{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T02:03:57Z","timestamp":1781229837880,"version":"3.54.1"},"reference-count":40,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T00:00:00Z","timestamp":1686700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CAMS Innovation Fund","award":["2022-I2M-1-014"],"award-info":[{"award-number":["2022-I2M-1-014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Chlorogenic acid (CHA) has been shown to have substantial biological activities, including anti-inflammatory, antioxidant, and antitumor effects. However, the pharmacological role of CHA in neuroblastoma has not yet been assessed. Neuroblastoma is a type of cancer that develops in undifferentiated sympathetic ganglion cells. This study aims to assess the antitumor activity of CHA against neuroblastoma and reveal its mechanism of action in cell differentiation. Methods: Be(2)-M17 and SH-SY5Y neuroblastoma cells were used to confirm the differentiation phenotype. Subcutaneous and orthotopic xenograft mouse models were also used to evaluate the antitumor activity of CHA. Seahorse assays and metabolomic analyses were further performed to investigate the roles of CHA and its target ACAT1 in mitochondrial metabolism. Results: CHA induced the differentiation of Be(2)-M17 and SH-SY5Y neuroblastoma cells in vivo and in vitro. The knockdown of mitochondrial ACAT1, which was inhibited by CHA, also resulted in differentiation characteristics in vivo and in vitro. A metabolomic analysis revealed that thiamine metabolism was involved in the differentiation of neuroblastoma cells. Conclusions: These results provide evidence that CHA shows good antitumor activity against neuroblastoma via the induction of differentiation, by which the ACAT1-TPK1-PDH pathway is involved. CHA is a potential drug candidate for neuroblastoma therapy.<\/jats:p>","DOI":"10.3390\/ph16060877","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T03:02:24Z","timestamp":1686711744000},"page":"877","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Chlorogenic Acid Induced Neuroblastoma Cells Differentiation via the ACAT1-TPK1-PDH Pathway"],"prefix":"10.3390","volume":"16","author":[{"given":"Shen","family":"You","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Jin","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-Yan","family":"Hou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Da","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Ting","family":"Du","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni-Na","family":"Xue","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Ji","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Guang","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6151","DOI":"10.1158\/1078-0432.CCR-16-1217","article-title":"Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter","volume":"23","author":"Ritthipichai","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.3727\/096504018X15179661552702","article-title":"Triptolide Inhibits Proliferation and Migration of Human Neuroblastoma SH-SY5Y Cells by Upregulating MicroRNA-181a","volume":"26","author":"Jiang","year":"2018","journal-title":"Oncol. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1080\/14656566.2021.1953470","article-title":"Advances in pharmacotherapy for neuroblastoma","volume":"22","author":"Pezeshki","year":"2021","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"eaao4680","DOI":"10.1126\/scitranslmed.aao4680","article-title":"Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma","volume":"10","author":"Lochmann","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"873","DOI":"10.7326\/0003-4819-97-6-873","article-title":"Neuroblastoma: Clinical perspectives, monoclonal antibodies, and retinoic acid","volume":"97","author":"Seeger","year":"1982","journal-title":"Ann. Intern. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1056\/NEJM199910143411601","article-title":"Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children\u2019s Cancer Group","volume":"341","author":"Matthay","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"103491","DOI":"10.1016\/j.jprot.2019.103491","article-title":"Bottom up proteomics reveals novel differentiation proteins in neuroblastoma cells treated with 13-cis retinoic acid","volume":"209","author":"Halakos","year":"2019","journal-title":"J. Proteom."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.canlet.2012.09.014","article-title":"Tyrosine phosphatase inhibitors combined with retinoic acid can enhance differentiation of neuroblastoma cells and trigger ERK- and AKT-dependent, p53-independent senescence","volume":"328","author":"Clark","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s13046-022-02367-5","article-title":"The MYCN inhibitor BGA002 restores the retinoic acid response leading to differentiation or apoptosis by the mTOR block in MYCN-amplified neuroblastoma","volume":"41","author":"Lampis","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4224","DOI":"10.1002\/cncr.30873","article-title":"Association of MYCN copy number with clinical features, tumor biology, and outcomes in neuroblastoma: A report from the Children\u2019s Oncology Group","volume":"123","author":"Campbell","year":"2017","journal-title":"Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"39011","DOI":"10.1038\/srep39011","article-title":"Chlorogenic acid inhibits glioblastoma growth through repolarizating macrophage from M2 to M1 phenotype","volume":"7","author":"Xue","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Wang, R., Yang, X., You, S., Hao, M., Li, J., Chen, X., and Jin, J. (2022). Chlorogenic Acid Relieves the Lupus Erythematosus-like Skin Lesions and Arthritis in MRL\/lpr Mice. Pharmaceuticals, 15.","DOI":"10.3390\/ph15111327"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6745","DOI":"10.7150\/thno.34674","article-title":"Chlorogenic acid effectively treats cancers through induction of cancer cell differentiation","volume":"9","author":"Huang","year":"2019","journal-title":"Theranostics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"116592","DOI":"10.1016\/j.lfs.2019.116592","article-title":"The recent insights into the function of ACAT1: A possible anti-cancer therapeutic target","volume":"232","author":"Goudarzi","year":"2019","journal-title":"Life Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.molcel.2013.12.026","article-title":"Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex","volume":"53","author":"Fan","year":"2014","journal-title":"Mol. Cell"},{"key":"ref_16","unstructured":"Batt, C.A., and Tortorello, M.L. (2014). Encyclopedia of Food Microbiology, Academic Press. [2nd ed.]."},{"key":"ref_17","unstructured":"Bettendorff, L., and Wins, P. (2021). Encyclopedia of Biological Chemistry II, Academic Press."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e14081","DOI":"10.1200\/JCO.2018.36.15_suppl.e14081","article-title":"First in human phase I study of chlorogenic acid injection in recurrent high grade glioma","volume":"36","author":"Li","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.cbi.2018.11.022","article-title":"Anti-proliferative and cytotoxic activities of the flavonoid isoliquiritigenin in the human neuroblastoma cell line SH-SY5Y","volume":"299","author":"Escobar","year":"2019","journal-title":"Chem. Biol. Interact."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12645","DOI":"10.1038\/ncomms12645","article-title":"Integrative proteomic profiling of ovarian cancer cell lines reveals precursor cell associated proteins and functional status","volume":"7","author":"Coscia","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Zhai, K., Brockm\u00fcller, A., Kubatka, P., Shakibaei, M., and B\u00fcsselberg, D. (2020). Curcumin\u2019s Beneficial Effects on Neuroblastoma: Mechanisms, Challenges, and Potential Solutions. Biomolecules, 10.","DOI":"10.3390\/biom10111469"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1158\/2159-8290.CD-17-0993","article-title":"MYC Drives a Subset of High-Risk Pediatric Neuroblastomas and Is Activated through Mechanisms Including Enhancer Hijacking and Focal Enhancer Amplification","volume":"8","author":"Zimmerman","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1001\/archneurpsyc.1927.02200340146015","article-title":"A Classification of the Tumors of the Glioma Group on a Histogenetic Basis with a Correlated Study of Prognosis","volume":"17","author":"Bailey","year":"1927","journal-title":"Arch. Neurol. Psychiatry"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"195","DOI":"10.3389\/fnagi.2019.00195","article-title":"Exploring the Mitochondrial Degradome by the TAILS Proteomics Approach in a Cellular Model of Parkinson\u2019s Disease","volume":"11","author":"Lualdi","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"ref_25","first-page":"589","article-title":"[Beta-Ketothiolase deficiency]","volume":"33","author":"Yamaguchi","year":"1988","journal-title":"Tanpakushitsu Kakusan Koso Protein Nucleic Acid Enzym."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.molcel.2016.10.014","article-title":"Tetrameric Acetyl-CoA Acetyltransferase 1 Is Important for Tumor Growth","volume":"64","author":"Fan","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.molcel.2016.02.004","article-title":"Metabolism and the UPR(mt)","volume":"61","author":"Lin","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1038\/s41467-019-09746-1","article-title":"The Stat3-Fam3a axis promotes muscle stem cell myogenic lineage progression by inducing mitochondrial respiration","volume":"10","author":"Sala","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1186\/s13018-020-01684-9","article-title":"Resveratrol can enhance osteogenic differentiation and mitochondrial biogenesis from human periosteum-derived mesenchymal stem cells","volume":"15","author":"Moon","year":"2020","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/nm.4059","article-title":"Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1","volume":"22","author":"Joyal","year":"2016","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/ncb3338","article-title":"A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation","volume":"18","author":"Li","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1158\/1078-0432.CCR-15-0460","article-title":"Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy","volume":"22","author":"Caino","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1038\/cdd.2017.95","article-title":"Germline BAP1 mutations induce a Warburg effect","volume":"24","author":"Bononi","year":"2017","journal-title":"Cell Death Differ."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1093\/neuonc\/noy117","article-title":"The secreted glycolytic enzyme GPI\/AMF stimulates glioblastoma cell migration and invasion in an autocrine fashion but can have anti-proliferative effects","volume":"20","author":"Maire","year":"2018","journal-title":"Neuro Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1126\/science.aar5986","article-title":"The nutrient environment affects therapy","volume":"360","author":"Muir","year":"2018","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.molmet.2019.11.011","article-title":"Targeting extracellular nutrient dependencies of cancer cells","volume":"33","author":"Williams","year":"2020","journal-title":"Mol. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/2049-3002-1-16","article-title":"Linking vitamin B1 with cancer cell metabolism","volume":"1","author":"Zastre","year":"2013","journal-title":"Cancer Metab."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Gangolf, M., Czerniecki, J., Radermecker, M., Detry, O., Nisolle, M., Jouan, C., Martin, D., Chantraine, F., Lakaye, B., and Wins, P. (2010). Thiamine status in humans and content of phosphorylated thiamine derivatives in biopsies and cultured cells. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013616"},{"key":"ref_39","first-page":"509","article-title":"Metabolic remodeling precedes mitochondrial outer membrane permeabilization in human glioma xenograft cells","volume":"40","author":"Ponnala","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"D1321","DOI":"10.1093\/nar\/gkaa698","article-title":"PCAT: An integrated portal for genomic and preclinical testing data of pediatric cancer patient-derived xenograft models","volume":"49","author":"Yang","year":"2021","journal-title":"Nucleic Acids Res."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/6\/877\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:54:33Z","timestamp":1760126073000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/6\/877"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,14]]},"references-count":40,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["ph16060877"],"URL":"https:\/\/doi.org\/10.3390\/ph16060877","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,14]]}}}