{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T10:32:15Z","timestamp":1787653935304,"version":"build-2736575974"},"reference-count":94,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,9]],"date-time":"2024-05-09T00:00:00Z","timestamp":1715212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Research on retinoid-based cancer prevention, spurred by the effects of vitamin A deficiency on gastric cancer and subsequent clinical studies on digestive tract cancer, unveils novel avenues for chemoprevention. Acyclic retinoids like 4,5-didehydrogeranylgeranoic acid (4,5-didehydroGGA) have emerged as potent agents against hepatocellular carcinoma (HCC), distinct from natural retinoids such as all-trans retinoic acid (ATRA). Mechanistic studies reveal GGA\u2019s unique induction of pyroptosis, a rapid cell death pathway, in HCC cells. GGA triggers mitochondrial superoxide hyperproduction and ER stress responses through Toll-like receptor 4 (TLR4) signaling and modulates autophagy, ultimately activating pyroptotic cell death in HCC cells. Unlike ATRA-induced apoptosis, GGA and palmitic acid (PA) induce pyroptosis, underscoring their distinct mechanisms. While all three fatty acids evoke mitochondrial dysfunction and ER stress responses, GGA and PA inhibit autophagy, leading to incomplete autophagic responses and pyroptosis, whereas ATRA promotes autophagic flux. In vivo experiments demonstrate GGA\u2019s potential as an anti-oncometabolite, inducing cell death selectively in tumor cells and thus suppressing liver cancer development. This review provides a comprehensive overview of the molecular mechanisms underlying GGA\u2019s anti-HCC effects and underscores its promising role in cancer prevention, highlighting its importance in HCC prevention.<\/jats:p>","DOI":"10.3390\/cells13100809","type":"journal-article","created":{"date-parts":[[2024,5,10]],"date-time":"2024-05-10T05:25:47Z","timestamp":1715318747000},"page":"809","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Induction of Hepatoma Cell Pyroptosis by Endogenous Lipid Geranylgeranoic Acid\u2014A Comparison with Palmitic Acid and Retinoic Acid"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2136-6752","authenticated-orcid":false,"given":"Yoshihiro","family":"Shidoji","sequence":"first","affiliation":[{"name":"Graduate School of Human Health Science, University of Nagasaki, Nagayo, Nagasaki 851-2195, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,9]]},"reference":[{"key":"ref_1","first-page":"469","article-title":"Formation of Gastric Carcinoma in Albino Rats Fed on Deficient Diets","volume":"10","author":"Fujimaki","year":"1926","journal-title":"J. Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1172\/JCI101268","article-title":"Metabolic Studies in Patients with Cancer of the Gastro-Intestinal Tract. I. Plasma Vitamin A Levels in Patients with Malignant Neoplastic Disease, Particularly of the Gastro-Intestinal Tract","volume":"20","author":"Abels","year":"1941","journal-title":"J. Clin. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1002\/1097-0142(1967)20:5<857::AID-CNCR2820200545>3.0.CO;2-3","article-title":"Experimental Cancer of the Lung. Inhibition by Vitamin A of the Induction of Tracheobronchial Squamous Metaplasia and Squamous Cell Tumors","volume":"20","author":"Saffiotti","year":"1967","journal-title":"Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1126\/science.278.5340.1073","article-title":"Recent Advances in Chemoprevention of Cancer","volume":"278","author":"Hong","year":"1997","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1093\/carcin\/21.7.1271","article-title":"Retinoids in Chemoprevention and Differentiation Therapy","volume":"21","author":"Hansen","year":"2000","journal-title":"Carcinogenesis"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1056\/NEJM199606133342402","article-title":"Prevention of Second Primary Tumors by an Acyclic Retinoid, Polyprenoic Acid, in Patients with Hepatocellular Carcinoma. Hepatoma Prevention Study Group","volume":"334","author":"Muto","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s00535-014-0956-9","article-title":"Peretinoin after Curative Therapy of Hepatitis C-related Hepatocellular Carcinoma: A Randomized Double-blind Placebo-controlled Study","volume":"50","author":"Okita","year":"2015","journal-title":"J. Gastroenterol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1007\/s00535-014-0996-1","article-title":"Survey of Survival among Patients with Hepatitis C virus-related Hepatocellular Carcinoma Treated with Peretinoin, an Acyclic Retinoid, after the Completion of a Randomized, Placebo-controlled Trial","volume":"50","author":"Okita","year":"2015","journal-title":"J. Gastroenterol."},{"key":"ref_9","first-page":"974","article-title":"In Vitro Binding Affinity of Novel Synthetic Polyprenoids (Polyprenoic Acids) to Cellular Retinoid-Binding Proteins","volume":"72","author":"Muto","year":"1981","journal-title":"Jpn. J. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1006\/bbrc.1995.1471","article-title":"Retinoid Agonist Activities of Synthetic Geranylgeranoic Acid Derivatives","volume":"209","author":"Araki","year":"1995","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100396","DOI":"10.1016\/j.jlr.2023.100396","article-title":"Geranylgeranoic Acid, a Bioactive and Endogenous Fatty Acid in Mammals: A Review","volume":"64","author":"Shidoji","year":"2023","journal-title":"J. Lipid Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.jhep.2017.11.014","article-title":"Lipotoxicity and the Gut-Liver Axis in NASH Pathogenesis","volume":"68","author":"Marra","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3323","DOI":"10.3390\/ijms16023323","article-title":"Reduction of Oxidative Stress Attenuates Lipoapoptosis Exacerbated by Hypoxia in Human Hepatocytes","volume":"16","author":"Hwang","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s40170-023-00328-w","article-title":"A HIF-1\u03b1 Inhibitor Combined with Palmitic Acid and L-Carnitine Treatment Can Prevent the Fat Metabolic Reprogramming under Hypoxia and Induce Apoptosis in Hepatocellular Carcinoma Cells","volume":"11","author":"Matsufuji","year":"2023","journal-title":"Cancer Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1007\/s11060-011-0556-y","article-title":"Reversible Upregulation of Tropomyosin-Related Kinase Receptor B by Geranylgeranoic Acid in Human Neuroblastoma SH-SY5Y Cells","volume":"104","author":"Sakane","year":"2011","journal-title":"J. Neurooncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1042\/BJ20110610","article-title":"Induction of an Incomplete Autophagic Response by Cancer-Preventive Geranylgeranoic Acid (GGA) in a Human Hepatoma-Derived Cell Line","volume":"440","author":"Okamoto","year":"2011","journal-title":"Biochem. J."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Iwao, C., and Shidoji, Y. (2015). Polyunsaturated Branched-Chain Fatty Acid Geranylgeranoic Acid Induces Unfolded Protein Response in Human Hepatoma Cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132761"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Yabuta, S., and Shidoji, Y. (2020). TLR4-Mediated Pyroptosis in Human Hepatoma-Derived HuH-7 Cells Induced by a Branched-Chain Polyunsaturated Fatty Acid, Geranylgeranoic Acid. Biosci. Rep., 40.","DOI":"10.1042\/BSR20194118"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1080\/01635581.2012.655401","article-title":"Rapid Downregulation of Cyclin D1 Induced by Geranylgeranoic Acid in Human Hepatoma Cells","volume":"64","author":"Shimonishi","year":"2012","journal-title":"Nutr. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1006\/bbrc.1996.5883","article-title":"Rapid Loss in the Mitochondrial Membrane Potential during Geranylgeranoic Acid-Induced Apoptosis","volume":"230","author":"Shidoji","year":"1997","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Shidoji, Y., and Iwao, C. (2021). A Rapid Increase in Lysophospholipids after Geranylgeranoic Acid Treatment in Human Hepatoma-Derived HuH-7 Cells Revealed by Metabolomics Analysis. Biochem. Biophys. Rep., 28.","DOI":"10.1016\/j.bbrep.2021.101176"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1002\/eji.200737882","article-title":"Endoplasmic Reticulum Stress and the Unfolded Protein Response Are Linked to Synergistic IFN-\u03b2 Induction via X-Box Binding Protein 1","volume":"38","author":"Smith","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/ni.1857","article-title":"TLR Activation of the Transcription Factor XBP1 Regulates Innate Immune Responses in Macrophages","volume":"11","author":"Martinon","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.jaut.2013.11.002","article-title":"TLR Dependent XBP-1 Activation Induces an Autocrine Loop in Rheumatoid Arthritis Synoviocytes","volume":"50","author":"Savic","year":"2014","journal-title":"J. Autoimmun."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Boukeileh, S., Darawshi, O., Shmuel, M., Mahameed, M., Wilhelm, T., Dipta, P., Forno, F., Praveen, B., Huber, M., and Levi-Schaffer, F. (2022). Endoplasmic Reticulum Homeostasis Regulates TLR4 Expression and Signaling in Mast Cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911826"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1083\/jcb.200310015","article-title":"Involvement of Caspase-4 in Endoplasmic Reticulum Stress-Induced Apoptosis and A\u03b2-Induced Cell Death","volume":"165","author":"Hitomi","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.neuint.2007.08.017","article-title":"Presenilin-1 Mutation Activates the Signaling Pathway of Caspase-4 in Endoplasmic Reticulum Stress-Induced Apoptosis","volume":"52","author":"Yukioka","year":"2008","journal-title":"Neurochem. Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6006","DOI":"10.1167\/iovs.09-3628","article-title":"Dual Involvement of Caspase-4 in Inflammatory and ER Stress-Induced Apoptotic Responses in Human Retinal Pigment Epithelial Cells","volume":"50","author":"Bian","year":"2009","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1218989","DOI":"10.3389\/fonc.2023.1218989","article-title":"NOTCH1-Mutated Chronic Lymphocytic Leukemia Displays High Endoplasmic Reticulum Stress Response with Druggable Potential","volume":"13","author":"Rompietti","year":"2023","journal-title":"Front. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Correia da Silva, D., Valent\u00e3o, P., and Pereira, D.M. (2022). A Survey of Naturally Occurring Molecules as New Endoplasmic Reticulum Stress Activators with Selective Anticancer Activity. Cancers, 15.","DOI":"10.1101\/2022.10.16.512420"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.bbrc.2022.03.156","article-title":"Mitochondrial Calpain-5 Truncates Caspase-4 during Endoplasmic Reticulum Stress","volume":"608","author":"Chukai","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"12625","DOI":"10.1073\/pnas.220247197","article-title":"PERK Mediates Cell-Cycle Exit during the Mammalian Unfolded Protein Response","volume":"97","author":"Brewer","year":"2000","journal-title":"Proc. Natl. Acad. Sci USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1101\/gad.408407","article-title":"Cytosolic Signaling Protein Ecsit Also Localizes to Mitochondria Where It Interacts with Chaperone NDUFAF1 and Functions in Complex I Assembly","volume":"21","author":"Vogel","year":"2007","journal-title":"Genes Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.1016\/j.celrep.2018.02.051","article-title":"An Essential Role for ECSIT in Mitochondrial Complex I Assembly and Mitophagy in Macrophages","volume":"22","author":"Carneiro","year":"2018","journal-title":"Cell Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"8248","DOI":"10.1038\/s41467-023-43865-0","article-title":"The Assembly of the Mitochondrial Complex I Assembly Complex Uncovers a Redox Pathway Coordination","volume":"14","author":"McGregor","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.3389\/fimmu.2020.01649","article-title":"Mitochondrial Reactive Oxygen Species: Double-Edged Weapon in Host Defense and Pathological Inflammation during Infection","volume":"11","author":"Silwal","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.it.2014.02.007","article-title":"Calcium Signaling and Mitochondrial Destabilization in the Triggering of the NLRP3 Inflammasome","volume":"35","author":"Horng","year":"2014","journal-title":"Trends Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1007\/s13105-022-00909-1","article-title":"Pyroptosis in Inflammation-Related Respiratory Disease","volume":"78","author":"Feng","year":"2022","journal-title":"J. Physiol. Biochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"101844","DOI":"10.1016\/j.smim.2023.101844","article-title":"The Noncanonical Inflammasome-Induced Pyroptosis and Septic Shock","volume":"70","author":"Wu","year":"2023","journal-title":"Semin. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0304-3835(98)00100-1","article-title":"Retinoic Acid-Induced Apoptosis Is Prevented by Serum Albumin and Enhanced by Lipiodol in Human Hepatoma Hep3B Cells","volume":"129","author":"Hsu","year":"1998","journal-title":"Cancer Lett."},{"key":"ref_41","first-page":"6793","article-title":"All-Trans-Retinoic Acid Inhibits the Malignant Behaviors of Hepatocarcinoma Cells by Regulating Autophagy","volume":"12","author":"Fang","year":"2020","journal-title":"Am. J. Transl. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1006\/bbrc.1995.1199","article-title":"Induction of Apoptosis by Acyclic Retinoid in the Human Hepatoma-Derived Cell Line, HuH-7","volume":"270","author":"Nakamura","year":"1995","journal-title":"Biochem. Biphys. Res. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5633","DOI":"10.3748\/wjg.v11.i36.5633","article-title":"Synergistic Effect of All-Trans-Retinoic Acid and Arsenic Trioxide on Growth Inhibition and Apoptosis in Human Hepatoma, Breast Cancer, and Lung Cancer Cells in Vitro","volume":"11","author":"Lin","year":"2005","journal-title":"World J. Gastroenterol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1111\/febs.12122","article-title":"All-Trans Retinoic Acid Protects Hepatocellular Carcinoma Cells against Serum-Starvation-Induced Cell Death by Upregulating Collagen 8A2","volume":"280","author":"Wang","year":"2013","journal-title":"FEBS J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2976","DOI":"10.1111\/jcmm.16338","article-title":"Mesenchymal Stromal Cells Protect Hepatocytes from Lipotoxicity through Alleviation of Endoplasmic Reticulum Stress by Restoring SERCA Activity","volume":"25","author":"Li","year":"2021","journal-title":"J. Cell Mol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12986-020-0434-8","article-title":"Oleic Acid Ameliorates Palmitic Acid Induced Hepatocellular Lipotoxicity by Inhibition of ER Stress and Pyroptosis","volume":"17","author":"Zeng","year":"2020","journal-title":"Nutr. Metab."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/s41419-022-05003-4","article-title":"Proteomic Analysis Reveals USP7 as a Novel Regulator of Palmitic Acid-Induced Hepatocellular Carcinoma Cell Death","volume":"13","author":"Saha","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/s41420-023-01379-0","article-title":"Lysosomal Ca2+ as a Mediator of Palmitate-Induced Lipotoxicity","volume":"9","author":"Oh","year":"2023","journal-title":"Cell Death Discov."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.jhep.2013.06.024","article-title":"Biological and Clinical Implications of Retinoic Acid-Responsive Genes in Human Hepatocellular Carcinoma Cells","volume":"59","author":"Kanki","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1038\/s41598-021-81678-7","article-title":"Intracellular Alpha-Fetoprotein Interferes with All-Trans Retinoic Acid Induced ATG7 Expression and Autophagy in Hepatocellular Carcinoma Cells","volume":"11","author":"Wang","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1016\/j.gendis.2022.04.011","article-title":"All-Trans Retinoic Acid Inhibits the Malignant Behaviors of Hepatocarcinoma Cells by Regulating Ferroptosis","volume":"9","author":"Sun","year":"2022","journal-title":"Genes Dis."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Jakaria, M., Belaidi, A.A., Bush, A.I., and Ayton, S. (2023). Vitamin A Metabolites Inhibit Ferroptosis. Biomed. Pharmacother., 164.","DOI":"10.1016\/j.biopha.2023.114930"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1016\/j.cmet.2018.03.014","article-title":"Evidence That TLR4 Is Not a Receptor for Saturated Fatty Acids but Mediates Lipid-Induced Inflammation by Reprogramming Macrophage Metabolism","volume":"27","author":"Lancaster","year":"2018","journal-title":"Cell Metab."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Nicholas, D.A., Zhang, K., Hung, C., Glasgow, S., Aruni, A.W., Unternaehrer, J., Payne, K.J., Langridge, W.H.R., and De Leon, M. (2017). Palmitic Acid Is a Toll-like Receptor 4 Ligand That Induces Human Dendritic Cell Secretion of IL-1\u03b2. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0176793"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.bcp.2018.02.022","article-title":"Lipid Bilayer Stress in Obesity-Linked Inflammatory and Metabolic Disorders","volume":"153","author":"Gianfrancesco","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"775382","DOI":"10.3389\/fnut.2021.775382","article-title":"Differential Effects of Oleic and Palmitic Acids on Lipid Droplet-Mitochondria Interaction in the Hepatic Cell Line HepG2","volume":"8","author":"Eynaudi","year":"2021","journal-title":"Front. Nutr."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41419-021-04476-z","article-title":"Role of Cardiolipins, Mitochondria, and Autophagy in the Differentiation Process Activated by All-Trans Retinoic Acid in Acute Promyelocytic Leukemia","volume":"13","author":"Gianni","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"113554","DOI":"10.1016\/j.fct.2022.113554","article-title":"Luteolin Ameliorates Palmitate-Induced Lipotoxicity in Hepatocytes by Mediating Endoplasmic Reticulum Stress and Autophagy","volume":"171","author":"Huang","year":"2023","journal-title":"Food Chem. Toxicol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.freeradbiomed.2008.04.029","article-title":"Fatty Acids as Modulators of the Cellular Production of Reactive Oxygen Species","volume":"45","author":"Wojtczak","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"23282","DOI":"10.1074\/jbc.M115.677542","article-title":"Sphingosine Kinase 1 Protects Hepatocytes from Lipotoxicity via Down-Regulation of IRE1\u03b1 Protein Expression","volume":"290","author":"Qi","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s11064-022-03750-6","article-title":"Sel1l May Contributes to the Determinants of Neuronal Lineage and Neuronal Maturation Regardless of Hrd1 via Atf6-Sel1l Signaling Affiliations","volume":"48","author":"Saito","year":"2023","journal-title":"Neurochem. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1111\/gtc.12074","article-title":"Membrane Lipid Saturation Activates IRE1\u03b1 without Inducing Clustering","volume":"18","author":"Kitai","year":"2013","journal-title":"Genes Cells"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.1089\/ars.2009.2463","article-title":"Redox Regulation of Nuclear Post-Translational Modifications during NF-\u039aB Activation","volume":"11","author":"Gloire","year":"2009","journal-title":"Antioxid. Redox Signal"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4419","DOI":"10.1038\/srep04419","article-title":"Induction of Nuclear Translocation of Mutant Cytoplasmic P53 by Geranylgeranoic Acid in a Human Hepatoma Cell Line","volume":"4","author":"Iwao","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1002\/hep.21752","article-title":"Palmitic Acid Induces Production of Proinflammatory Cytokine Interleukin-8 from Hepatocytes","volume":"46","author":"Barve","year":"2007","journal-title":"Hepatology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1152\/ajpgi.00304.2014","article-title":"Hepatic TLR4 Signaling in Obese NAFLD","volume":"309","author":"Sharifnia","year":"2015","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1179\/1973947814Y.0000000200","article-title":"All-Trans Retinoic Acid and Arsenic Trioxide Induce Apoptosis and Modulate Intracellular Concentrations of Calcium in Hepatocellular Carcinoma Cells","volume":"26","author":"Wei","year":"2014","journal-title":"J. Chemother."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1053\/j.gastro.2015.12.037","article-title":"Lipid-Induced Signaling Causes Release of Inflammatory Extracellular Vesicles from Hepatocytes","volume":"150","author":"Hirsova","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s11010-019-03535-6","article-title":"Saturated Fatty Acid Stimulates Production of Extracellular Vesicles by Renal Tubular Epithelial Cells","volume":"458","author":"Cobbs","year":"2019","journal-title":"Mol. Cell Biochem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1194\/jlr.R066357","article-title":"Lipotoxicity: Many Roads to Cell Dysfunction and Cell Death Lipotoxic Lethal and Sublethal Stress Signaling in Hepatocytes: Relevance to NASH Pathogenesis","volume":"57","author":"Hirsova","year":"2016","journal-title":"J. Lipid Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1194\/jlr.M700184-JLR200","article-title":"Lysophosphatidylcholine as a Death Effector in the Lipoapoptosis of Hepatocytes","volume":"49","author":"Han","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1007\/s11745-011-3593-6","article-title":"Effect of Synthetic Ligands of PPAR \u03b1, \u03b2\/\u03b4, \u03b3, RAR, RXR and LXR on the Fatty Acid Composition of Phospholipids in Mice","volume":"46","author":"Weiss","year":"2011","journal-title":"Lipids"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1080\/15548627.2021.1920818","article-title":"Lipotoxicity Reduces DDX58\/Rig-1 Expression and Activity Leading to Impaired Autophagy and Cell Death","volume":"18","author":"Frietze","year":"2022","journal-title":"Autophagy"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/imr.12613","article-title":"Autophagy Limits Activation of the Inflammasomes","volume":"281","author":"Takahama","year":"2018","journal-title":"Immunol. Rev."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1111\/febs.16317","article-title":"P62\/SQSTM1 in Liver Diseases: The Usual Suspect with Multifarious Identities","volume":"290","author":"Tan","year":"2023","journal-title":"FEBS J."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Ciesielska, K., and Gajewska, M. (2023). Fatty Acids as Potent Modulators of Autophagy Activity in White Adipose Tissue. Biomolecules, 13.","DOI":"10.3390\/biom13020255"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"176","DOI":"10.3389\/fendo.2019.00176","article-title":"Palmitic Acid Reduces the Autophagic Flux and Insulin Sensitivity through the Activation of the Free Fatty Acid Receptor 1 (FFAR1) in the Hypothalamic Neuronal Cell Line N43\/5","volume":"10","author":"Burgos","year":"2019","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"9158","DOI":"10.1074\/jbc.M113.531202","article-title":"Lysosomes Integrate Metabolic-Inflammatory Cross-Talk in Primary Macrophage Inflammasome Activation","volume":"289","author":"Weber","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1161\/ATVBAHA.117.310581","article-title":"Saturated Fatty Acids Undergo Intracellular Crystallization and Activate the NLRP3 Inflammasome in Macrophages","volume":"38","author":"Karasawa","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Yao, Q., Liu, J., Cui, Q., Jiang, T., Xie, X., Du, X., Zhao, Z., Lai, B., Xiao, L., and Wang, N. (2022). CCN1\/Integrin A5\u03b21 Instigates Free Fatty Acid-Induced Hepatocyte Lipid Accumulation and Pyroptosis through NLRP3 Inflammasome Activation. Nutrients, 14.","DOI":"10.3390\/nu14183871"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1152\/ajpgi.00301.2011","article-title":"Mechanisms of Lysophosphatidylcholine-Induced Hepatocyte Lipoapoptosis","volume":"302","author":"Kakisaka","year":"2012","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1002\/1873-3468.14291","article-title":"Lysophosphatidylcholine Disrupts Cell Adhesion and Induces Anoikis in Hepatocytes","volume":"596","author":"Chen","year":"2022","journal-title":"FEBS Lett."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1111\/imr.12287","article-title":"Pyroptotic Cell Death Defends against Intracellular Pathogens","volume":"265","author":"Jorgensen","year":"2015","journal-title":"Immunol. Rev."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1118449","DOI":"10.3389\/fimmu.2023.1118449","article-title":"Programmed Cell Death and Lipid Metabolism of Macrophages in NAFLD","volume":"14","author":"Xiao","year":"2023","journal-title":"Front. Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Bourne, C.M., and Taabazuing, C.Y. (2024). Harnessing Pyroptosis for Cancer Immunotherapy. Cells, 13.","DOI":"10.3390\/cells13040346"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1002\/hep4.1801","article-title":"Role of Cholesterol-Associated Steatohepatitis in the Development of NASH","volume":"6","author":"Horn","year":"2022","journal-title":"Hepatol. Commun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1194\/jlr.M090548","article-title":"Unequivocal Evidence for Endogenous Geranylgeranoic Acid Biosynthesized from Mevalonate in Mammalian Cells","volume":"60","author":"Shidoji","year":"2019","journal-title":"J. Lipid Res."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Tabata, Y., Omori, M., and Shidoji, Y. (2021). Age-Dependent Decrease in Hepatic Geranylgeranoic Acid Content in C3H\/HeN Mice and Its Oral Supplementation Prevents Spontaneous Hepatoma. Metabolites, 11.","DOI":"10.1101\/2021.04.16.440102"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/0304-3835(88)90065-1","article-title":"Effect of Dietary Phenobarbital on Spontaneous Hepatic Tumorigenesis in Germfree C3H\/He Male Mice","volume":"39","author":"Mizutani","year":"1988","journal-title":"Cancer Lett."},{"key":"ref_90","first-page":"487","article-title":"Inhibition of Spontaneous Hepatocarcinogenesis by 4,5-Didehydrogeranylgeranoic Acid: Effects of Small-Dose and Infrequent Administration","volume":"3","author":"Omori","year":"2023","journal-title":"Int. J. Transl. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2820","DOI":"10.1158\/0008-5472.CAN-20-3730","article-title":"Oncometabolites in Cancer: Current Understanding and Challenges","volume":"81","author":"Liu","year":"2021","journal-title":"Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/mc.2940100306","article-title":"Positive and Negative Regulations of Albumin Gene Expression by Retinoids in Human Hepatoma Cell Lines","volume":"10","author":"Yamada","year":"1994","journal-title":"Mol. Carcinog."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Brown, G. (2023). Targeting the Retinoic Acid Pathway to Eradicate Cancer Stem Cells. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032373"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Papadakos, S.P., Arvanitakis, K., Stergiou, I.E., Vallilas, C., Sougioultzis, S., Germanidis, G., and Theocharis, S. (2023). Interplay of Extracellular Vesicles and TLR4 Signaling in Hepatocellular Carcinoma Pathophysiology and Therapeutics. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15102460"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/10\/809\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:42:43Z","timestamp":1760107363000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/10\/809"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,9]]},"references-count":94,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["cells13100809"],"URL":"https:\/\/doi.org\/10.3390\/cells13100809","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,9]]}}}