{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:55:31Z","timestamp":1792176931077,"version":"4.4.0"},"reference-count":108,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is now recognized as the leading cause of chronic liver disease worldwide. MASLD spans a spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and is linked to progressive fibrosis and ultimately hepatocellular carcinoma (HCC). Growing evidence implicates cellular senescence (CS) and lipid droplets (LDs) as key drivers of disease progression, although their interaction remains poorly characterized. This review provides an integrative and stage-dependent synthesis of current mechanistic insights into how bidirectional crosstalk between CS and LD regulation shapes the transition from steatosis to MASH. Senescent hepatocytes display altered lipid metabolism, including upregulation of receptors such as cluster of differentiation (CD) 36, enhancing lipid uptake to meet increased energy demands. Initially, elevated free fatty acid influx can activate peroxisome-proliferator-activated receptor alpha (PPAR\u03b1), promoting fatty acid oxidation (FAO) as a compensatory response. Over time, persistent CS under steatotic conditions leads to mitochondrial dysfunction and suppression of fatty acid oxidation (FAO), while the senescence-associated secretory phenotype (SASP), largely driven by nuclear factor\u2014kappa B (NF-\u03baB) signaling, promotes chronic hepatic inflammation. By framing LDs as active modulators of senescence-associated signaling rather than passive lipid stores, this review highlights how disruption of senescence\u2013lipid feedback loops may represent a disease-modifying opportunity in MASLD progression.<\/jats:p>","DOI":"10.3390\/ijms27021066","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T13:59:54Z","timestamp":1769003994000},"page":"1066","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["The Interplay Between Cellular Senescence and Lipid Metabolism in the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3763-4064","authenticated-orcid":false,"given":"Eleftheria M.","family":"Mastoridou","sequence":"first","affiliation":[{"name":"Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4134-6177","authenticated-orcid":false,"given":"Anna C.","family":"Goussia","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8930-5383","authenticated-orcid":false,"given":"Agapi","family":"Kataki","sequence":"additional","affiliation":[{"name":"Laboratory of Surgical Research, First Department of Propaedeutic Surgery, Hippocration Hospital of Athens, Athens Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7804-1472","authenticated-orcid":false,"given":"Efthymios","family":"Koniaris","sequence":"additional","affiliation":[{"name":"Department of Pathology-Anatomy, Hippocration Hospital of Athens, Athens Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6466-5747","authenticated-orcid":false,"given":"Georgios K.","family":"Glantzounis","sequence":"additional","affiliation":[{"name":"HPB Unit, Department of Surgery, University General Hospital of Ioannina, School of Medicine, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3932-6652","authenticated-orcid":false,"given":"Alexandra","family":"Papoudou-Bai","sequence":"additional","affiliation":[{"name":"Pathology Department, German Medical Institute (GMI), Limassol 4040, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8916-3276","authenticated-orcid":false,"given":"Panagiotis","family":"Kanavaros","sequence":"additional","affiliation":[{"name":"Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7402-4919","authenticated-orcid":false,"given":"Antonia V.","family":"Charchanti","sequence":"additional","affiliation":[{"name":"Department of Anatomy-Histology-Embryology, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s12944-024-02108-x","article-title":"Updated mechanisms of MASLD pathogenesis","volume":"23","author":"Li","year":"2024","journal-title":"Lipids Health Dis."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.jhep.2016.05.030","article-title":"Senescence in chronic liver disease: Is the future in aging?","volume":"65","author":"Aravinthan","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1016\/j.biopha.2017.11.075","article-title":"Cellular senescence and liver disease: Mechanisms and therapeutic strategies","volume":"96","author":"Guo","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Aravinthan, A., Pietrosi, G., Hoare, M., Jupp, J., Marshall, A., Verrill, C., Davies, S., Bateman, A., Sheron, N., and Allison, M. (2013). Hepatocyte expression of the senescence marker p21 is linked to fibrosis and an adverse liver-related outcome in alcohol-related liver disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0072904"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.jhep.2012.10.031","article-title":"Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease","volume":"58","author":"Aravinthan","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Bonnet, L., Alexandersson, I., Baboota, R.K., Kroon, T., Oscarsson, J., Smith, U., and Boucher, J. (2022). Cellular senescence in hepatocytes contributes to metabolic disturbances in NASH. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.957616"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Rao, G., Peng, X., Li, X., An, K., He, H., Fu, X., Li, S., and An, Z. (2023). Unmasking the enigma of lipid metabolism in metabolic dysfunction-associated steatotic liver disease: From mechanism to the clinic. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1294267"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1007\/s00018-025-05848-w","article-title":"Interrogating the regulatory epigenome of cellular senescence","volume":"82","author":"Thanos","year":"2025","journal-title":"Cell Mol. Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/0014-4827(61)90192-6","article-title":"The serial cultivation of human diploid cell strains","volume":"25","author":"Hayflick","year":"1961","journal-title":"Exp. Cell Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/ncomms1473","article-title":"p53 and p16(INK4A) independent induction of senescence by chromatin-dependent alteration of S-phase progression","volume":"2","author":"Prieur","year":"2011","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Alessio, N., Aprile, D., Cappabianca, S., Peluso, G., Di Bernardo, G., and Galderisi, U. (2021). Different Stages of Quiescence, Senescence, and Cell Stress Identified by Molecular Algorithm Based on the Expression of Ki67, RPS6, and Beta-Galactosidase Activity. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063102"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"81099","DOI":"10.18632\/oncotarget.12752","article-title":"Is senescence-associated \u03b2-galactosidase a marker of neuronal senescence?","volume":"7","author":"Piechota","year":"2016","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"37","DOI":"10.18632\/aging.100527","article-title":"Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues","volume":"5","author":"Georgakopoulou","year":"2013","journal-title":"Aging"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1016\/j.biocel.2003.08.009","article-title":"Lipofuscin","volume":"36","author":"Terman","year":"2004","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.exer.2005.01.007","article-title":"RPE lipofuscin and its role in retinal pathobiology","volume":"80","author":"Sparrow","year":"2005","journal-title":"Exp. Eye Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1055\/s-0040-1722262","article-title":"Cellular Senescence in Liver Disease and Regeneration","volume":"41","author":"Gadd","year":"2021","journal-title":"Semin. Liver Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/978-1-62703-239-1_12","article-title":"Detection of senescence-associated heterochromatin foci (SAHF)","volume":"965","author":"Aird","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/nature02118","article-title":"A DNA damage checkpoint response in telomere-initiated senescence","volume":"426","author":"Reaper","year":"2003","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1038\/ncb2784","article-title":"A complex secretory program orchestrated by the inflammasome controls paracrine senescence","volume":"15","author":"Acosta","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Reid, M.V., Fredickson, G., and Mashek, D.G. (2024). Mechanisms coupling lipid droplets to MASLD pathophysiology. Hepatology, Online ahead of print.","DOI":"10.1097\/HEP.0000000000001141"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1002\/jcp.20753","article-title":"Formation of elongated giant mitochondria in DFO-induced cellular senescence: Involvement of enhanced fusion process through modulation of Fis1","volume":"209","author":"Yoon","year":"2006","journal-title":"J. Cell Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"eado5887","DOI":"10.1126\/sciadv.ado5887","article-title":"Mitochondrial fatty acid oxidation drives senescence","volume":"10","author":"Yamauchi","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.cell.2019.10.005","article-title":"Cellular Senescence: Defining a Path Forward","volume":"179","author":"Gorgoulis","year":"2019","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.exger.2016.05.010","article-title":"Keeping the senescence secretome under control: Molecular reins on the senescence-associated secretory phenotype","volume":"82","author":"Malaquin","year":"2016","journal-title":"Exp. Gerontol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1055\/a-2186-3557","article-title":"Mechanisms of Lipid Droplet Accumulation in Steatotic Liver Diseases","volume":"43","author":"Dempsey","year":"2023","journal-title":"Semin. Liver Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.18632\/aging.101452","article-title":"Small extracellular vesicles and their miRNA cargo are anti-apoptotic members of the senescence-associated secretory phenotype","volume":"10","author":"Latreille","year":"2018","journal-title":"Aging"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"109953","DOI":"10.1016\/j.abb.2024.109953","article-title":"Network of extracellular vesicles surrounding senescent cells","volume":"754","author":"Okawa","year":"2024","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1186\/s12964-023-01280-4","article-title":"Meta-analysis of senescent cell secretomes to identify common and specific features of the different senescent phenotypes: A tool for developing new senotherapeutics","volume":"21","author":"Oguma","year":"2023","journal-title":"Cell Commun. Signal"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Karras, A., Lioulios, G., Kantartzi, K., Fylaktou, A., Panagoutsos, S., and Stangou, M. (2025). Measuring the Senescence-Associated Secretory Phenotype. Biomedicines, 13.","DOI":"10.3390\/biomedicines13092062"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Liao, Z., Yeo, H.L., Wong, S.W., and Zhao, Y. (2021). Cellular Senescence: Mechanisms and Therapeutic Potential. Biomedicines, 9.","DOI":"10.3390\/biomedicines9121769"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2579","DOI":"10.1101\/gad.179515.111","article-title":"The role of nuclear lamin B1 in cell proliferation and senescence","volume":"25","author":"Shimi","year":"2011","journal-title":"Genes Dev."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Kumari, R., and Jat, P. (2021). Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.645593"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4951","DOI":"10.1111\/febs.17227","article-title":"NF\u03baB dynamics-dependent epigenetic changes modulate inflammatory gene expression and induce cellular senescence","volume":"291","author":"Tabata","year":"2024","journal-title":"FEBS J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/ncb3225","article-title":"mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype","volume":"17","author":"Herranz","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4212","DOI":"10.1093\/emboj\/cdg417","article-title":"Reversal of human cellular senescence: Roles of the p53 and p16 pathways","volume":"22","author":"Krtolica","year":"2003","journal-title":"EMBO J."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Hamsanathan, S., and Gurkar, A.U. (2022). Lipids as Regulators of Cellular Senescence. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.796850"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1101\/gad.284851.116","article-title":"A senescence secretory switch mediated by PI3K\/AKT\/mTOR activation controls chemoprotective endothelial secretory responses","volume":"30","author":"Bent","year":"2016","journal-title":"Genes Dev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.cell.2017.02.004","article-title":"mTOR Signaling in Growth, Metabolism, and Disease","volume":"168","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1111\/acel.12592","article-title":"Quantitative identification of senescent cells in aging and disease","volume":"16","author":"Biran","year":"2017","journal-title":"Aging Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/978-1-62703-239-1_8","article-title":"Colorimetric detection of senescence-associated \u03b2 galactosidase","volume":"965","author":"Itahana","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Chou, L.Y., Ho, C.T., and Hung, S.C. (2022). Paracrine Senescence of Mesenchymal Stromal Cells Involves Inflammatory Cytokines and the NF-\u03baB Pathway. Cells, 11.","DOI":"10.3390\/cells11203324"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1146\/annurev-pathol-121808-102144","article-title":"The senescence-associated secretory phenotype: The dark side of tumor suppression","volume":"5","author":"Desprez","year":"2010","journal-title":"Annu. Rev. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Millner, A., and Atilla-Gokcumen, G.E. (2020). Lipid Players of Cellular Senescence. Metabolites, 10.","DOI":"10.3390\/metabo10090339"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"17075","DOI":"10.1038\/cddiscovery.2017.75","article-title":"A signature of enhanced lipid metabolism, lipid peroxidation and aldehyde stress in therapy-induced senescence","volume":"3","author":"Flor","year":"2017","journal-title":"Cell Death Discov."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"102294","DOI":"10.1016\/j.arr.2024.102294","article-title":"Lipids and lipid metabolism in cellular senescence: Emerging targets for age-related diseases","volume":"97","author":"Zeng","year":"2024","journal-title":"Ageing Res. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"106404","DOI":"10.1016\/j.prostaglandins.2019.106404","article-title":"Cd36 gene expression in adipose and hepatic tissue mediates the lipids accumulation in liver of obese rats with sucrose-induced hepatic steatosis","volume":"147","year":"2020","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"EMBR201745274","DOI":"10.15252\/embr.201745274","article-title":"CD36 initiates the secretory phenotype during the establishment of cellular senescence","volume":"19","author":"Chong","year":"2018","journal-title":"EMBO Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/s41419-019-1550-0","article-title":"FASN activity is important for the initial stages of the induction of senescence","volume":"10","author":"Jordan","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Danielli, M., Perne, L., Jarc Jovi\u010di\u0107, E., and Petan, T. (2023). Lipid droplets and polyunsaturated fatty acid trafficking: Balancing life and death. Front. Cell Dev. Biol., 11, Erratum in Front. Cell Dev. Biol. 2023, 11, 1175493. https:\/\/doi.org\/10.3389\/fcell.2023.1175493.","DOI":"10.3389\/fcell.2023.1104725"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Fan, H., and Tan, Y. (2024). Lipid Droplet-Mitochondria Contacts in Health and Disease. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25136878"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"25152564241304196","DOI":"10.1177\/25152564241304196","article-title":"ER-LD Membrane Contact Sites: A Budding Area in the Pathogen Survival Strategy","volume":"7","author":"Angara","year":"2024","journal-title":"Contact"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1016\/j.bbadis.2017.07.019","article-title":"Lipid droplet proteins and metabolic diseases","volume":"1864","author":"Xu","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/s41514-025-00291-4","article-title":"Mitochondrial dysfunction in cellular senescence: A bridge to neurodegenerative disease","volume":"11","author":"Hruby","year":"2025","journal-title":"npj Aging"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1016\/j.celrep.2015.01.043","article-title":"Analysis of p53 transactivation domain mutants reveals Acad11 as a metabolic target important for p53 pro-survival function","volume":"10","author":"Jiang","year":"2015","journal-title":"Cell Rep."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Vasileiou, P.V.S., Evangelou, K., Vlasis, K., Fildisis, G., Panayiotidis, M.I., Chronopoulos, E., Passias, P.G., Kouloukoussa, M., Gorgoulis, V.G., and Havaki, S. (2019). Mitochondrial Homeostasis and Cellular Senescence. Cells, 8.","DOI":"10.3390\/cells8070686"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Bang, S., Choi, S.H., and Jeong, S.M. (2025). Beyond Bioenergetics: Emerging Roles of Mitochondrial Fatty Acid Oxidation in Stress Response and Aging. Cells, 14.","DOI":"10.3390\/cells14241956"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1101\/gad.331272.119","article-title":"Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence","volume":"34","author":"Vizioli","year":"2020","journal-title":"Genes Dev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"102149","DOI":"10.1016\/j.isci.2021.102149","article-title":"GSK3 inhibitor ameliorates steatosis through the modulation of mitochondrial dysfunction in hepatocytes of obese patients","volume":"24","author":"Li","year":"2021","journal-title":"iScience"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.jhep.2010.11.021","article-title":"Presence and significance of microvesicular steatosis in nonalcoholic fatty liver disease","volume":"55","author":"Tandra","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1007\/s11695-023-06467-9","article-title":"Microvesicular Steatosis in Individuals with Obesity: A Histological Marker of Non-alcoholic Fatty Liver Disease Severity","volume":"33","author":"Germano","year":"2023","journal-title":"Obes. Surg."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0168-8278(97)82328-8","article-title":"Microvesicular steatosis and steatohepatitis: Role of mitochondrial dysfunction and lipid peroxidation","volume":"26","author":"Fromenty","year":"1997","journal-title":"J. Hepatol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e30579","DOI":"10.1002\/jcb.30579","article-title":"Perilipins: A family of five fat-droplet storing proteins that play a significant role in fat homeostasis","volume":"125","author":"Chandrasekaran","year":"2024","journal-title":"J. Cell Biochem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"24231","DOI":"10.1074\/jbc.M116.759795","article-title":"Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome","volume":"291","author":"Libby","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1111\/his.12038","article-title":"Adipophilin\/perilipin-2 as a lipid droplet-specific marker for metabolically active cells and diseases associated with metabolic dysregulation","volume":"62","author":"Straub","year":"2013","journal-title":"Histopathology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1194\/jlr.M035063","article-title":"Perilipin-2-null mice are protected against diet-induced obesity, adipose inflammation, and fatty liver disease","volume":"54","author":"McManaman","year":"2013","journal-title":"J. Lipid Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.yexcr.2015.10.021","article-title":"Pathophysiology of lipid droplet proteins in liver diseases","volume":"340","author":"Carr","year":"2016","journal-title":"Exp. Cell Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e14111","DOI":"10.1111\/acel.14111","article-title":"Downregulation of PLIN2 in human dermal fibroblasts impairs mitochondrial function in an age-dependent fashion and induces cell senescence via GDF15","volume":"23","author":"Chiariello","year":"2024","journal-title":"Aging Cell"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.jhep.2013.11.007","article-title":"Perilipin discerns chronic from acute hepatocellular steatosis","volume":"60","author":"Pawella","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1111\/liv.14492","article-title":"Disruption of Plin5 degradation by CMA causes lipid homeostasis imbalance in NAFLD","volume":"40","author":"Ma","year":"2020","journal-title":"Liver Int."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1002\/hep.27409","article-title":"Perilipin 5 improves hepatic lipotoxicity by inhibiting lipolysis","volume":"61","author":"Wang","year":"2015","journal-title":"Hepatology"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Cinato, M., Andersson, L., Miljanovic, A., Laudette, M., Kunduzova, O., Bor\u00e9n, J., and Levin, M.C. (2024). Role of Perilipins in Oxidative Stress-Implications for Cardiovascular Disease. Antioxidants, 13.","DOI":"10.3390\/antiox13020209"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/j.jhep.2014.10.039","article-title":"Molecular mechanism of PPAR\u03b1 action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease","volume":"62","author":"Pawlak","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Lin, Y., Wang, Y., and Li, P.F. (2022). PPAR\u03b1: An emerging target of metabolic syndrome, neurodegenerative and cardiovascular diseases. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1074911"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"8330","DOI":"10.18632\/oncotarget.2212","article-title":"Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF-\u03baB signaling pathway","volume":"5","author":"Zhang","year":"2014","journal-title":"Oncotarget"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Todisco, S., Santarsiero, A., Convertini, P., De Stefano, G., Gilio, M., Iacobazzi, V., and Infantino, V. (2022). PPAR Alpha as a Metabolic Modulator of the Liver: Role in the Pathogenesis of Nonalcoholic Steatohepatitis (NASH). Biology, 11.","DOI":"10.3390\/biology11050792"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1042\/BCJ20210139","article-title":"Inhibitory feedback control of NF-\u03baB signalling in health and disease","volume":"478","author":"Prescott","year":"2021","journal-title":"Biochem. J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1136\/gutjnl-2023-330595","article-title":"MASLD: A systemic metabolic disorder with cardiovascular and malignant complications","volume":"73","author":"Targher","year":"2024","journal-title":"Gut"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1038\/sigtrans.2017.23","article-title":"NF-\u03baB signaling in inflammation","volume":"2","author":"Liu","year":"2017","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"286249","DOI":"10.1155\/2008\/286249","article-title":"The Role of NF-kappaB in PPARalpha-Mediated Hepatocarcinogenesis","volume":"2008","author":"Glauert","year":"2008","journal-title":"PPAR Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1074\/mcp.RA118.000961","article-title":"Hepatic Mitochondrial Defects in a Nonalcoholic Fatty Liver Disease Mouse Model Are Associated with Increased Degradation of Oxidative Phosphorylation Subunits","volume":"17","author":"Lee","year":"2018","journal-title":"Mol. Cell Proteom."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"154708","DOI":"10.1016\/j.metabol.2021.154708","article-title":"Mitochondrial dynamics and nonalcoholic fatty liver disease (NAFLD): New perspectives for a fairy-tale ending?","volume":"117","author":"Longo","year":"2021","journal-title":"Metabolism"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.jhep.2022.09.020","article-title":"Mitochondrial alterations in fatty liver diseases","volume":"78","author":"Fromenty","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"17310","DOI":"10.1074\/jbc.RA120.012543","article-title":"CDKN2A\/p16INK4a suppresses hepatic fatty acid oxidation through the AMPK\u03b12-SIRT1-PPAR\u03b1 signaling pathway","volume":"295","author":"Deleye","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Kudlova, N., De Sanctis, J.B., and Hajduch, M. (2022). Cellular Senescence: Molecular Targets, Biomarkers, and Senolytic Drugs. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23084168"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"100301","DOI":"10.1016\/j.jhepr.2021.100301","article-title":"Evaluating causality of cellular senescence in non-alcoholic fatty liver disease","volume":"3","author":"Meijnikman","year":"2021","journal-title":"JHEP Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"17851","DOI":"10.3748\/wjg.v20.i47.17851","article-title":"Senescent human hepatocytes express a unique secretory phenotype and promote macrophage migration","volume":"20","author":"Irvine","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1021\/acs.nanolett.3c03689","article-title":"Senescence of Hepatic Stellate Cells by Specific Delivery of Manganese for Limiting Liver Fibrosis","volume":"24","author":"Gu","year":"2024","journal-title":"Nano Lett."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e14502","DOI":"10.1111\/acel.14502","article-title":"Aging-Associated Liver Sinusoidal Endothelial Cells Dysfunction Aggravates the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease","volume":"24","author":"Dai","year":"2025","journal-title":"Aging Cell"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Wu, Q., Yang, Y., Lin, S., Geller, D.A., and Yan, Y. (2025). The microenvironment in the development of MASLD-MASH-HCC and associated therapeutic in MASH-HCC. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1569915"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.4161\/cc.28471","article-title":"Gene polymorphisms of cellular senescence marker p21 and disease progression in non-alcohol-related fatty liver disease","volume":"13","author":"Aravinthan","year":"2014","journal-title":"Cell Cycle"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"15691","DOI":"10.1038\/ncomms15691","article-title":"Cellular senescence drives age-dependent hepatic steatosis","volume":"8","author":"Ogrodnik","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.jhep.2015.02.019","article-title":"PPAR\u03b1 gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis","volume":"63","author":"Francque","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1038\/s41556-024-01543-3","article-title":"Hepatocellular senescence induces multi-organ senescence and dysfunction via TGF\u03b2","volume":"26","author":"Kiourtis","year":"2024","journal-title":"Nat. Cell Biol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1038\/ncb2811","article-title":"Transmitting senescence to the cell neighbourhood","volume":"15","author":"Hoare","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"156051","DOI":"10.1016\/j.metabol.2024.156051","article-title":"Impaired unsaturated fatty acid elongation alters mitochondrial function and accelerates metabolic dysfunction-associated steatohepatitis progression","volume":"162","author":"Vouilloz","year":"2025","journal-title":"Metabolism"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1111\/apt.18059","article-title":"Review article: Hepatic steatosis and its associations with acute and chronic liver diseases","volume":"60","author":"Koenig","year":"2024","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1100\/tsw.2002.100","article-title":"Stress-induced premature senescence or stress-induced senescence-like phenotype: One in vivo reality, two possible definitions?","volume":"2","author":"Toussaint","year":"2002","journal-title":"Sci. World J."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/S0968-0004(02)02110-2","article-title":"Oxidative stress shortens telomeres","volume":"27","year":"2002","journal-title":"Trends Biochem. Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1053\/hupa.2001.22747","article-title":"Replicative senescence in normal liver, chronic hepatitis C, and hepatocellular carcinomas","volume":"32","author":"Paradis","year":"2001","journal-title":"Hum. Pathol."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Yakubo, S., Abe, H., Li, Y., Kudo, M., Kimura, A., Wakabayashi, T., Watanabe, Y., Kimura, N., Setsu, T., and Yokoo, T. (2024). Dasatinib and Quercetin as Senolytic Drugs Improve Fat Deposition and Exhibit Antifibrotic Effects in the Medaka Metabolic Dysfunction-Associated Steatotic Liver Disease Model. Diseases, 12.","DOI":"10.3390\/diseases12120317"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/s43587-025-00811-7","article-title":"A BCL-xL\/BCL-2 PROTAC effectively clears senescent cells in the liver and reduces MASH-driven hepatocellular carcinoma in mice","volume":"5","author":"Yang","year":"2025","journal-title":"Nat. Aging"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.jhep.2025.08.021","article-title":"Cellular senescence in liver diseases: From molecular drivers to therapeutic targeting","volume":"84","author":"Du","year":"2026","journal-title":"J. Hepatol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.cmet.2020.04.001","article-title":"Benefits of Metformin in Attenuating the Hallmarks of Aging","volume":"32","author":"Kulkarni","year":"2020","journal-title":"Cell Metab."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.2169\/internalmedicine.4337-24","article-title":"Pemafibrate Reduced Liver Stiffness in Patients with Metabolic Dysfunction-associated Steatotic Liver Disease Complicated with Hyperlipidemia and Liver Fibrosis with a Fibrosis-4 Index Above 1.3","volume":"64","author":"Ichikawa","year":"2025","journal-title":"Intern. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"91","DOI":"10.33160\/yam.2025.05.002","article-title":"Selective PPAR\u03b1 Modulator (SPPARM\u03b1) in the Era of the MASLD Pandemic: Current Insights and Future Prospects","volume":"68","author":"Sugihara","year":"2025","journal-title":"Yonago Acta Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"e088862","DOI":"10.1136\/bmjopen-2024-088862","article-title":"Pemafibrate for treating MASLD complicated by hypertriglyceridaemia: A multicentre, open-label, randomised controlled trial study protocol","volume":"14","author":"Iwaki","year":"2024","journal-title":"BMJ Open"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Jamal, F., Elshaer, A., Odeh, N.B., Alatout, M.H., Shahin, T., Worden, A.R., Albunni, H.N., Lizaola-Mayo, B.C., Jayasekera, C.R., and Chascsa, D.M.H. (2025). Resmetirom in the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease and Steatohepatitis. 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