{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:22:45Z","timestamp":1792804965158,"version":"4.5.0"},"reference-count":109,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T00:00:00Z","timestamp":1771718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hennings Cancer gift from the Elson S. Floyd College of Medicine","award":["GF003245"],"award-info":[{"award-number":["GF003245"]}],"id":[{"id":"https:\/\/ror.org\/04d8byx33","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Intramural Research Fund","award":["ZIA AA000036"],"award-info":[{"award-number":["ZIA AA000036"]}]},{"name":"National Institute on Alcohol Abuse and Alcoholism at the National Institutes of Health","award":["R24 AA026801"],"award-info":[{"award-number":["R24 AA026801"]}],"id":[{"id":"https:\/\/ror.org\/02jzrsm59","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute on Alcohol Abuse and Alcoholism at the National Institutes of Health","award":["R01 AA029859"],"award-info":[{"award-number":["R01 AA029859"]}],"id":[{"id":"https:\/\/ror.org\/02jzrsm59","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institute on Alcohol Abuse and Alcoholism at the National Institutes of Health","award":["R01 AA031197"],"award-info":[{"award-number":["R01 AA031197"]}],"id":[{"id":"https:\/\/ror.org\/02jzrsm59","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Oxidative alcohol metabolism in the liver relies on sequential enzymatic reactions involving alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and aldehyde dehydrogenase (ALDH) isozymes. However, the circadian regulation of these enzymes, their susceptibility to genetic, environmental, and metabolic disruption, and their functional implications toward alcohol-mediated tissue injury remain incompletely defined. To address this gap, we performed a comprehensive integrative analysis of the publicly available circadian transcriptome datasets spanning genetic clock disruption, acute sleep deprivation, chronic high-fat diet feeding, and occupational shift work to systematically characterize the temporal regulation and disruption vulnerability of the major alcohol-metabolizing enzymes. Mouse tissue-cycling analyses revealed pronounced gene- and tissue-specific diurnal regulation, with Adh1 oscillating primarily in adipose tissues; Cyp2e1 and mitochondrial Aldh2 cycling broadly across kidney, aorta, lung, adrenal gland, and liver; and cytosolic Aldh1b1 being uniformly arrhythmic. In the liver, Cyp2e1 and Aldh2 exhibited robust ~24 h oscillations that peaked during the light\/resting phase, while Adh1 showed inconsistent rhythmicity and Aldh1b1 remained arrhythmic. Notably, Cyp2e1 and Aldh2 rhythms persisted in Bmal1 knockout and Clock mutant livers under light\u2013dark conditions, despite complete loss of core clock gene oscillations, yet were abolished in constant darkness, revealing that systemic zeitgeber cues can mask the loss of intrinsic clock function to maintain apparent rhythmicity in these metabolic genes. Systematic cross-paradigm comparison established a novel gene-specific vulnerability hierarchy. Aldh2 was found to be most disrupted by environmental and metabolic perturbations, with acute sleep deprivation eliminating its rhythmicity and temporal expression pattern and a Western-style high-fat diet inducing pronounced phase delays and rhythm loss relative to low-fat diet controls. Both disruptions paralleled alterations in hepatocyte nuclear factor 4\u03b1 (Hnf4a), newly implicating HNF4\u03b1 as a potential mediator of ALDH2 circadian instability. In humans, ALDH2 and CYP2E1 exhibited conserved but phase-inverted circadian rhythms across multiple tissues relative to mice, and, importantly, night-shift workers showed markedly dampened and phase-shifted ALDH2 rhythms in peripheral blood mononuclear cells, providing the molecular link between occupational circadian misalignment and impaired acetaldehyde detoxification. Collectively, our detailed and innovative analytical approach reveals gene- and tissue-specific circadian regulation of alcohol-metabolizing enzymes, identifies ALDH2 as uniquely vulnerable to circadian misalignment, underscores the importance of circadian timing for optimal hepatic detoxification and resistance to tissue injury, and suggests that monitoring circadian rhythms could help tailor individualized advice on alcohol consumption for shift workers and populations with irregular sleep schedules, informing precision medicine approaches for alcohol-related disorders.<\/jats:p>","DOI":"10.3390\/ijms27042041","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T08:58:21Z","timestamp":1771837101000},"page":"2041","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Diurnal Regulation and Gene-Specific Vulnerability of Oxidative Alcohol-Metabolizing Enzymes to Circadian Disruption"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0498-3342","authenticated-orcid":false,"given":"Yool","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA"},{"name":"Department of Integrative Physiology and Neuroscience, College of Veterinary Medicine, Washington State University, Pullman, WA 99164, USA"},{"name":"Sleep and Performance Research Center, Washington State University, Spokane, WA 99202, USA"},{"name":"Steve Gleason Institute for Neuroscience, Washington State University, Spokane, WA 99202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7969-3369","authenticated-orcid":false,"given":"Ali","family":"Keshavarzian","sequence":"additional","affiliation":[{"name":"Rush Center for Integrated Microbiome and Chronobiology Research, Rush University Medical Center, Chicago, IL 60612, USA"},{"name":"Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL 60612, USA"},{"name":"Departments of Physiology, Rush University Medical Center, Chicago, IL 60612, USA"},{"name":"Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3954-3497","authenticated-orcid":false,"given":"Byoung-Joon","family":"Song","sequence":"additional","affiliation":[{"name":"Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/nrendo.2014.78","article-title":"Circadian clock control of endocrine factors","volume":"10","author":"Gamble","year":"2014","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1038\/s41575-023-00792-1","article-title":"Circadian regulation of liver function: From molecular mechanisms to disease pathophysiology","volume":"20","author":"Bolshette","year":"2023","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/s41583-018-0026-z","article-title":"Generation of circadian rhythms in the suprachiasmatic nucleus","volume":"19","author":"Hastings","year":"2018","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/nrg.2016.150","article-title":"Transcriptional architecture of the mammalian circadian clock","volume":"18","author":"Takahashi","year":"2017","journal-title":"Nat. Rev. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Lee, Y., and Wisor, J.P. (2021). Multi-Modal Regulation of Circadian Physiology by Interactive Features of Biological Clocks. Biology, 11.","DOI":"10.3390\/biology11010021"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7487304211044301","DOI":"10.1177\/07487304211044301","article-title":"Circadian Rhythms, Disease and Chronotherapy","volume":"36","author":"Lee","year":"2021","journal-title":"J. Biol. Rhythm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"16219","DOI":"10.1073\/pnas.1408886111","article-title":"A circadian gene expression atlas in mammals: Implications for biology and medicine","volume":"111","author":"Zhang","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"eaao0318","DOI":"10.1126\/science.aao0318","article-title":"Diurnal transcriptome atlas of a primate across major neural and peripheral tissues","volume":"359","author":"Mure","year":"2018","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"eaat8806","DOI":"10.1126\/scitranslmed.aat8806","article-title":"A database of tissue-specific rhythmically expressed human genes has potential applications in circadian medicine","volume":"10","author":"Ruben","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0092-8674(02)00722-5","article-title":"Coordinated transcription of key pathways in the mouse by the circadian clock","volume":"109","author":"Panda","year":"2002","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Hunter, A.L., and Ray, D.W. (2019). Circadian Clock Regulation of Hepatic Energy Metabolism Regulatory Circuits. Biology, 8.","DOI":"10.3390\/biology8040079"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"eaav2642","DOI":"10.1126\/science.aav2642","article-title":"The forebrain synaptic transcriptome is organized by clocks but its proteome is driven by sleep","volume":"366","author":"Noya","year":"2019","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.cels.2024.06.005","article-title":"Model integration of circadian- and sleep-wake-driven contributions to rhythmic gene expression reveals distinct regulatory principles","volume":"15","author":"Jan","year":"2024","journal-title":"Cell Syst."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1016\/j.cell.2013.11.034","article-title":"Reprogramming of the circadian clock by nutritional challenge","volume":"155","author":"Patel","year":"2013","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1016\/j.cell.2018.08.042","article-title":"Atlas of Circadian Metabolism Reveals System-wide Coordination and Communication between Clocks","volume":"174","author":"Dyar","year":"2018","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Yan, L., Sundaram, S., Rust, B.M., Palmer, D.G., Johnson, L.K., and Zeng, H. (2022). Consumption of a high-fat diet alters transcriptional rhythmicity in liver from pubertal mice. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.1068350"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5540","DOI":"10.1073\/pnas.1720719115","article-title":"Simulated night shift work induces circadian misalignment of the human peripheral blood mononuclear cell transcriptome","volume":"115","author":"Kervezee","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1177\/0748730419826694","article-title":"Shift Work Disrupts Circadian Regulation of the Transcriptome in Hospital Nurses","volume":"34","author":"Resuehr","year":"2019","journal-title":"J. Biol. Rhythm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e12726","DOI":"10.1111\/jpi.12726","article-title":"Night shift schedule causes circadian dysregulation of DNA repair genes and elevated DNA damage in humans","volume":"70","author":"Koritala","year":"2021","journal-title":"J. Pineal Res."},{"key":"ref_20","first-page":"476","article-title":"THE IMPACT OF SHIFT WORK ON THE METABOLISM AND CIRCADIAN RHYTHM IN NURSES AND MEDICAL TECHNICIANS","volume":"60","author":"Ljevak","year":"2022","journal-title":"Acta Clin. Croat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"25250","DOI":"10.1073\/pnas.1911189116","article-title":"Distinct metabolic adaptation of liver circadian pathways to acute and chronic patterns of alcohol intake","volume":"116","author":"Gaucher","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","unstructured":"Willis, C.R.G., Ganjayi, M.S., Brown, A.M., Moser, S.E., Szewczyk, N.J., Clark, B.C., and Baumann, C.W. (2025). Chronic alcohol intake elicits distinct multi-omic profiles in the liver. bioRxiv."},{"key":"ref_23","first-page":"245","article-title":"Overview: How is alcohol metabolized by the body?","volume":"29","author":"Zakhari","year":"2006","journal-title":"Alcohol Res. Health"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1055\/a-2551-3320","article-title":"Alcohol-Metabolizing Enzymes, Liver Diseases and Cancer","volume":"45","author":"Liu","year":"2025","journal-title":"Semin. Liver Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.omtm.2019.08.004","article-title":"Gene Therapy Correction of Aldehyde Dehydrogenase 2 Deficiency","volume":"15","author":"Matsumura","year":"2019","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"102753","DOI":"10.1016\/j.ebiom.2020.102753","article-title":"Novel and prevalent non-East Asian ALDH2 variants; Implications for global susceptibility to aldehydes\u2019 toxicity","volume":"55","author":"Chen","year":"2020","journal-title":"EBioMedicine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5971","DOI":"10.1038\/s41467-023-41570-6","article-title":"A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators","volume":"14","author":"Chang","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Seike, T., Chen, C.H., and Mochly-Rosen, D. (2023). Impact of common ALDH2 inactivating mutation and alcohol consumption on Alzheimer\u2019s disease. Front. Aging Neurosci., 15.","DOI":"10.3389\/fnagi.2023.1223977"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"102577","DOI":"10.1016\/j.redox.2022.102577","article-title":"ALDH2 deficiency increases susceptibility to binge alcohol-induced gut leakiness, endotoxemia, and acute liver injury in mice through the gut-liver axis","volume":"59","author":"Rungratanawanich","year":"2023","journal-title":"Redox Biol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ray, B., Rungratanawanich, W., LeFort, K.R., Chidambaram, S.B., and Song, B.J. (2024). Mitochondrial Aldehyde Dehydrogenase 2 (ALDH2) Protects against Binge Alcohol-Mediated Gut and Brain Injury. Cells, 13.","DOI":"10.3390\/cells13110927"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"G185","DOI":"10.1152\/ajpgi.00354.2012","article-title":"Role for intestinal CYP2E1 in alcohol-induced circadian gene-mediated intestinal hyperpermeability","volume":"305","author":"Forsyth","year":"2013","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1016\/j.freeradbiomed.2013.09.009","article-title":"CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis","volume":"65","author":"Abdelmegeed","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.freeradbiomed.2014.08.030","article-title":"Binge alcohol promotes hypoxic liver injury through a CYP2E1-HIF-1\u03b1-dependent apoptosis pathway in mice and humans","volume":"77","author":"Yun","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.redox.2014.10.002","article-title":"Intestinal CYP2E1: A mediator of alcohol-induced gut leakiness","volume":"3","author":"Forsyth","year":"2014","journal-title":"Redox Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.alcohol.2014.07.021","article-title":"Circadian rhythms, alcohol and gut interactions","volume":"49","author":"Forsyth","year":"2015","journal-title":"Alcohol"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2504","DOI":"10.3390\/biom5042504","article-title":"The Molecular Circadian Clock and Alcohol-Induced Liver Injury","volume":"5","author":"Udoh","year":"2015","journal-title":"Biomolecules"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"G364","DOI":"10.1152\/ajpgi.00010.2018","article-title":"Emerging role of circadian clock disruption in alcohol-induced liver disease","volume":"315","author":"Bailey","year":"2018","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1111\/acer.13612","article-title":"Circadian Mechanisms in Alcohol Use Disorder and Tissue Injury","volume":"42","author":"Davis","year":"2018","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0022-3565(25)32009-4","article-title":"Circadian rhythms in the biological response and disposition of ethanol in the mouse","volume":"213","author":"Deimling","year":"1980","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1111\/acer.13513","article-title":"CREB Protein Mediates Alcohol-Induced Circadian Disruption and Intestinal Permeability","volume":"41","author":"Davis","year":"2017","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Filiano, A.N., Millender-Swain, T., Johnson, R., Young, M.E., Gamble, K.L., and Bailey, S.M. (2013). Chronic ethanol consumption disrupts the core molecular clock and diurnal rhythms of metabolic genes in the liver without affecting the suprachiasmatic nucleus. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0071684"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Summa, K.C., Voigt, R.M., Forsyth, C.B., Shaikh, M., Cavanaugh, K., Tang, Y., Vitaterna, M.H., Song, S., Turek, F.W., and Keshavarzian, A. (2013). Disruption of the Circadian Clock in Mice Increases Intestinal Permeability and Promotes Alcohol-Induced Hepatic Pathology and Inflammation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0067102"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1111\/acer.12834","article-title":"Chronic Alcohol Exposure and the Circadian Clock Mutation Exert Tissue-Specific Effects on Gene Expression in Mouse Hippocampus, Liver, and Proximal Colon","volume":"39","author":"Summa","year":"2015","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Rizk, A.A., Jenkins, B.W., Al-Sabagh, Y., Hamidullah, S., Reitz, C.J., Rasouli, M., Martino, T.A., and Khokhar, J.Y. (2022). The Impact of Sex, Circadian Disruption, and the Clock. Genes, 13.","DOI":"10.3390\/genes13040701"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"109132","DOI":"10.1016\/j.cbi.2020.109132","article-title":"Interaction of alcohol with time of eating on markers of circadian dyssynchrony and colon tissue injury","volume":"325","author":"Bishehsari","year":"2020","journal-title":"Chem. Biol. Interact."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e2400234","DOI":"10.1002\/mnfr.202400234","article-title":"Effect of Alcohol on Clock Synchrony and Tissue Circadian Homeostasis in Mice","volume":"68","author":"Santovito","year":"2024","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2509281","DOI":"10.1080\/19490976.2025.2509281","article-title":"Impact of peripheral circadian misalignment and alcohol on the resiliency of intestinal barrier and microbiota","volume":"17","author":"Tran","year":"2025","journal-title":"Gut Microbes"},{"key":"ref_48","first-page":"E1916","article-title":"Circadian clock-dependent and -independent posttranscriptional regulation underlies temporal mRNA accumulation in mouse liver","volume":"115","author":"Wang","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"D1009","DOI":"10.1093\/nar\/gks1161","article-title":"CircaDB: A database of mammalian circadian gene expression profiles","volume":"41","author":"Pizarro","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"324ra316","DOI":"10.1126\/scitranslmed.aad3305","article-title":"Timing of expression of the core clock gene Bmal1 influences its effects on aging and survival","volume":"8","author":"Yang","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1006\/abbi.2001.2713","article-title":"Transcriptional control of the human aldehyde dehydrogenase 2 promoter by hepatocyte nuclear factor 4: Inhibition by cyclic AMP and COUP transcription factors","volume":"398","author":"You","year":"2002","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Papatheodorou, I., Galatou, E., Panagiotidis, G.D., Ravingerov\u00e1, T., and Lazou, A. (2021). Cardioprotective Effects of PPAR\u03b2\/\u03b4 Activation against Ischemia\/Reperfusion Injury in Rat Heart Are Associated with ALDH2 Upregulation, Amelioration of Oxidative Stress and Preservation of Mitochondrial Energy Production. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126399"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/s12943-022-01579-9","article-title":"An EHMT2\/NFYA-ALDH2 signaling axis modulates the RAF pathway to regulate paclitaxel resistance in lung cancer","volume":"21","author":"Wang","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"112625","DOI":"10.1016\/j.physbeh.2019.112625","article-title":"Physiological, behavioral and environmental factors influence bifurcated circadian entrainment in mice","volume":"210","author":"Walbeek","year":"2019","journal-title":"Physiol. Behav."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/0024-3205(86)90030-5","article-title":"Circadian rhythms in the activities of brain and liver aldehyde dehydrogenase isozymes in mice","volume":"38","author":"Yamazaki","year":"1986","journal-title":"Life Sci."},{"key":"ref_56","first-page":"369","article-title":"[Diurnal differences in alcohol absorption]","volume":"26","author":"Husslein","year":"1989","journal-title":"Blutalkohol"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"zsad250","DOI":"10.1093\/sleep\/zsad250","article-title":"Sleep and circadian influences on blood alcohol concentration","volume":"46","author":"Miller","year":"2023","journal-title":"Sleep"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Vera, L.M., Bello, C., Paredes, J.F., Carmona-Anto\u00f1anzas, G., and S\u00e1nchez-V\u00e1zquez, F.J. (2018). Ethanol toxicity differs depending on the time of day. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0190406"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1002\/hep.22304","article-title":"The molecular mechanism regulating 24-hour rhythm of CYP2E1 expression in the mouse liver","volume":"48","author":"Matsunaga","year":"2008","journal-title":"Hepatology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5389","DOI":"10.1172\/JCI70317","article-title":"Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration","volume":"123","author":"Musiek","year":"2013","journal-title":"J. Clin. Invest."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Kornmann, B., Schaad, O., Bujard, H., Takahashi, J.S., and Schibler, U. (2007). System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biol., 5.","DOI":"10.1371\/journal.pbio.0050034"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.bbi.2009.06.001","article-title":"Sleep loss activates cellular markers of inflammation: Sex differences","volume":"24","author":"Irwin","year":"2010","journal-title":"Brain Behav. Immun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.beem.2010.08.014","article-title":"Sleep loss and inflammation","volume":"24","author":"Mullington","year":"2010","journal-title":"Best. Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1177\/09727531241275347","article-title":"Sleep and Immune System Crosstalk: Implications for Inflammatory Homeostasis and Disease Pathogenesis","volume":"32","author":"Singh","year":"2025","journal-title":"Ann. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.bbi.2024.09.029","article-title":"Sleep loss-induced oncogenic pathways are mediated via the neuron-specific interleukin-1 receptor accessory protein (AcPb)","volume":"123","author":"Lee","year":"2025","journal-title":"Brain Behav. Immun."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Kalyan, M., Tousif, A.H., Sonali, S., Vichitra, C., Sunanda, T., Praveenraj, S.S., Ray, B., Gorantla, V.R., Rungratanawanich, W., and Mahalakshmi, A.M. (2022). Role of Endogenous Lipopolysaccharides in Neurological Disorders. Cells, 11.","DOI":"10.3390\/cells11244038"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"G1004","DOI":"10.1152\/ajpgi.00002.2015","article-title":"Decreased melatonin secretion is associated with increased intestinal permeability and marker of endotoxemia in alcoholics","volume":"308","author":"Swanson","year":"2015","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"G192","DOI":"10.1152\/ajpgi.00087.2016","article-title":"Night workers with circadian misalignment are susceptible to alcohol-induced intestinal hyperpermeability with social drinking","volume":"311","author":"Swanson","year":"2016","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/s42003-024-06288-1","article-title":"Downregulation of HNF4A enables transcriptomic reprogramming during the hepatic acute-phase response","volume":"7","author":"Ehle","year":"2024","journal-title":"Commun. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"E12305","DOI":"10.1073\/pnas.1816411115","article-title":"Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks","volume":"115","author":"Qu","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"6350","DOI":"10.1038\/s41467-021-26567-3","article-title":"HNF4A defines tissue-specific circadian rhythms by beaconing BMAL1::CLOCK chromatin binding and shaping the rhythmic chromatin landscape","volume":"12","author":"Qu","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"4349","DOI":"10.1038\/s41467-018-06648-6","article-title":"Incompatibility of the circadian protein BMAL1 and HNF4\u03b1 in hepatocellular carcinoma","volume":"9","author":"Fekry","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1002\/hep.1840140509","article-title":"Investigation of the role of polymorphisms at the alcohol and aldehyde dehydrogenase loci in genetic predisposition to alcohol-related end-organ damage","volume":"14","author":"Day","year":"1991","journal-title":"Hepatology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1136\/gut.47.2.256","article-title":"Association of aldehyde dehydrogenase 2 gene polymorphism with multiple oesophageal dysplasia in head and neck cancer patients","volume":"47","author":"Muto","year":"2000","journal-title":"Gut"},{"key":"ref_75","first-page":"111","article-title":"The Role of Mitochondrial Aldehyde Dehydrogenase 2 (ALDH2) in Neuropathology and Neurodegeneration","volume":"25","author":"Chen","year":"2016","journal-title":"Acta Neurol. Taiwan."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1146\/annurev.pharmtox.44.101802.121704","article-title":"Oxidative stress, toxicology, and pharmacology of CYP2E1","volume":"44","author":"Caro","year":"2004","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.freeradbiomed.2007.11.004","article-title":"CYP2E1 and oxidative liver injury by alcohol","volume":"44","author":"Lu","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.jhep.2012.08.018","article-title":"CYP2E1 and oxidant stress in alcoholic and non-alcoholic fatty liver disease","volume":"58","author":"Leung","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Harjum\u00e4ki, R., Pridgeon, C.S., and Ingelman-Sundberg, M. (2021). CYP2E1 in Alcoholic and Non-Alcoholic Liver Injury. Roles of ROS, Reactive Intermediates and Lipid Overload. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22158221"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1016\/j.jprot.2011.05.013","article-title":"Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications","volume":"74","author":"Song","year":"2011","journal-title":"J. Proteom."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1056\/NEJM198408233110815","article-title":"Ethanol and arterial disease","volume":"311","author":"Mikhailidis","year":"1984","journal-title":"N. Engl. J. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"G521","DOI":"10.1152\/ajpgi.00399.2003","article-title":"Oxidative modification of hepatic mitochondria protein thiols: Effect of chronic alcohol consumption","volume":"286","author":"Venkatraman","year":"2004","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1002\/hep.21372","article-title":"Inactivation of oxidized and S-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats","volume":"44","author":"Moon","year":"2006","journal-title":"Hepatology"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1177\/1535370213520109","article-title":"Impairment of aldehyde dehydrogenase-2 by 4-hydroxy-2-nonenal adduct formation and cardiomyocyte hypertrophy in mice fed a high-fat diet and injected with low-dose streptozotocin","volume":"239","author":"Mali","year":"2014","journal-title":"Exp. Biol. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.redox.2015.09.040","article-title":"Critical role of c-jun N-terminal protein kinase in promoting mitochondrial dysfunction and acute liver injury","volume":"6","author":"Jang","year":"2015","journal-title":"Redox Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.redox.2014.10.004","article-title":"Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications","volume":"3","author":"Song","year":"2014","journal-title":"Redox Biol."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Ballway, J.W., and Song, B.J. (2021). Translational Approaches with Antioxidant Phytochemicals against Alcohol-Mediated Oxidative Stress, Gut Dysbiosis, Intestinal Barrier Dysfunction, and Fatty Liver Disease. Antioxidants, 10.","DOI":"10.3390\/antiox10030384"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Ruiter-Lopez, L., Khan, M.A.S., Wang, X., and Song, B.J. (2025). Roles of Oxidative Stress and Autophagy in Alcohol-Mediated Brain Damage. Antioxidants, 14.","DOI":"10.3390\/antiox14030302"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"4455","DOI":"10.1038\/s41598-019-40989-6","article-title":"Night workers have lower levels of antioxidant defenses and higher levels of oxidative stress damage when compared to day workers","volume":"9","author":"Teixeira","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1080\/07420528.2021.1989446","article-title":"A systematic review of the relationship between night shift work and oxidative stress","volume":"39","author":"Gibson","year":"2022","journal-title":"Chronobiol. Int."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"108048","DOI":"10.1016\/j.envint.2023.108048","article-title":"Chrono-modulated effects of external stressors on oxidative stress and damage in humans: A scoping review on night shift work","volume":"178","author":"Makris","year":"2023","journal-title":"Environ. Int."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1136\/oemed-2024-109824","article-title":"Melatonin supplementation and oxidative DNA damage repair capacity among night shift workers: A randomised placebo-controlled trial","volume":"82","author":"Zanif","year":"2025","journal-title":"Occup. Environ. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.alcohol.2013.09.001","article-title":"Inhibition of human alcohol and aldehyde dehydrogenases by acetaminophen: Assessment of the effects on first-pass metabolism of ethanol","volume":"47","author":"Lee","year":"2013","journal-title":"Alcohol"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"114982","DOI":"10.1016\/j.taap.2020.114982","article-title":"Aldehyde dehydrogenase-2 activation decreases acetaminophen hepatotoxicity by prevention of mitochondrial depolarization","volume":"396","author":"Wimborne","year":"2020","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.trsl.2020.04.004","article-title":"Disrupted diurnal oscillation of gut-derived Short chain fatty acids in shift workers drinking alcohol: Possible mechanism for loss of resiliency of intestinal barrier in disrupted circadian host","volume":"221","author":"Swanson","year":"2020","journal-title":"Transl. Res."},{"key":"ref_96","first-page":"E1132","article-title":"Effects of insufficient sleep on circadian rhythmicity and expression amplitude of the human blood transcriptome","volume":"110","author":"Archer","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e15","DOI":"10.35371\/aoem.2019.31.e15","article-title":"Relationship between shift work and liver enzymes: A cross-sectional study based on the Korea National Health and Examination Survey (2007\u20132015)","volume":"31","author":"Choi","year":"2019","journal-title":"Ann. Occup. Environ. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"610","DOI":"10.3109\/07420528.2012.675848","article-title":"Alcohol consumption patterns of shiftworkers compared with dayworkers","volume":"29","author":"Dorrian","year":"2012","journal-title":"Chronobiol. Int."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1159\/000507573","article-title":"Shiftwork and Alcohol Consumption: A Systematic Review of the Literature","volume":"27","author":"Richter","year":"2021","journal-title":"Eur. Addict. Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/s41386-019-0446-0","article-title":"Alcohol use disorder and sleep disturbances: A feed-forward allostatic framework","volume":"45","author":"Koob","year":"2020","journal-title":"Neuropsychopharmacology"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1177\/07487304231179600","article-title":"Meta-analysis of Diurnal Transcriptomics in Mouse Liver Reveals Low Repeatability of Rhythm Analyses","volume":"38","author":"Brooks","year":"2023","journal-title":"J. Biol. Rhythm."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1053\/j.gastro.2016.07.036","article-title":"Circadian Rhythms in Gastrointestinal Health and Diseases","volume":"151","author":"Bishehsari","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Radi, S.H., Vemuri, K., Martinez-Lomeli, J., and Sladek, F.M. (2023). HNF4\u03b1 isoforms: The fraternal twin master regulators of liver function. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1226173"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Alam, M.F., Laskar, A.A., Maryam, L., and Younus, H. (2016). Activation of Human Salivary Aldehyde Dehydrogenase by Sulforaphane: Mechanism and Significance. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168463"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1016\/j.jhep.2014.12.022","article-title":"Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice","volume":"62","author":"Zhong","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/ng.2653","article-title":"The Genotype-Tissue Expression (GTEx) project","volume":"45","author":"Consortium","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"5312","DOI":"10.1073\/pnas.1619320114","article-title":"CYCLOPS reveals human transcriptional rhythms in health and disease","volume":"114","author":"Anafi","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3351","DOI":"10.1093\/bioinformatics\/btw405","article-title":"MetaCycle: An integrated R package to evaluate periodicity in large scale data","volume":"32","author":"Wu","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"104121","DOI":"10.1016\/j.ebiom.2022.104121","article-title":"Digital circadian and sleep health in individual hospital shift workers: A cross sectional telemonitoring study","volume":"81","author":"Zhang","year":"2022","journal-title":"EBioMedicine"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/2041\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T08:59:40Z","timestamp":1771837180000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/2041"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,22]]},"references-count":109,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27042041"],"URL":"https:\/\/doi.org\/10.3390\/ijms27042041","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,22]]}}}