{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:05:25Z","timestamp":1785420325889,"version":"3.56.0"},"reference-count":106,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"European Union (EU) within the Italian Ministry of Health","doi-asserted-by":"publisher","award":["PNRR-MCNT1-2023-12378252"],"award-info":[{"award-number":["PNRR-MCNT1-2023-12378252"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana Ricerca sul Cancro","doi-asserted-by":"crossref","award":["#19548"],"award-info":[{"award-number":["#19548"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004710","name":"Fondazione Umberto Veronesi","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004710","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/041g7jm83","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>The liver ranks among the peripheral organs exhibiting the most robust circadian rhythmicity, with glucose homeostasis, lipid metabolism, and bile acid turnover governed by tightly phased diurnal oscillations. Mitochondria execute these programs, their output coordinated with the hepatocyte circadian state. The mitochondrial network undergoes dynamic remodeling across the 24 h cycle, encompassing oscillatory changes in bioenergetics, fusion\u2013fission balance, and quality control. This interplay is bidirectional: core clock components drive rhythmic remodeling via cyclin-dependent kinase 1\/mitogen-activated protein kinase (CDK1\/MAPK)-dependent phosphorylation of dynamin-related protein 1 (DRP1) and the NAD+\u2013SIRT1\/SIRT3 axis, while retrograde signals modulate clock amplitude and entrainment. Circadian disruption is associated with mitochondrial dysfunction implicated in MASLD onset and progression to MASH and HCC, though this evidence remains largely correlative and derives predominantly from rodent models. This review integrates clock\u2013mitochondria coupling with metabolic liver disease. Restoring this coupling has been proposed as a candidate chronotherapeutic strategy, supported by preliminary rhythmicity data in primary human hepatocytes and a hepatocellular carcinoma cell line, though causal validation in healthy human liver is lacking. Time-restricted feeding, NAD+ precursors, PPAR agonists, and ACC inhibitors converge on clock-regulated pathways and may benefit from circadian-informed timing, though this remains unverified.<\/jats:p>","DOI":"10.3390\/biology15141197","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T07:54:13Z","timestamp":1784534053000},"page":"1197","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Biological Clock\u2013Mitochondria Axis in the Liver: From Molecular Mechanisms to Metabolic Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6038-0493","authenticated-orcid":false,"given":"Virginia","family":"Manuti","sequence":"first","affiliation":[{"name":"Cancer Cell Signaling Unit, Fondazione IRCCS \u201cCasa Sollievo della Sofferenza\u201d, Viale Padre Pio 7, 71013 San Giovanni Rotondo, Italy"},{"name":"Center for Research and Innovation in Medicine (C.R.E.A.T.E.), Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3295-5624","authenticated-orcid":false,"given":"Emanuele","family":"Murgo","sequence":"additional","affiliation":[{"name":"Center for Research and Innovation in Medicine (C.R.E.A.T.E.), Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy"},{"name":"Chronobiology Laboratory, Fondazione IRCCS \u201cCasa Sollievo della Sofferenza\u201d, Viale Padre Pio 7, 71013 San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2361-7045","authenticated-orcid":false,"given":"Anna Alessia","family":"Saponaro","sequence":"additional","affiliation":[{"name":"Cancer Cell Signaling Unit, Fondazione IRCCS \u201cCasa Sollievo della Sofferenza\u201d, Viale Padre Pio 7, 71013 San Giovanni Rotondo, Italy"},{"name":"Center for Research and Innovation in Medicine (C.R.E.A.T.E.), Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6485-3533","authenticated-orcid":false,"given":"Umberto","family":"Sfregola","sequence":"additional","affiliation":[{"name":"Center for Research and Innovation in Medicine (C.R.E.A.T.E.), Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0936-8843","authenticated-orcid":false,"given":"Moris","family":"Sangineto","sequence":"additional","affiliation":[{"name":"Center for Research and Innovation in Medicine (C.R.E.A.T.E.), Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy"},{"name":"C.U.R.E. (University Center for Liver Disease Research and Treatment), Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9875-019X","authenticated-orcid":false,"given":"Rosanna","family":"Villani","sequence":"additional","affiliation":[{"name":"Center for Research and Innovation in Medicine (C.R.E.A.T.E.), Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy"},{"name":"C.U.R.E. (University Center for Liver Disease Research and Treatment), Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6424-7841","authenticated-orcid":false,"given":"Gaetano","family":"Serviddio","sequence":"additional","affiliation":[{"name":"Center for Research and Innovation in Medicine (C.R.E.A.T.E.), Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy"},{"name":"C.U.R.E. (University Center for Liver Disease Research and Treatment), Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3535-7635","authenticated-orcid":false,"given":"Gianluigi","family":"Mazzoccoli","sequence":"additional","affiliation":[{"name":"Chronobiology Laboratory, Fondazione IRCCS \u201cCasa Sollievo della Sofferenza\u201d, Viale Padre Pio 7, 71013 San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6927-403X","authenticated-orcid":false,"given":"Tommaso","family":"Colangelo","sequence":"additional","affiliation":[{"name":"Cancer Cell Signaling Unit, Fondazione IRCCS \u201cCasa Sollievo della Sofferenza\u201d, Viale Padre Pio 7, 71013 San Giovanni Rotondo, Italy"},{"name":"Center for Research and Innovation in Medicine (C.R.E.A.T.E.), Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/nature00965","article-title":"Coordination of Circadian Timing in Mammals","volume":"418","author":"Reppert","year":"2002","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/s41580-019-0179-2","article-title":"Molecular Mechanisms and Physiological Importance of Circadian Rhythms","volume":"21","author":"Patke","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/s42255-021-00395-7","article-title":"The Liver-Clock Coordinates Rhythmicity of Peripheral Tissues in Response to Feeding","volume":"3","author":"Manella","year":"2021","journal-title":"Nat. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"21453","DOI":"10.1073\/pnas.0909591106","article-title":"Time of Feeding and the Intrinsic Circadian Clock Drive Rhythms in Hepatic Gene Expression","volume":"106","author":"Vollmers","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/s41580-018-0096-9","article-title":"Crosstalk between Metabolism and Circadian Clocks","volume":"20","author":"Reinke","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.cmet.2018.01.011","article-title":"Circadian Control of DRP1 Activity Regulates Mitochondrial Dynamics and Bioenergetics","volume":"27","author":"Schmitt","year":"2018","journal-title":"Cell Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.cmet.2015.08.006","article-title":"Hepatic Bmal1 Regulates Rhythmic Mitochondrial Dynamics and Promotes Metabolic Fitness","volume":"22","author":"Jacobi","year":"2015","journal-title":"Cell Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"110635","DOI":"10.1016\/j.celrep.2022.110635","article-title":"CLOCK Regulates Drp1 mRNA Stability and Mitochondrial Homeostasis by Interacting with PUF60","volume":"39","author":"Xu","year":"2022","journal-title":"Cell Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1002\/jnr.22609","article-title":"Circadian Rhythm of Metabolic Oscillation in Suprachiasmatic Nucleus Depends on the Mitochondrial Oxidation State, Reflected by Cytochrome C Oxidase and Lactate Dehydrogenase","volume":"89","author":"Isobe","year":"2011","journal-title":"J. Neurosci. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1016\/j.jhep.2023.06.003","article-title":"A Multisociety Delphi Consensus Statement on New Fatty Liver Disease Nomenclature","volume":"79","author":"Rinella","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1097\/HEP.0000000000000004","article-title":"The Global Epidemiology of Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH): A Systematic Review","volume":"77","author":"Younossi","year":"2023","journal-title":"Hepatology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/j.jhep.2023.04.036","article-title":"Changing Epidemiology, Global Trends and Implications for Outcomes of NAFLD","volume":"79","author":"Wong","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1053\/j.gastro.2018.06.083","article-title":"Mitochondrial Dysfunction and Signaling in Chronic Liver Diseases","volume":"155","author":"Mansouri","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1002\/hep.26226","article-title":"Mitochondrial Adaptations and Dysfunctions in Nonalcoholic Fatty Liver Disease","volume":"58","author":"Begriche","year":"2013","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.jhep.2019.03.020","article-title":"The Circadian Clock and Liver Function in Health and Disease","volume":"71","author":"Mukherji","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s00125-008-1194-6","article-title":"Clock Gene Expression in Peripheral Leucocytes of Patients with Type 2 Diabetes","volume":"52","author":"Ando","year":"2009","journal-title":"Diabetologia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s10238-013-0235-8","article-title":"A Ticking Clock Links Metabolic Pathways and Organ Systems Function in Health and Disease","volume":"14","author":"Vinciguerra","year":"2014","journal-title":"Clin. Exp. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.cmet.2015.05.023","article-title":"NAD(+) Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus","volume":"22","author":"Menzies","year":"2015","journal-title":"Cell Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.cmet.2017.11.002","article-title":"NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR","volume":"27","author":"Yoshino","year":"2018","journal-title":"Cell Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1007\/s40265-016-0646-4","article-title":"Chronotherapy: Intuitive, Sound, Founded\u2026But Not Broadly Applied","volume":"76","author":"Selfridge","year":"2016","journal-title":"Drugs"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/j.jhep.2021.12.039","article-title":"Is It Time for Chronopharmacology in NASH?","volume":"76","author":"Marjot","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_23","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_24","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1016\/j.cell.2019.04.025","article-title":"Defining the Independence of the Liver Circadian Clock","volume":"177","author":"Koronowski","year":"2019","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5541","DOI":"10.1073\/pnas.1118726109","article-title":"Coordination of the Transcriptome and Metabolome by the Circadian Clock","volume":"109","author":"Patel","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1073\/pnas.1114410109","article-title":"The Human Circadian Metabolome","volume":"109","author":"Dallmann","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.cell.2008.07.002","article-title":"The NAD+-Dependent Deacetylase SIRT1 Modulates CLOCK-Mediated Chromatin Remodeling and Circadian Control","volume":"134","author":"Nakahata","year":"2008","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1126\/science.1172156","article-title":"AMPK Regulates the Circadian Clock by Cryptochrome Phosphorylation and Degradation","volume":"326","author":"Lamia","year":"2009","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nature05767","article-title":"Transcriptional Coactivator PGC-1alpha Integrates the Mammalian Clock and Energy Metabolism","volume":"447","author":"Liu","year":"2007","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15172","DOI":"10.1073\/pnas.0806717105","article-title":"Physiological Significance of a Peripheral Tissue Circadian Clock","volume":"105","author":"Lamia","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5537","DOI":"10.1038\/s41467-024-49852-3","article-title":"Environmental Circadian Disruption Re-Writes Liver Circadian Proteomes","volume":"15","author":"Duong","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1016\/S2468-1253(21)00169-2","article-title":"Sleep and Liver Disease: A Bidirectional Relationship","volume":"6","author":"Marjot","year":"2021","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.tem.2015.12.001","article-title":"Mitochondrial Dynamics and Metabolic Regulation","volume":"27","author":"Wai","year":"2016","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1038\/nrm3013","article-title":"Mitochondrial Fusion and Fission in Cell Life and Death","volume":"11","author":"Westermann","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"101566","DOI":"10.1016\/j.molmet.2022.101566","article-title":"The Mitochondrial Fission Protein Drp1 in Liver Is Required to Mitigate NASH and Prevents the Activation of the Mitochondrial ISR","volume":"64","author":"Steffen","year":"2022","journal-title":"Mol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1080\/19768354.2024.2347503","article-title":"Circadian Coordination: Understanding Interplay between Circadian Clock and Mitochondria","volume":"28","author":"Kim","year":"2024","journal-title":"Anim. Cells Syst."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"C1158","DOI":"10.1152\/ajpcell.00551.2022","article-title":"Circadian Regulation of Liver Metabolism: Experimental Approaches in Human, Rodent, and Cellular Models","volume":"325","author":"Daniels","year":"2023","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"21583","DOI":"10.1074\/jbc.C700083200","article-title":"Cyclic AMP-Dependent Protein Kinase Phosphorylation of Drp1 Regulates Its GTPase Activity and Mitochondrial Morphology","volume":"282","author":"Chang","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/sj.embor.7401062","article-title":"Reversible Phosphorylation of Drp1 by Cyclic AMP-Dependent Protein Kinase and Calcineurin Regulates Mitochondrial Fission and Cell Death","volume":"8","author":"Cribbs","year":"2007","journal-title":"EMBO Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1002\/jcb.23419","article-title":"Calcineurin Serves in the Circadian Output Pathway to Regulate the Daily Rhythm of L-Type Voltage-Gated Calcium Channels in the Retina","volume":"113","author":"Huang","year":"2012","journal-title":"J. Cell. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"15803","DOI":"10.1073\/pnas.0808249105","article-title":"Dephosphorylation by Calcineurin Regulates Translocation of Drp1 to Mitochondria","volume":"105","author":"Cereghetti","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s44323-025-00068-8","article-title":"Glucocorticoid-Dependence and Independence of the Circadian Liver Transcriptome","volume":"3","author":"Maidstone","year":"2026","journal-title":"npj Biol. Timing Sleep"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"bqad128","DOI":"10.1210\/endocr\/bqad128","article-title":"Acute Deletion of the Glucocorticoid Receptor in Hepatocytes Disrupts Postprandial Lipid Metabolism in Male Mice","volume":"164","author":"Correia","year":"2023","journal-title":"Endocrinology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4454","DOI":"10.1172\/JCI96138","article-title":"REVERBa Couples the Circadian Clock to Hepatic Glucocorticoid Action","volume":"128","author":"Caratti","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Lambertucci, F., Castinetti, F., Martins, I., L\u00f3pez-Ot\u00edn, C., and Kroemer, G. (Cell Metab., 2026). Pro-Aging Effects of Chronic Glucocorticoid Signaling, Cell Metab., in press.","DOI":"10.1016\/j.cmet.2026.05.002"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/jpi.12162","article-title":"Melatonin: A Well-Documented Antioxidant with Conditional pro-Oxidant Actions","volume":"57","author":"Zhang","year":"2014","journal-title":"J. Pineal Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e2508809122","DOI":"10.1073\/pnas.2508809122","article-title":"STAR\/STARD1: A Mitochondrial Intermembrane Space Cholesterol Shuttle Degraded through Mitophagy","volume":"122","author":"Koganti","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4264","DOI":"10.1038\/s41467-021-24543-5","article-title":"Single-Nucleus RNA-Seq2 Reveals Functional Crosstalk between Liver Zonation and Ploidy","volume":"12","author":"Richter","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1002\/hep4.1854","article-title":"Single-Cell, Single-Nucleus, and Spatial RNA Sequencing of the Human Liver Identifies Cholangiocyte and Mesenchymal Heterogeneity","volume":"6","author":"Andrews","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e13915","DOI":"10.1111\/apha.13915","article-title":"The Role of the Circadian Clock in the Development, Progression, and Treatment of Non-Alcoholic Fatty Liver Disease","volume":"237","author":"Demir","year":"2023","journal-title":"Acta Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"154337","DOI":"10.1016\/j.metabol.2020.154337","article-title":"Perturbation of the Circadian Clock and Pathogenesis of NAFLD","volume":"111S","author":"Mukherji","year":"2020","journal-title":"Metabolism"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1126\/science.1108750","article-title":"Obesity and Metabolic Syndrome in Circadian Clock Mutant Mice","volume":"308","author":"Turek","year":"2005","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1016\/j.ccell.2016.10.007","article-title":"Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis","volume":"30","author":"Kettner","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Gu, W., Li, T., Huang, Y., Wang, R., Zhang, L., Chen, R., Li, R., and Liu, C. (2024). Metabolic Profile and Lipid Metabolism Phenotype in Mice with Conditional Deletion of Hepatic BMAL1. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25116070"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4242","DOI":"10.3748\/wjg.v13.i31.4242","article-title":"Common Genetic Variations in CLOCK Transcription Factor Are Associated with Nonalcoholic Fatty Liver Disease","volume":"13","author":"Sookoian","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/sj.ijo.0803778","article-title":"Association between Polymorphisms in the Clock Gene, Obesity and the Metabolic Syndrome in Man","volume":"32","author":"Scott","year":"2008","journal-title":"Int. J. Obes."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"660","DOI":"10.3109\/07420528.2014.886587","article-title":"CRY1 Circadian Gene Variant Interacts with Carbohydrate Intake for Insulin Resistance in Two Independent Populations: Mediterranean and North American","volume":"31","author":"Dashti","year":"2014","journal-title":"Chronobiol. Int."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1136\/oemed-2019-106220","article-title":"Rotating Night Shift Work and Non-Alcoholic Fatty Liver Disease among Steelworkers in China: A Cross-Sectional Survey","volume":"77","author":"Zhang","year":"2020","journal-title":"Occup. Environ. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.1038\/emboj.2011.322","article-title":"Temporal Orchestration of Circadian Autophagy Rhythm by C\/EBP\u03b2","volume":"30","author":"Ma","year":"2011","journal-title":"EMBO J."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1101\/gad.237081.113","article-title":"The Circadian Clock Regulates Rhythmic Activation of the NRF2\/Glutathione-Mediated Antioxidant Defense Pathway to Modulate Pulmonary Fibrosis","volume":"28","author":"Gibbs","year":"2014","journal-title":"Genes Dev."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Chen, J., Jian, L., Guo, Y., Tang, C., Huang, Z., and Gao, J. (2024). Liver Cell Mitophagy in Metabolic Dysfunction-Associated Steatotic Liver Disease and Liver Fibrosis. Antioxidants, 13.","DOI":"10.3390\/antiox13060729"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Liu, S., Wang, L., Zhu, L., Zhao, T., Han, P., Yan, F., Wang, X., Li, C., Wang, Z., and Yang, B.-F. (2025). Mechanism and Regulation of Mitophagy in Liver Diseases: A Review. Front. Cell Dev. Biol., 13.","DOI":"10.3389\/fcell.2025.1614940"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1172\/JCI83885","article-title":"Hepatocyte Mitochondrial DNA Drives Nonalcoholic Steatohepatitis by Activation of TLR9","volume":"126","author":"Santoro","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1038\/s41467-020-16092-0","article-title":"Hepatocyte Mitochondria-Derived Danger Signals Directly Activate Hepatic Stellate Cells and Drive Progression of Liver Fibrosis","volume":"11","author":"An","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1136\/gutjnl-2012-302962","article-title":"Epigenetic Modification of Liver Mitochondrial DNA Is Associated with Histological Severity of Nonalcoholic Fatty Liver Disease","volume":"62","author":"Pirola","year":"2013","journal-title":"Gut"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1243417","DOI":"10.1126\/science.1243417","article-title":"Circadian Clock NAD+ Cycle Drives Mitochondrial Oxidative Metabolism in Mice","volume":"342","author":"Peek","year":"2013","journal-title":"Science"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1073\/pnas.1217632110","article-title":"Circadian Acetylome Reveals Regulation of Mitochondrial Metabolic Pathways","volume":"110","author":"Masri","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.cell.2008.06.050","article-title":"SIRT1 Regulates Circadian Clock Gene Expression through PER2 Deacetylation","volume":"134","author":"Asher","year":"2008","journal-title":"Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.cmet.2014.11.001","article-title":"Time-Restricted Feeding Is a Preventative and Therapeutic Intervention against Diverse Nutritional Challenges","volume":"20","author":"Chaix","year":"2014","journal-title":"Cell Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1016\/j.cmet.2012.04.019","article-title":"Time-Restricted Feeding without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed a High-Fat Diet","volume":"15","author":"Hatori","year":"2012","journal-title":"Cell Metab."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e233513","DOI":"10.1001\/jamanetworkopen.2023.3513","article-title":"Effects of Time-Restricted Eating on Nonalcoholic Fatty Liver Disease: The TREATY-FLD Randomized Clinical Trial","volume":"6","author":"Wei","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1016\/j.jhep.2025.06.005","article-title":"Efficacy and Safety of Time-Restricted Eating in Metabolic Dysfunction-Associated Steatotic Liver Disease","volume":"83","author":"Oh","year":"2025","journal-title":"J. Hepatol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1016\/j.cmet.2018.04.010","article-title":"Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes","volume":"27","author":"Sutton","year":"2018","journal-title":"Cell Metab."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1111\/apt.70044","article-title":"Effects of a 12-Week Mediterranean-Type Time-Restricted Feeding Protocol in Patients With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Randomised Controlled Trial-The \u201cCHRONO-NAFLD Project.\u201d","volume":"61","author":"Tsitsou","year":"2025","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1093\/ajcn\/nqy132","article-title":"A Randomized Placebo-Controlled Clinical Trial of Nicotinamide Riboside in Obese Men: Safety, Insulin-Sensitivity, and Lipid-Mobilizing Effects","volume":"108","author":"Dollerup","year":"2018","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1002\/hep.32778","article-title":"Nicotinamide Riboside and Pterostilbene Reduces Markers of Hepatic Inflammation in NAFLD: A Double-Blind, Placebo-Controlled Clinical Trial","volume":"78","author":"Dellinger","year":"2023","journal-title":"Hepatology"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Yang, H., Mayneris-Perxachs, J., Boqu\u00e9, N., Del Bas, J.M., Arola, L., Yuan, M., T\u00fcrkez, H., Uhl\u00e9n, M., Bor\u00e9n, J., and Zhang, C. (2021). Combined Metabolic Activators Decrease Liver Steatosis by Activating Mitochondrial Metabolism in Hamsters Fed with a High-Fat Diet. Biomedicines, 9.","DOI":"10.1101\/2021.02.19.431968"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1507\/endocrj.EJ19-0313","article-title":"Effect of Oral Administration of Nicotinamide Mononucleotide on Clinical Parameters and Nicotinamide Metabolite Levels in Healthy Japanese Men","volume":"67","author":"Irie","year":"2020","journal-title":"Endocr. J."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.cell.2006.06.050","article-title":"Nuclear Receptor Expression Links the Circadian Clock to Metabolism","volume":"126","author":"Yang","year":"2006","journal-title":"Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1074\/jbc.271.3.1764","article-title":"Expression of the Peroxisome Proliferator-Activated Receptor Alpha Gene Is Stimulated by Stress and Follows a Diurnal Rhythm","volume":"271","author":"Lemberger","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1210\/me.2006-0052","article-title":"Reciprocal Regulation of Brain and Muscle Arnt-like Protein 1 and Peroxisome Proliferator-Activated Receptor Alpha Defines a Novel Positive Feedback Loop in the Rodent Liver Circadian Clock","volume":"20","author":"Canaple","year":"2006","journal-title":"Mol. Endocrinol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3639","DOI":"10.1016\/j.febslet.2008.09.046","article-title":"Circadian Expression of FGF21 Is Induced by PPARalpha Activation in the Mouse Liver","volume":"582","author":"Oishi","year":"2008","journal-title":"FEBS Lett."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1056\/NEJMoa2036205","article-title":"A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH","volume":"385","author":"Francque","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1053\/j.gastro.2018.07.027","article-title":"GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients With Nonalcoholic Fatty Liver Disease","volume":"155","author":"Loomba","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1126\/science.1198125","article-title":"A Circadian Rhythm Orchestrated by Histone Deacetylase 3 Controls Hepatic Lipid Metabolism","volume":"331","author":"Feng","year":"2011","journal-title":"Science"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"14468","DOI":"10.1073\/pnas.1222647110","article-title":"Extensive Diversity in Circadian Regulation of Plasma Lipids and Evidence for Different Circadian Metabolic Phenotypes in Humans","volume":"110","author":"Chua","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.cmet.2017.08.011","article-title":"Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation","volume":"26","author":"Kim","year":"2017","journal-title":"Cell Metab."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.jhep.2019.10.023","article-title":"Insulin Sensitizer MSDC-0602K in Non-Alcoholic Steatohepatitis: A Randomized, Double-Blind, Placebo-Controlled Phase IIb Study","volume":"72","author":"Harrison","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_89","first-page":"E1673","article-title":"Circadian Control of Oscillations in Mitochondrial Rate-Limiting Enzymes and Nutrient Utilization by PERIOD Proteins","volume":"113","author":"Robles","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1056\/NEJMoa2309000","article-title":"A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis","volume":"390","author":"Harrison","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1007\/s40265-024-02045-0","article-title":"Resmetirom: First Approval","volume":"84","author":"Keam","year":"2024","journal-title":"Drugs"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1146\/annurev-physiol-021115-105339","article-title":"Understanding the Physiology of FGF21","volume":"78","author":"Fisher","year":"2016","journal-title":"Annu. Rev. Physiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1373\/clinchem.2010.155184","article-title":"Circadian Rhythm of Circulating Fibroblast Growth Factor 21 Is Related to Diurnal Changes in Fatty Acids in Humans","volume":"57","author":"Yu","year":"2011","journal-title":"Clin. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1038\/nm.3249","article-title":"FGF21 Regulates Metabolism and Circadian Behavior by Acting on the Nervous System","volume":"19","author":"Bookout","year":"2013","journal-title":"Nat. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1016\/S0140-6736(18)31785-9","article-title":"Pegbelfermin (BMS-986036), a PEGylated Fibroblast Growth Factor 21 Analogue, in Patients with Non-Alcoholic Steatohepatitis: A Randomised, Double-Blind, Placebo-Controlled, Phase 2a Trial","volume":"392","author":"Sanyal","year":"2019","journal-title":"Lancet"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1111\/j.1749-6632.1991.tb27245.x","article-title":"Chronopharmacokinetics and Chronopharmacodynamics of Cardiovascular Active Drugs. Propranolol, Organic Nitrates, Nifedipine","volume":"618","author":"Lemmer","year":"1991","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1016\/S0140-6736(85)91551-X","article-title":"Maintenance Chemotherapy for Childhood Acute Lymphoblastic Leukaemia: Better in the Evening","volume":"2","author":"Rivard","year":"1985","journal-title":"Lancet"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1097\/00043426-199703000-00002","article-title":"Impact of Morning versus Evening Schedule for Oral Methotrexate and 6-Mercaptopurine on Relapse Risk for Children with Acute Lymphoblastic Leukemia","volume":"19","author":"Schmiegelow","year":"1997","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/07420528.2020.1850468","article-title":"Guidelines for the Design and Conduct of Human Clinical Trials on Ingestion-Time Differences\u2014Chronopharmacology and Chronotherapy\u2014Of Hypertension Medications","volume":"38","author":"Hermida","year":"2021","journal-title":"Chronobiol. Int."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1056\/NEJMoa2413258","article-title":"Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis","volume":"392","author":"Sanyal","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"eadm9281","DOI":"10.1126\/sciadv.adm9281","article-title":"Autonomous Circadian Rhythms in the Human Hepatocyte Regulate Hepatic Drug Metabolism and Inflammatory Responses","volume":"10","author":"March","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"149542","DOI":"10.1016\/j.bbabio.2025.149542","article-title":"Circadian Clockwork Controls the Balance between Mitochondrial Turnover and Dynamics: What Is Life \u2026 without Time Marking?","volume":"1866","author":"Cela","year":"2025","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1126\/science.1223710","article-title":"Identification of Small Molecule Activators of Cryptochrome","volume":"337","author":"Hirota","year":"2012","journal-title":"Science"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/s41467-024-55325-4","article-title":"Spatial Transcriptomics of Healthy and Fibrotic Human Liver at Single-Cell Resolution","volume":"16","author":"Watson","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1083\/jcb.201603039","article-title":"Mito-QC Illuminates Mitophagy and Mitochondrial Architecture in Vivo","volume":"214","author":"McWilliams","year":"2016","journal-title":"J. Cell Biol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"3753","DOI":"10.1080\/15548627.2021.1896924","article-title":"Mt-Keima Detects PINK1-PRKN Mitophagy in Vivo with Greater Sensitivity than Mito-QC","volume":"17","author":"Liu","year":"2021","journal-title":"Autophagy"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/14\/1197\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T04:19:45Z","timestamp":1784693985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/15\/14\/1197"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,20]]},"references-count":106,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["biology15141197"],"URL":"https:\/\/doi.org\/10.3390\/biology15141197","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,20]]}}}