeficiency virus protease-inhibitor-induced hepatic lipotoxicity in mice","volume":"57","author":"Wang","year":"2013","journal-title":"Hepatology"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Zha, B.S., Wan, X., Zhang, X., Zha, W., Zhou, J., Wabitsch, M., Wang, G., Lyall, V., Hylemon, P.B., and Zhou, H. (2013). HIV protease inhibitors disrupt lipid metabolism by activating endoplasmic reticulum stress and inhibiting autophagy activity in adipocytes. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0059514"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.coph.2014.07.008","article-title":"HIV protease inhibitors in gut barrier dysfunction and liver injury","volume":"19","author":"Wu","year":"2014","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1002\/hep4.1030","article-title":"Disrupted ER-to-Golgi Trafficking Underlies Anti-HIV Drugs and Alcohol-Induced Cellular Stress and Hepatic Injury","volume":"1","author":"Han","year":"2017","journal-title":"Hepatol. Commun."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1111\/acer.14034","article-title":"Protective Effects of Facilitated Removal of Blood Alcohol and Acetaldehyde Against Liver Injury in Animal Models Fed Alcohol and Anti-HIV Drugs","volume":"43","author":"Han","year":"2019","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/acer.12608","article-title":"Effects of combined alcohol and anti-HIV drugs on cellular stress responses in primary hepatocytes and hepatic stellate and kupffer cells","volume":"39","author":"Hu","year":"2015","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.jhep.2013.06.005","article-title":"ER stress in human hepatic cells treated with Efavirenz: Mitochondria again","volume":"59","author":"Apostolova","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1042\/BJ20150195","article-title":"Lopimune-induced mitochondrial toxicity is attenuated by increased uncou-pling protein-2 level in treated mouse hepatocytes","volume":"468","author":"Bahr","year":"2015","journal-title":"Biochem. J."},{"key":"ref_124","first-page":"E117","article-title":"An inhibitor of HIV-1 protease modulates constitutive eIF2\u03b1 dephosphorylation to trigger a specific integrated stress response","volume":"113","author":"Bujisic","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1002\/hep4.1515","article-title":"Ritonavir and Lopinavir Suppress RCE1 and CAAX Rab Proteins Sensitizing the Liver to Organelle Stress and Injury","volume":"4","author":"Khalatbari","year":"2020","journal-title":"Hepatol. Commun."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1002\/hep4.1887","article-title":"Adverse Effects of Anti-Covid-19 Drug Candidates and Alcohol on Cellular Stress Responses of Hepatocytes","volume":"6","author":"Khalatbari","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1080\/0968768031000122548","article-title":"ER-to-Golgi transport: COP I and COP II function (Review)","volume":"20","author":"Duden","year":"2003","journal-title":"Mol. Membr. Biol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1146\/annurev.cellbio.20.010403.105307","article-title":"Bi-directional protein transport between the ER and Golgi","volume":"20","author":"Lee","year":"2004","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1111\/tra.12654","article-title":"COPII-mediated trafficking at the ER\/ERGIC interface","volume":"20","author":"Peotter","year":"2019","journal-title":"Traffic"},{"key":"ref_130","first-page":"14","article-title":"Dissecting the Role of Disturbed ER-Golgi Trafficking in Antivirals and Alcohol Abuse-Induced Pathogenesis of Liver Disorders","volume":"3","author":"Ji","year":"2017","journal-title":"J. Drug Abus."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.ceb.2018.10.002","article-title":"Lipid exchange and signaling at ER-Golgi contact sites","volume":"57","author":"Mesmin","year":"2019","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1097\/00002030-200311210-00005","article-title":"Some HIV protease inhibitors alter lamin A\/C maturation and stability, SREBP-1 nuclear localization and adipocyte differentiation","volume":"17","author":"Caron","year":"2003","journal-title":"Aids"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"11041","DOI":"10.1073\/pnas.96.20.11041","article-title":"A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood","volume":"96","author":"Brown","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"13432","DOI":"10.1073\/pnas.0704212104","article-title":"HIV protease inhibitors block the zinc metalloproteinase ZMPSTE24 and lead to an accumulation of prelamin A in cells","volume":"104","author":"Coffinier","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1002\/pro.3074","article-title":"Human CaaX protease ZMPSTE24 expressed in yeast: Structure and inhibition by HIV protease inhibitors","volume":"26","author":"Clark","year":"2017","journal-title":"Protein Sci."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"9797","DOI":"10.1074\/jbc.M709629200","article-title":"A potent HIV protease inhibitor, darunavir, does not inhibit ZMPSTE24 or lead to an accumulation of farnesyl-prelamin A in cells","volume":"283","author":"Coffinier","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"19814","DOI":"10.1074\/jbc.RA119.010295","article-title":"Endoplasmic reticulum stress differentially inhibits endoplasmic reticulum and inner nuclear membrane protein quality control degradation pathways","volume":"294","author":"Buchanan","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"16113","DOI":"10.1074\/jbc.AC120.016191","article-title":"Overlapping function of Hrd1 and Ste24 in translocon quality control provides robust channel surveillance","volume":"295","author":"Runnebohm","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1515\/BC.2009.080","article-title":"ZMPSTE24, an integral membrane zinc metalloprotease with a connection to progeroid disorders","volume":"390","author":"Barrowman","year":"2009","journal-title":"Biol. Chem."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.atherosclerosis.2015.12.012","article-title":"LMNA mutations resulting in lipodystrophy and HIV protease inhibitors trigger vascular smooth muscle cell senescence and calcification: Role of ZMPSTE24 downregulation","volume":"245","author":"Afonso","year":"2016","journal-title":"Atherosclerosis"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1080\/10409238.2018.1431606","article-title":"Rce1: Mechanism and inhibition","volume":"53","author":"Hampton","year":"2018","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1152\/physrev.00059.2009","article-title":"Role of Rab GTPases in membrane traffic and cell physiology","volume":"91","author":"Hutagalung","year":"2011","journal-title":"Physiol. Rev."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/nrm2728","article-title":"Rab GTPases as coordinators of vesicle traffic","volume":"10","author":"Stenmark","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1080\/21541248.2017.1384087","article-title":"Rab proteins as major determinants of the Golgi complex structure","volume":"9","author":"Goud","year":"2018","journal-title":"Small GTPases"},{"key":"ref_145","doi-asserted-by":"crossref","unstructured":"Pulido, M.R., Diaz-Ruiz, A., Jim\u00e9nez-G\u00f3mez, Y., Garcia-Navarro, S., Gracia-Navarro, F., Tinahones, F., L\u00f3pez-Miranda, J., Fr\u00fchbeck, G., V\u00e1zquez-Mart\u00ednez, R., and Malag\u00f3n, M.M. (2011). Rab18 dynamics in adipocytes in relation to lipogenesis, lipolysis and obesity. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022931"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1111\/acer.12271","article-title":"Rab GTPases associate with isolated lipid droplets (LDs) and show altered content after ethanol administration: Potential role in alcohol-impaired LD metabolism","volume":"38","author":"Rasineni","year":"2014","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1002\/cbin.10650","article-title":"Rab proteins as regulators of lipid droplet formation and lipolysis","volume":"40","author":"Li","year":"2016","journal-title":"Cell Biol. Int."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1139\/Y09-014","article-title":"Therapeutic effects of Nigella sativa on chronic HAART-induced hyperinsulinemia in rats","volume":"87","author":"Chandra","year":"2009","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1080\/13880209.2021.1931353","article-title":"Possible therapeutic effects of Nigella sativa and its thymoquinone on COVID-19","volume":"59","author":"Khazdair","year":"2021","journal-title":"Pharm. Biol."},{"key":"ref_150","first-page":"1014","article-title":"Thymoquinone against infectious diseases: Perspectives in recent pandemics and future therapeutics","volume":"24","author":"Tania","year":"2021","journal-title":"Iran J. Basic Med. Sci."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.2147\/DDDT.S308863","article-title":"Thymoquinone: A Promising Natural Compound with Potential Benefits for COVID-19 Prevention and Cure","volume":"15","author":"Badary","year":"2021","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_152","doi-asserted-by":"crossref","unstructured":"Nzuza, S., Zondi, S., and Owira, P.M.O. (2017). Naringin prevents HIV-1 protease inhibitors-induced metabolic complications in vivo. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183355"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"307","DOI":"10.2133\/dmpk.25.307","article-title":"The influence of aged garlic extract on the uptake of saquinavir and darunavir into HepG2 cells and rat liver slices","volume":"25","author":"Berginc","year":"2010","journal-title":"Drug Metab. Pharmacokinet."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"506","DOI":"10.2174\/1570162X14666160520114639","article-title":"Naringin Ameliorates HIV-1 Nucleoside Reverse Transcriptase Inhibitors-Induced Mitochondrial Toxicity","volume":"14","author":"Oluwafeyisetan","year":"2016","journal-title":"Curr. HIV Res."},{"key":"ref_155","first-page":"195","article-title":"Alcoholic Extract of Lotus Leaves Improves Lipid Profile in Rats with HIV Protease Inhibitor-induced Dyslipidaemia","volume":"64","author":"Su","year":"2015","journal-title":"West Indian Med. J."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"6481192","DOI":"10.1155\/2022\/6481192","article-title":"Formononetin Inhibits Hepatic I\/R-Induced Injury through Regulating PHB2\/PINK1\/Parkin Pathway","volume":"2022","author":"Ma","year":"2022","journal-title":"Oxid Med. Cell Longev."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"109213","DOI":"10.1016\/j.cbi.2020.109213","article-title":"Molecular mechanisms of protective roles of isoflavones against chemicals-induced liver injuries","volume":"329","author":"Alipour","year":"2020","journal-title":"Chem. Biol. Interact."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s43094-021-00309-0","article-title":"Flavonoid compounds of buah merah (Pandanus conoideus Lamk) as a potent SARS-CoV-2 main protease inhibitor: In silico approach","volume":"7","author":"Umar","year":"2021","journal-title":"Future J. Pharm. Sci."},{"key":"ref_159","doi-asserted-by":"crossref","unstructured":"Hu, T., Wang, J., Li, W., Liu, M., Han, N., Yuan, M., Du, L., and Tang, H. (2022). Endoplasmic Reticulum Stress in Hepatitis B Virus and Hepatitis C Virus Infection. Viruses, 14.","DOI":"10.3390\/v14122630"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.3389\/fphar.2020.01095","article-title":"Pathological Aspects of COVID-19 as a Conformational Disease and the Use of Pharmacological Chaperones as a Potential Therapeutic Strategy","volume":"11","author":"Aoe","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1038\/s41467-020-15067-5","article-title":"Pharmacological induction of selective endoplasmic reticulum retention as a strategy for cancer therapy","volume":"11","author":"Mahameed","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1126\/science.1128294","article-title":"Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes","volume":"313","author":"Ozcan","year":"2006","journal-title":"Science"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1194\/jlr.M077537","article-title":"Chemical chaperone 4-phenyl butyric acid (4-PBA) reduces hepatocellular lipid accumulation and lipotoxicity through induction of autophagy","volume":"58","author":"Nissar","year":"2017","journal-title":"J. Lipid Res."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.2337\/db10-0308","article-title":"Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women","volume":"59","author":"Kars","year":"2010","journal-title":"Diabetes"},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Kusaczuk, M. (2019). Tauroursodeoxycholate-Bile Acid with Chaperoning Activity: Molecular and Cellular Effects and Therapeutic Perspectives. Cells, 8.","DOI":"10.3390\/cells8121471"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"16275","DOI":"10.3390\/ijms160716275","article-title":"Experimental Evidence Shows Salubrinal, an eIF2\u03b1 Dephosphorylation Inhibitor, Reduces Xenotoxicant-Induced Cellular Damage","volume":"16","author":"Matsuoka","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.2174\/1381612033454441","article-title":"Prodrugs of HIV protease inhibitors","volume":"9","author":"Vierling","year":"2003","journal-title":"Curr. Pharm. Des."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ijpharm.2008.03.031","article-title":"Peptide prodrugs: Improved oral absorption of lopinavir, a HIV protease inhibitor","volume":"359","author":"Agarwal","year":"2008","journal-title":"Int. J. Pharm."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"3553","DOI":"10.1021\/acs.jmedchem.9b00002","article-title":"Design, Synthesis, and Pharmacokinetic Evaluation of Phosphate and Amino Acid Ester Prodrugs for Improving the Oral Bioavailability of the HIV-1 Protease Inhibitor Atazanavir","volume":"62","author":"Subbaiah","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"112749","DOI":"10.1016\/j.ejmech.2020.112749","article-title":"(Carbonyl)oxyalkyl linker-based amino acid prodrugs of the HIV-1 protease inhibitor atazanavir that enhance oral bioavailability and plasma trough concentration","volume":"207","author":"Subbaiah","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.2217\/nnm.12.181","article-title":"Surface-stabilized lopinavir nanoparticles enhance oral bioavailability without coadministration of ritonavir","volume":"8","author":"Jain","year":"2013","journal-title":"Nanomedicine"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.jconrel.2016.02.001","article-title":"Development and in vivo evaluation of child-friendly lopinavir\/ritonavir pediatric granules utilizing novel in situ self-assembly nanoparticles","volume":"226","author":"Pham","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.addr.2009.11.020","article-title":"Nanotechnology applications for improved delivery of antiretroviral drugs to the brain","volume":"62","author":"Wong","year":"2010","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"396","DOI":"10.2174\/157016210791330356","article-title":"Enhancing the delivery of anti retroviral drug \u201cSaquinavir\u201d across the blood brain barrier using nanoparticles","volume":"8","author":"Mahajan","year":"2010","journal-title":"Curr. HIV Res."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.1182\/blood-2006-03-012534","article-title":"Development of a macrophage-based nanoparticle platform for antiretroviral drug delivery","volume":"108","author":"Dou","year":"2006","journal-title":"Blood"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1007\/s11481-010-9198-7","article-title":"Nanoformulated antiretroviral drug combinations extend drug release and antiretroviral responses in HIV-1-infected macrophages: Implications for neuroAIDS therapeutics","volume":"5","author":"Nowacek","year":"2010","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"2520","DOI":"10.1002\/jps.24046","article-title":"Evaluation of atazanavir and darunavir interactions with lipids for developing pH-responsive anti-HIV drug combination nanoparticles","volume":"103","author":"Duan","year":"2014","journal-title":"J. Pharm. Sci."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1080\/21691401.2019.1616553","article-title":"Oral delivery of indinavir using mPEG-PCL nanoparticles: Preparation, optimization, cellular uptake, transport and pharmacokinetic evaluation","volume":"47","author":"Kurd","year":"2019","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"532","DOI":"10.3109\/10717544.2014.930760","article-title":"Atazanavir-loaded Eudragit RL 100 nanoparticles to improve oral bioavailability: Optimization and in vitro\/in vivo appraisal","volume":"23","author":"Singh","year":"2016","journal-title":"Drug Deliv."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.actbio.2018.04.045","article-title":"Nanoparticle-in-microparticle oral drug delivery system of a clinically relevant darunavir\/ritonavir antiretroviral combination","volume":"74","author":"Augustine","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"11175","DOI":"10.1073\/pnas.95.19.11175","article-title":"Endoplasmic reticulum membrane localization of Rce1p and Ste24p, yeast proteases involved in carboxyl-terminal CAAX protein processing and amino-terminal a-factor cleavage","volume":"95","author":"Schmidt","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1126\/science.1232048","article-title":"Structure of the integral membrane protein CAAX protease Ste24p","volume":"339","author":"Pryor","year":"2013","journal-title":"Science"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1038\/nchem.2591","article-title":"Mass spectrometry captures off-target drug binding and provides mechanistic insights into the human metalloprotease ZMPSTE24","volume":"8","author":"Mehmood","year":"2016","journal-title":"Nat. Chem."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"5079","DOI":"10.1016\/j.jmb.2020.03.016","article-title":"Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology","volume":"432","author":"Goblirsch","year":"2020","journal-title":"J. Mol. Biol."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1021\/ar7001232","article-title":"Design of HIV protease inhibitors targeting protein backbone: An effective strategy for combating drug resistance","volume":"41","author":"Ghosh","year":"2008","journal-title":"Acc. Chem. Res"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"11762","DOI":"10.1039\/D2CC04541A","article-title":"Beyond darunavir: Recent development of next generation HIV-1 protease inhibitors to combat drug resistance","volume":"58","author":"Ghosh","year":"2022","journal-title":"Chem. Commun."},{"key":"ref_187","doi-asserted-by":"crossref","unstructured":"La Monica, G., Lauria, A., Bono, A., and Martorana, A. (2021). Off-Target-Based Design of Selective HIV-1 PROTEASE Inhibitors. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22116070"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"105523","DOI":"10.1016\/j.compbiomed.2022.105523","article-title":"In silico evaluation of atazanavir as a potential HIV main protease inhibitor and its comparison with new designed analogs","volume":"145","author":"Yoosefian","year":"2022","journal-title":"Comput. Biol. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/7938\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:24:29Z","timestamp":1760124269000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/7938"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,27]]},"references-count":188,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24097938"],"URL":"https:\/\/doi.org\/10.3390\/ijms24097938","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,27]]}}}